How is human herpesvirus 6 spread?

Human herpesvirus 6 (HHV-6) is the common collective name for human herpesvirus 6A (HHV-6A) and human herpesvirus 6B (HHV-6B). These closely related viruses are two of the nine herpesviruses known to have humans as their primary host.

Human herpesvirus 6

HHV-6A and HHV-6B are double stranded DNA viruses within the betaherpesvirinae subfamily and of the genus "Roseolovirus". HHV-6A and HHV-6B infect almost all of the human populations that have been tested.

HHV-6A has been described as more neurovirulent, and as such is more frequently found in patients with neuroinflammatory diseases such as multiple sclerosis. HHV-6 (and HHV-7) levels in the brain are also elevated in people with Alzheimer’s disease.

HHV-6B primary infection is the cause of the common childhood illness exanthema subitum (also known as roseola infantum or sixth disease). Additionally, HHV-6B reactivation is common in transplant recipients, which can cause several clinical manifestations such as encephalitis, bone marrow suppression, and pneumonitis.

A variety of tests are used in the detection HHV-6, some of which do not differentiate the two species.

During 1986, Syed Zaki Salahuddin, Dharam Ablashi, and Robert Gallo cultivated peripheral blood mononuclear cells from patients with AIDS and lymphoproliferative illnesses.
Short-lived, large, refractile cells that frequently contained intranuclear and/or intracytoplasmic inclusion bodies were documented. Electron microscopy revealed a novel virus that they named Human B-Lymphotrophic Virus (HBLV).

Shortly after its discovery, Ablashi et al. described five cell lines that can be infected by the newly discovered HBLV. They published that HSB-2, a particular T-cell line, is highly susceptible to infection. Ablashi's pioneering research concluded by suggesting that the virus name be changed from HBLV to HHV-6, in accord with the published provisional classification of herpes viruses.

Years later, HHV-6 was divided into subtypes. Early research (1992) described two very similar, yet unique variants: HHV-6A and HHV-6B. The distinction was warranted due to unique restriction endonuclease cleavages, monoclonal antibody reactions, and growth patterns.

HHV-6A includes several adult-derived strains and its disease spectrum is not well defined, although it is thought by some to be more neurovirulent. HHV-6B is commonly detected in children with roseola infantum, as it is the etiologic agent for this condition. Within these two viruses is a sequence homology of 95%.

In 2012, HHV-6A and HHV-6B were officially recognized as distinct species.

HHV-6A and HHV-6B were recognized by the International Committee on Taxonomy of Viruses (ICTV) as distinct species in 2012. Human Roseoloviruses include HHV-6A, HHV-6B and HHV-7.

"Herpesvirus" was established as a genus in 1971 in the first report of the ICTV. This genus consisted of 23 viruses among 4 groups. In 1976, a second ICTV report was released in which this genus was elevated to the family level — the "herpetoviridae". Because of possible confusion with viruses derived from reptiles, the family name was changed in the third report (1979) to "herpesviridae". In this report, the family "Herpesviridae" was divided into 3 subfamilies ("alphaherpesvirinae", "betaherpesvirinae" and "gammaherpesvirinae") and 5 unnamed genera; 21 viruses were recognized as members of the family.

In 2009, the order "Herpesvirales" was created. This was necessitated by the discovery that the herpes viruses of fish and molluscs are only distantly related to those of birds and mammals. Order "Herpesvirales" contains three families, the "Herpesviridae", which contains the long-recognized herpesviruses of mammals, birds, and reptiles, plus two new families — the family "Alloherpesviridae" which incorporates herpes viruses of bony fish and frogs, and the family "Malacoherpesviridae" which contains viruses of molluscs.

As of 2012, this order currently has 3 families, 4 subfamilies (1 unassigned), 18 genera (4 unassigned) and 97 species.

The diameter of an HHV-6 virion is about 2000 Angstroms. The virion's outer portion consists of a lipid bilayer membrane that contains viral glycoproteins and is derived from that of the host. Below this membrane envelope is a tegument which surrounds an icosahedral capsid, composed of 162 capsomeres. The protective capsid of HHV-6 contains double stranded linear DNA.

During maturation of HHV-6 virions, human cell membranes are used to form viral lipid envelopes (as is characteristic of all enveloped viruses). During this process HHV-6 utilizes lipid rafts, which are membranous microdomains enriched by cholesterol, sphingolipids, and glycosylphosphatidylinositol-anchored proteins. Early researchers suspected that HHV-6 virions mature in the nucleus; some even incorrectly published this, as they generalized and applied to HHV-6 what was known about other viruses. However, researched published in 2009 suggests that the HHV-6 virus utilizes trans-Golgi-network-derived vesicles for assembly.

The genetic material of HHV-6 is composed of linear (circular during an active infection), double stranded DNA which contains an origin of replication, two 8–10 kb left and right direct repeat termini, and a unique segment that is 143–145kb.

The origin of replication (often labeled as "oriLyt" in the literature) is where DNA replication begins. The direct repeat termini (DR and DR) possess a repeated TTAGGG sequence, identical to that of human telomeres. Variability in the number of telomeric repeats is observed in the range of 15–180. These termini also contain pac-1 and pac-2 cleavage and packing signals that are conserved among herpesviruses.

The unique segment contains seven major core gene blocks (U27-U37, U38-U40, U41-U46, U48-U53, U56-U57, U66EX2-U77, and U81-U82), which is also characteristic of herpesviruses. These conserved genes code for proteins that are involved in replication, cleavage, and packing of the viral genome into a mature virion. Additionally, they code for a number of immunomodulatory proteins. The unique segment also possesses a block of genes (U2-U19) that are conserved among HHV-6, HHV-7, and Cytomegaloviruses (the betaherpesviruses). A number of the unique segment genes are associated with, for instance, the HCMV US22 family. The table below outlines some of their known properties.

When an extracellular HHV-6 virion comes across human cells, it encounters the human receptor protein cluster of differentiation 46 (CD46), which plays a role in regulating the complement system. The CD46 protein possesses a single variable region, as a result of alternative splicing. As such, at least fourteen isoforms of CD46 exist, all of which bind HHV-6a.

The extracellular region of CD46 contains four short consensus repeats of about 60 amino acids that fold into a compact beta-barrel domain surrounded by flexible loops. As has been demonstrated for CD46 with other ligands, the CD46 protein structure linearizes upon binding HHV-6. While their precise interaction has not yet been determined, the second and third SCR domains have been demonstrated as required for HHV-6 receptor binding and cellular entry.

Mori et al. first identified the gene product gQ1, a glycoprotein unique to HHV-6, and found that it forms a complex with gH and gL glycoproteins. They believed that this heterotrimer complex served as the viral ligand for CD46. Soon thereafter, another glycoprotein named gQ2 was identified and found to be part of the gH/gL/gQ1 ligand complex, forming a heterotetramer that was positively identified as the viral CD46 ligand. The exact process of entry is not yet well understood.

The salivary glands have been described as an in vivo reservoir for HHV-6 infection.

Researchers have shown that T cells are highly infectable by HHV-6.

During the year 2011, researchers at the National Institutes of Health attempted to elucidate the then unknown method whereby HHV-6a gains entry into the nervous system. As such, they autopsied the brains of around 150 subjects. When various anatomical regions were assayed for their viral load, olfactory tissues were found to have the highest HHV-6 content. They concluded that these tissues are the entry point for HHV-6a.

The results above are consistent with those of previous studies that involved HSV-1 (and a number of other viruses), which also disseminates into the CNS through olfactory tissue.

Researchers also hypothesized that olfactory ensheathing cells (OECs), a group of specialized glial cells found in the nasal cavity, may have a role in HHV-6 infectivity. They suspected this association as a result of OECs having properties similar to those of astrocytes, another type of glial cell that was previously identified as being susceptible to HHV-6 infection. Research continued by infecting OECs in vitro with both types of HHV-6. Ultimately, only OECs in which HHV-6a was used tested positive for signs of de novo viral synthesis, as is also characteristic of astrocytes.

Once inside, two outcomes have been described: active and inactive infections.

Active infections involve the linear dsDNA genome circularizing by end to end covalent linkages. This process was first reported for the herpes simplex virus. Once circularized, HHV-6 begins to express what are known as "immediate early" genes. These gene products are believed to be transcription activators and may be regulated by the expression of viral micro RNAs. Subsequent expression of "early genes" then occurs and activates, for instance, viral DNA polymerases. Early genes are also involved in the rolling circle replication that follows.

HHV-6’s replication results in the formation of concatemers, which are long molecules that contain several repeats of a DNA sequence. These long concatemers are then cleaved between the pac-1 and pac-2 regions by ribozymes for packaging of the genome into individual virions.

Not all newly infected cells begin rolling circle replication. In fact, herpes comes from the Greek word herpein, meaning "to creep." Herpesviruses are 'to creep' in that they may enter a latent stage, inactively infecting their human host. Since its discovery in 1993, this phenomenon has been found among all of the betaherpesviruses.

Other betaherpesviruses establish latency as a nuclear episome, which is a circular DNA molecule (analogous to plasmids). For HHV-6, latency is believed to occur exclusively through the integration of viral telomeric repeats into human subtelomeric regions. Only one other virus is known to achieve latency in this fashion. This phenomenon is possible as a result of the telomeric repeats found within the direct repeat termini of HHV-6’s genome.

The right direct repeat terminus integrates within 5 to 41 human telomere repeats, and preferentially does so into the proximal end of chromosomes 9, 17, 18, 19, and 22, but has also occasionally been found in chromosomes 10 and 11. Nearly 70 million individuals are suspected to carry chromosomally integrated HHV-6.

A number of genes expressed by HHV-6 are unique to its inactive latency stage. These genes involve maintaining the genome and avoiding destruction of the host cell. For instance, the U94 protein is believed to repress genes that are involved in cellular lysis (apoptosis) and also may aid in telomeric integration. Once stored in human telomeres, the virus is reactivated intermittently.

The specific triggers for reactivation are not well understood. Some researchers have suggested that injury, physical or emotional stress, and hormonal imbalances could be involved.

Researchers during 2011 discovered that reactivation can positively be triggered in vitro by histone deacetylase inhibitors. Once reactivation begins, the rolling circle process is initiated and concatemers are formed as described above.

Human herpesvirus 6 lives primarily on humans and, while variants of the virus can cause mild to fatal illnesses, can live commensally on its host. It has been demonstrated that HHV-6 fosters the progression of HIV-1 upon coinfection in T cells. HHV-6 upregulates the expression of the primary HIV receptor CD4, thus expanding the range of HIV susceptible cells. Several studies also have shown that HHV-6 infection increases production of inflammatory cytokines that enhance in vitro expression of HIV-1, such as TNF-alpha, IL-1 beta, and IL-8. A more recent in vivo study shows HHV-6A coinfection to dramatically accelerate the progression from HIV to AIDS in pigtailed macaques.

HHV-6 has also been demonstrated to transactivate Epstein–Barr virus.

Humans acquire the virus at an early age, some as early as less than one month of age. HHV-6 primary infections account for up to 20% of infant emergency room visits for fever in the United States and are associated with several more severe complications, such as encephalitis, lymphadenopathy, myocarditis and myelosuppression. The prevalence of the virus in the body increases with age (rates of infection are highest among infant between 6 and 12 months old) and it is hypothesized that this is due to the loss of maternal antibodies in a child that protect him or her from infections.

There are inconsistencies with the correlations between age and seropositivity: According to some reports there is a decrease of seropositivity with the increase of age, while some indicate no significant decline, and others report an increased rate of seropositivity for individuals age 62 and older. After primary infection, latency is established in salivary glands, hematopoietic stem cells, and other cells, and exists for the lifetime of the host.

The virus is known to be widespread around the world. An HHV-6 infection rate of 64-83% by age 13 months has been reported for countries including the United States, United Kingdom, Japan and Taiwan. Studies have found seroprevalence varying "from approximately 39 to 80% among ethnically diverse adult populations from Tanzania, Malaysia, Thailand, and Brazil." There are no significant differences among ethnic groups living in the same geographical location or between sexes. While HHV-6B is present in almost all of the world’s populations, HHV-6A appears to be less frequent in Japan, North America, and Europe.

Transmission is believed to occur most frequently through the shedding of viral particles into saliva. Both HHV-6B and HHV-7 are found in human saliva, the former being at a lower frequency. Studies report varying rates of prevalence of HHV-6 in saliva (between 3–90%), and have also described the salivary glands as an in vivo reservoir for HHV-6. The virus infects the salivary glands, establishes latency, and periodically reactivates to spread infection to other hosts.

Vertical transmission has also been described, and occurs in approximately 1% of births in the United States. This form is easily identifiable as the viral genome is contained within every cell of an infected individual.

Examination of a series of tonsils with Western blotting gave a 100% detection rate for HHV-6.

The classical presentation of primary HHV-6b infection is as exanthema subitum (ES) or "roseola", featuring a high temperature followed by a rash. However, one study (1997) indicated that a rash is not a distinguishing feature of HHV-6 infection, with rates similar to non-HHV-6 infections (10–20% of febrile children in both groups). HHV-6 infections more frequently present with high temperatures (over 40C), at a rate of around two thirds compared to less than half in the non-HHV-6 patients. Similarly significant differences were seen in malaise, irritability, and tympanic membrane inflammation.

Primary infection in adults tend to be more severe.

Diagnosis for the virus, particularly HHV-6B, is vital for the patient because of the infection’s adverse effects. Symptoms that point to this infection, such as rashes, go unnoticed in patients that receive antibiotics because they can be misinterpreted as a side-effect of the medicine. HHV-6B is known to be associated with the childhood disease roseola infantum, as well as other illnesses caused by the infection. These include hepatitis, febrile convulsions, and encephalitis. Children who suffer from exanthema subitum, caused by an HHV-6B infection, experience fevers lasting 3 to 5 days; rashes on the torso, neck, and face; and sometimes febrile convulsions, however, the symptoms are not always present together. Primary infections in adults are rare since most occurrences are in children. When the infection does occur for the first time in an adult the symptoms can be severe.

The virus periodically re-activates from its latent state, with HHV-6 DNA being detectable in 20–25% of healthy adults in the United States. In the immunocompetent setting, these re-activations are often asymptomatic, but in immunosuppressed individuals there can be serious complications. HHV-6 re-activation causes severe disease in transplant recipients and can lead to graft rejection, often in consort with other betaherpesviridae. Likewise in HIV/AIDS, HHV-6 re-activations cause disseminated infections leading to end organ disease and death. Although up to 100% of the population are exposed (seropositive) to HHV-6, most by 3 years of age, there are rare cases of primary infections in adults. In the United States, these have been linked more with HHV-6a, which is thought to be more pathogenic and more neurotropic and has been linked to several central nervous system-related disorders.

HHV-6 has been reported in multiple sclerosis patients and has been implicated as a co-factor in several other diseases, including chronic fatigue syndrome, fibromyalgia, AIDS, optic neuritis, cancer, and temporal lobe epilepsy.

Multiple sclerosis (MS) is an autoimmune and inflammatory disorder of the nervous system that results in demyelination of axons in the brain and spinal cord. The history of MS in the context of HHV-6 began during 1995 when Peter Challoner, a scientist at PathoGenesis Corporation of Seattle, began looking for non-human genetic sequences in the brains of MS patients. He found an unusually high expression of HHV-6 DNA within oligodendrocytes. He also noticed a higher concentration of infected cells in areas where demyelination had occurred. His research was likely the first published study to suggest a link between HHV-6 and MS.

MS prevalence increases in populations as they are farther from the Equator. Incidence is three times higher in those born 42 degrees latitude north and above than in those born 37 degrees north and below. Individuals are also less likely to present with MS as an adult if their childhood was spent in a low incidence region. The possibility of a causative infectious agent in association with MS has been evaluated through the lens of these epidemiological findings.

To explain the data above, two hypotheses were proposed. The first is known as the Poliomyelitis hypothesis and suggests that infection at a young age confers immunity but adult infection increases MS risk. The second is known as the Prevalence hypothesis, and suggests that MS is caused by a pathogen that is more common in regions with high rates of MS. This pathogen would be widespread and cause an asymptomatic (latent) infection in most individuals. Only rarely and years after the primary infection does this hypothetical agent cause the neurological symptoms of MS. A third hypothesis essentially combines these two and also suggests the involvement of multiple pathogens. The third may best apply to the epidemiological data.

The Epstein–Barr virus (EBV) paradox is also noteworthy, as HHV-6 has been reported to transactivate EBV. Individuals are at a 10-fold less risk of MS if they are seronegative for EBV. However, among individuals who are positive, those that acquire EBV infection later in life are at a 3-fold greater risk for MS.

Research suggests that viral infections can be tied even closer to MS. EBV antibodies in healthy individuals remain constant, whereas antibody levels in individuals who later develop MS begin to increase and plateau between 20 and 30 years of age, regardless of age of onset.

More specific to HHV-6, researchers in 2004 discovered that the initial stages of MS are associated with high levels of the active virus. Soon thereafter, researchers discovered that levels of active HHV-6 are also elevated during relapses/exacerbations of MS.

Researchers have demonstrated that levels of HHV-6 IgG1 and IgM antibodies are elevated in MS patients relative to controls. In fact, research published in 2014 found that increases in anti-HHV-6A/B IgG and IgM titers are predictive of MS relapse.

Analysis of the epidemiological, serological, and immunological data above supports the association between an infectious agent and MS. However, the exact mechanism of a possible viral influence on the manifestation of MS is less clear. Although, a few mechanisms have been suggested: molecular mimicry, phosphorylation pathways, and cytokines.

The first study to specifically investigate HHV-6-related demyelination appeared in the literature during 1996, when a previously healthy 19-month-old child developed acute encephalopathy. Levels of myelin basic protein were elevated in his cerebrospinal fluid, suggesting that demyelination was occurring. This link was almost forgotten, until four years later when an MS-related study was published showing an HHV-6 prevalence of 90% among demyelinated brain tissues. In comparison, a mere 13% of disease-free brain tissues possessed the virus.

The molecular mimicry hypothesis, in which T cells are essentially confusing an HHV-6 viral protein with myelin basic protein, first appeared around this time. Early on in the development of this hypothesis (2002), Italian researchers used the HHV-6a variant along with bovine myelin basic protein to generate cross-reactive T cell lines. These were compared to the T cells of individuals with MS as well as those of controls, and no significant difference was found between the two. Their early research suggested that molecular mimicry may not be a mechanism that is involved in MS.

A few months later, researchers in the United States created a synthetic peptide with a sequence identical to that of an HHV-6 peptide. They were able to show that T cells were activated by this peptide. These activated T cells also recognized and initiated an immune response against a synthetically created peptide sequence that is identical to part of human myelin basic protein. During their research, they found that the levels of these cross-reactive T cells are significantly elevated in MS patients. Their research concluded by suggesting that HHV-6 may indeed be a causative agent for MS.

Several similar studies followed. A study from October 2014 supported the role of long-term HHV-6 infection with demyelination in progressive neurological diseases.

Myelin basic protein (MBP) regularly exchanges phosphate groups with the environment, and its ability to do so has implications for proper myelin sheath integrity. More specifically, two threonine residues on MBP have been identified as the phosphorylation targets of glycogen synthase kinase and mitogen-activated protein kinase. Their action on MBP is said to aid in its ability to polymerize and bundle myelin. Phosphorylated MBP is also more resistant to several proteases.

Among individuals with MS, these target threonines have been found to be phosphorylated less often. In fact, HHV-6 produces a transmembrane protein, known as U24, that is also a phosphorylation target of the kinases mentioned previously. Our kinases act on an HHV-6 protein due to a shared sequence of seven amino acids (MBP=IVTPRTPPPSQGK; U24=MDPPRTPPPSYSE). As a result, essential post-translational modifications may not be occurring for MBPs in individuals with active HHV-6 infections.
HHV-6 has been shown to infect olfactory ensheathing cells (OECs). OECs have been investigated thoroughly in relation to spinal cord injuries, amyotrophic lateral sclerosis, and other neurodegenerative diseases. Researchers suggest that these cells possess a unique ability to remyelinate injured neurons.

Some of the genes expressed by HHV-6 manipulate host levels of various cytokines (see section on gene products). For instance, infected cells have increased levels of interleukin-8, which is believed to induce MMP-9 repression. Elevated levels of MMP-9 have been found among individuals with MS.

HHV-6 reactivation has also been implicated in the exacerbation of MS via a shift in Th lymphocyte subsets.

Chronic fatigue syndrome (CFS) is a debilitating illness, cause of which is unknown. Patients with CFS have abnormal neurological, immunological, and metabolic findings.

For many, but not all, patients who meet criteria for CFS, the illness begins with an acute, infectious-like syndrome. Cases of CFS can follow well-documented infections with several infectious agents. A study of 259 patients with a "CFS-like" illness published shortly after HHV-6 was discovered used primary lymphocyte cultures to identify people with active replication of HHV-6. Such active replication was found in 70% of the patients vs. 20% of the control subjects (P < 10-8). The question raised but not answered by this study was whether the illness caused subtle immune deficiency that led to reactivation of HHV-6, or whether reactivation of HHV-6 led to the symptoms of the illness.

Subsequent studies employing only serological techniques that do not distinguish active from latent infection have produced mixed results: most, but not all, have found an association between CFS and HHV-6 infection.

Other studies have employed assays that can detect active infection: primary cell culture, PCR of serum or plasma, or IgM early antigen antibody assays. The majority of these studies have shown an association between CFS and active HHV-6 infection, although a few have not.

In summary, active infection with HHV-6 is present in a substantial fraction of patients with CFS. Moreover, HHV-6 is known to infect cells of the nervous system and immune system, organ systems with demonstrable abnormalities in CFS. Despite this association, it remains unproven that reactivated HHV-6 infection is a cause of CFS.

Hashimoto's thyroiditis is the most common thyroid disease and is characterized by abundant lymphocyte infiltrate and thyroid impairment. Recent research suggests a potential role for HHV-6 (possibly variant A) in the development or triggering of Hashimoto's thyroiditis.

The role of HHV-6 during pregnancy leading to inflammation in the amniotic cavity has been studied.

HHV-6A DNA was found in the endometrium of almost half of a group of infertile women, but in none of the fertile control group. Natural killer cells specific for HHV-6A, and high uterine levels of certain cytokines, were also found in the endometrium of the infertile women positive for HHV-6A. The authors suggest that HHV-6A may prove to be an important factor in female infertility.

Many human oncogenic viruses have been identified. For instance, HHV-8 is linked to Kaposi's sarcoma, the Epstein–Barr virus to Burkitt's lymphoma, and HPV to cervical cancer. In fact, the World Health Organization estimated (2002) that 17.8% of human cancers were caused by infection. The typical methods whereby viruses initiate oncogenesis involve suppressing the host’s immune system, causing inflammation, or altering genes.

HHV-6 has been detected in lymphomas, leukemias, cervical cancers, and brain tumors. Various medulloblastoma cell lines as well as the cells of other brain tumors have been demonstrated to express the CD46 receptor. Viral DNA has also been identified in many other non-pathological brain tissues, but the levels are lower.

The human P53 protein functions as a tumor suppressor. Individuals who do not properly produce this protein experience a higher incidence of cancer, a phenomenon known as Li-Fraumeni syndrome. One of HHV-6’s gene products, the U14 protein, binds P53 and incorporates it into virions. Another gene product, the ORF-1 protein, can also bind and inactivate P53. Cells expressing the ORF-1 gene have even been shown to produce fibrosarcomas when injected into mice.

Another product of HHV-6, the immediate early protein U95, has been shown to bind nuclear factor-kappa B. Deregulation of this factor is associated with cancer.

HHV-6 induced ocular inflammation has been reported three times. All three were reported in elderly individuals, two during 2007 and one during 2011. The first two were reported in Japan and France, the most recent one in Japan.

These were believed to have occurred as a result of a reactivation, as anti-HHV-6 IgM antibody levels were low.

Epilepsy of the mesial temporal lobe is associated with HHV-6 infection. Within this region of the brain exists three structures: the amygdala, hippocampus, and parahippocampal gyrus. Mesial temporal lobe epilepsy (MTLE) is the most common form of chronic epilepsy and its underlying mechanism is not fully understood.

Researchers consistently report having found HHV-6 DNA in tissues that were removed from patients with MTLE. Studies have demonstrated a tendency for HHV-6 to aggregate in the temporal lobe, with the highest concentrations in astrocytes of the hippocampus.

However, one group of researchers ultimately concluded that HHV-6 may not be involved in MTLE related to Mesial Temporal Sclerosis.

The virus is a common cause of liver dysfunction and acute liver failure, and has recently been linked to periportal confluent necrosis. Furthermore, HHV-6 DNA is often detectable only in the biopsy tissues as DNA levels fall below the level of detection in blood in persistent cases.

There are no pharmaceuticals approved specifically for treating HHV-6 infection, although the usage of "Cytomegalovirus" treatments (valganciclovir, ganciclovir, cidofovir, and foscarnet) have shown some success. These drugs are given with the intent of inhibiting proper DNA polymerization by competing with deoxy triphosphate nucleotides or specifically inactivating viral DNA polymerases.

Finding a treatment can be difficult when HHV-6 reactivation occurs following transplant surgery because transplant medications include immunosuppressants.

Human herpesvirus 6

Human herpesvirus 6 (HHV-6) is the common collective name for human herpesvirus 6A (HHV-6A) and human herpesvirus 6B (HHV-6B). These closely related viruses are two of the nine herpesviruses known to have humans as their primary host.

HHV-6A and HHV-6B are double stranded DNA viruses within the betaherpesvirinae subfamily and of the genus "Roseolovirus". HHV-6A and HHV-6B infect almost all of the human populations that have been tested.

HHV-6A has been described as more neurovirulent, and as such is more frequently found in patients with neuroinflammatory diseases such as multiple sclerosis. HHV-6 (and HHV-7) levels in the brain are also elevated in people with Alzheimer’s disease.

HHV-6B primary infection is the cause of the common childhood illness exanthema subitum (also known as roseola infantum or sixth disease). Additionally, HHV-6B reactivation is common in transplant recipients, which can cause several clinical manifestations such as encephalitis, bone marrow suppression, and pneumonitis.

A variety of tests are used in the detection HHV-6, some of which do not differentiate the two species.

Shortly after its discovery, Ablashi et al. described five cell lines that can be infected by the newly discovered HBLV. They published that HSB-2, a particular T-cell line, is highly susceptible to infection. Ablashi's pioneering research concluded by suggesting that the virus name be changed from HBLV to HHV-6, in accord with the published provisional classification of herpes viruses.

Years later, HHV-6 was divided into subtypes. Early research (1992) described two very similar, yet unique variants: HHV-6A and HHV-6B. The distinction was warranted due to unique restriction endonuclease cleavages, monoclonal antibody reactions, and growth patterns.

HHV-6A includes several adult-derived strains and its disease spectrum is not well defined, although it is thought by some to be more neurovirulent. HHV-6B is commonly detected in children with roseola infantum, as it is the etiologic agent for this condition. Within these two viruses is a sequence homology of 95%.

In 2012, HHV-6A and HHV-6B were officially recognized as distinct species.

HHV-6A and HHV-6B were recognized by the International Committee on Taxonomy of Viruses (ICTV) as distinct species in 2012. Human Roseoloviruses include HHV-6A, HHV-6B and HHV-7.

As of 2012, this order currently has 3 families, 4 subfamilies (1 unassigned), 18 genera (4 unassigned) and 97 species.

The diameter of an HHV-6 virion is about 2000 Angstroms. The virion's outer portion consists of a lipid bilayer membrane that contains viral glycoproteins and is derived from that of the host. Below this membrane envelope is a tegument which surrounds an icosahedral capsid, composed of 162 capsomeres. The protective capsid of HHV-6 contains double stranded linear DNA.

The genetic material of HHV-6 is composed of linear (circular during an active infection), double stranded DNA which contains an origin of replication, two 8–10 kb left and right direct repeat termini, and a unique segment that is 143–145kb.

When an extracellular HHV-6 virion comes across human cells, it encounters the human receptor protein cluster of differentiation 46 (CD46), which plays a role in regulating the complement system. The CD46 protein possesses a single variable region, as a result of alternative splicing. As such, at least fourteen isoforms of CD46 exist, all of which bind HHV-6a.

The salivary glands have been described as an in vivo reservoir for HHV-6 infection.

Researchers have shown that T cells are highly infectable by HHV-6.

The results above are consistent with those of previous studies that involved HSV-1 (and a number of other viruses), which also disseminates into the CNS through olfactory tissue.

Once inside, two outcomes have been described: active and inactive infections.

HHV-6’s replication results in the formation of concatemers, which are long molecules that contain several repeats of a DNA sequence. These long concatemers are then cleaved between the pac-1 and pac-2 regions by ribozymes for packaging of the genome into individual virions.

Not all newly infected cells begin rolling circle replication. In fact, herpes comes from the Greek word herpein, meaning "to creep." Herpesviruses are 'to creep' in that they may enter a latent stage, inactively infecting their human host. Since its discovery in 1993, this phenomenon has been found among all of the betaherpesviruses.

The right direct repeat terminus integrates within 5 to 41 human telomere repeats, and preferentially does so into the proximal end of chromosomes 9, 17, 18, 19, and 22, but has also occasionally been found in chromosomes 10 and 11. Nearly 70 million individuals are suspected to carry chromosomally integrated HHV-6.

A number of genes expressed by HHV-6 are unique to its inactive latency stage. These genes involve maintaining the genome and avoiding destruction of the host cell. For instance, the U94 protein is believed to repress genes that are involved in cellular lysis (apoptosis) and also may aid in telomeric integration. Once stored in human telomeres, the virus is reactivated intermittently.

The specific triggers for reactivation are not well understood. Some researchers have suggested that injury, physical or emotional stress, and hormonal imbalances could be involved.

Researchers during 2011 discovered that reactivation can positively be triggered in vitro by histone deacetylase inhibitors. Once reactivation begins, the rolling circle process is initiated and concatemers are formed as described above.

HHV-6 has also been demonstrated to transactivate Epstein–Barr virus.

Vertical transmission has also been described, and occurs in approximately 1% of births in the United States. This form is easily identifiable as the viral genome is contained within every cell of an infected individual.

Examination of a series of tonsils with Western blotting gave a 100% detection rate for HHV-6.

Primary infection in adults tend to be more severe.

HHV-6 has been reported in multiple sclerosis patients and has been implicated as a co-factor in several other diseases, including chronic fatigue syndrome, fibromyalgia, AIDS, optic neuritis, cancer, and temporal lobe epilepsy.

The Epstein–Barr virus (EBV) paradox is also noteworthy, as HHV-6 has been reported to transactivate EBV. Individuals are at a 10-fold less risk of MS if they are seronegative for EBV. However, among individuals who are positive, those that acquire EBV infection later in life are at a 3-fold greater risk for MS.

Research suggests that viral infections can be tied even closer to MS. EBV antibodies in healthy individuals remain constant, whereas antibody levels in individuals who later develop MS begin to increase and plateau between 20 and 30 years of age, regardless of age of onset.

More specific to HHV-6, researchers in 2004 discovered that the initial stages of MS are associated with high levels of the active virus. Soon thereafter, researchers discovered that levels of active HHV-6 are also elevated during relapses/exacerbations of MS.

Researchers have demonstrated that levels of HHV-6 IgG1 and IgM antibodies are elevated in MS patients relative to controls. In fact, research published in 2014 found that increases in anti-HHV-6A/B IgG and IgM titers are predictive of MS relapse.

Analysis of the epidemiological, serological, and immunological data above supports the association between an infectious agent and MS. However, the exact mechanism of a possible viral influence on the manifestation of MS is less clear. Although, a few mechanisms have been suggested: molecular mimicry, phosphorylation pathways, and cytokines.

Several similar studies followed. A study from October 2014 supported the role of long-term HHV-6 infection with demyelination in progressive neurological diseases.

Some of the genes expressed by HHV-6 manipulate host levels of various cytokines (see section on gene products). For instance, infected cells have increased levels of interleukin-8, which is believed to induce MMP-9 repression. Elevated levels of MMP-9 have been found among individuals with MS.

HHV-6 reactivation has also been implicated in the exacerbation of MS via a shift in Th lymphocyte subsets.

Chronic fatigue syndrome (CFS) is a debilitating illness, cause of which is unknown. Patients with CFS have abnormal neurological, immunological, and metabolic findings.

Subsequent studies employing only serological techniques that do not distinguish active from latent infection have produced mixed results: most, but not all, have found an association between CFS and HHV-6 infection.

Other studies have employed assays that can detect active infection: primary cell culture, PCR of serum or plasma, or IgM early antigen antibody assays. The majority of these studies have shown an association between CFS and active HHV-6 infection, although a few have not.

In summary, active infection with HHV-6 is present in a substantial fraction of patients with CFS. Moreover, HHV-6 is known to infect cells of the nervous system and immune system, organ systems with demonstrable abnormalities in CFS. Despite this association, it remains unproven that reactivated HHV-6 infection is a cause of CFS.

Hashimoto's thyroiditis is the most common thyroid disease and is characterized by abundant lymphocyte infiltrate and thyroid impairment. Recent research suggests a potential role for HHV-6 (possibly variant A) in the development or triggering of Hashimoto's thyroiditis.

The role of HHV-6 during pregnancy leading to inflammation in the amniotic cavity has been studied.

HHV-6A DNA was found in the endometrium of almost half of a group of infertile women, but in none of the fertile control group. Natural killer cells specific for HHV-6A, and high uterine levels of certain cytokines, were also found in the endometrium of the infertile women positive for HHV-6A. The authors suggest that HHV-6A may prove to be an important factor in female infertility.

HHV-6 has been detected in lymphomas, leukemias, cervical cancers, and brain tumors. Various medulloblastoma cell lines as well as the cells of other brain tumors have been demonstrated to express the CD46 receptor. Viral DNA has also been identified in many other non-pathological brain tissues, but the levels are lower.

Another product of HHV-6, the immediate early protein U95, has been shown to bind nuclear factor-kappa B. Deregulation of this factor is associated with cancer.

HHV-6 induced ocular inflammation has been reported three times. All three were reported in elderly individuals, two during 2007 and one during 2011. The first two were reported in Japan and France, the most recent one in Japan.

These were believed to have occurred as a result of a reactivation, as anti-HHV-6 IgM antibody levels were low.

Epilepsy of the mesial temporal lobe is associated with HHV-6 infection. Within this region of the brain exists three structures: the amygdala, hippocampus, and parahippocampal gyrus. Mesial temporal lobe epilepsy (MTLE) is the most common form of chronic epilepsy and its underlying mechanism is not fully understood.

Researchers consistently report having found HHV-6 DNA in tissues that were removed from patients with MTLE. Studies have demonstrated a tendency for HHV-6 to aggregate in the temporal lobe, with the highest concentrations in astrocytes of the hippocampus.

However, one group of researchers ultimately concluded that HHV-6 may not be involved in MTLE related to Mesial Temporal Sclerosis.

The virus is a common cause of liver dysfunction and acute liver failure, and has recently been linked to periportal confluent necrosis. Furthermore, HHV-6 DNA is often detectable only in the biopsy tissues as DNA levels fall below the level of detection in blood in persistent cases.

There are no pharmaceuticals approved specifically for treating HHV-6 infection, although the usage of "Cytomegalovirus" treatments (valganciclovir, ganciclovir, cidofovir, and foscarnet) have shown some success. These drugs are given with the intent of inhibiting proper DNA polymerization by competing with deoxy triphosphate nucleotides or specifically inactivating viral DNA polymerases.

Finding a treatment can be difficult when HHV-6 reactivation occurs following transplant surgery because transplant medications include immunosuppressants.


When was Madelyne "Maddie" Jennifer Pryor-Summers first introduced by Marvel Comics?

Madelyne Pryor was introduced during the acclaimed 1983 "Uncanny X-Men" run that saw long-time writer Chris Claremont pair with artist Paul Smith for a series of issues that would see the Jean Grey look-alike marry the retired X-Men leader Scott Summers (Cyclops).

Madelyne Pryor

Madelyne "Maddie" Jennifer Pryor-Summers is a fictional supervillainess appearing in American comic books published by Marvel Comics, primarily featured off-and-on as an antagonist of the X-Men. Originally the love interest and first wife of X-Men leader Cyclops (Scott Summers), she became a long-standing member of the "X-Men" supporting cast, until a series of traumas—being abandoned by her husband, losing her infant son, and discovering that she was a clone of Jean Grey—eventually led to her being manipulated into becoming a supervillain. She and Cyclops are the parents of Nathan Summers (Cable). Her biography has been rendered particularly complicated because of the many retcons involved in the publication history of both her character and that of Jean Grey.

Madelyne's hairstyle design was modeled off the book's editor at the time, Louise Jones (later Louise Simonson)—a design retained on the character until 1988. Claremont named the character after Steeleye Span singer Maddy Prior. Claremont had already created a character named "Maddy Pryor", a little girl that appeared very briefly in "Avengers Annual" #10 (1981), and has no in-story connections to the X-Men character. Claremont, nonetheless, years later took an opportunity to indulge in an in-joke: in "Uncanny X-Men" #238 (1988), a similar child would appear as Madelyne's mental image of herself, wearing the same clothes as the little girl from "Avengers Annual" #10, repeating the girl's same line of dialogue, but also singing "Gone to America", one of Steeleye Span's biggest hits.

According to Claremont, the original link between Madelyne Pryor and Jean Grey was entirely the product of Mastermind. Seeking revenge against the X-Men after Jean (as Phoenix) had driven him insane, Mastermind uses his powers of illusion to convince Scott and the others that Madelyne is Phoenix incarnate—a cosmic threat—in an attempt to have the team kill her. Mastermind's plan fails, and Madelyne and Cyclops are married shortly after. Claremont had conceived Madelyne as a device to write Scott Summers out of the X-Men and have him retire "happily ever after" with Madelyne and their child.

The story became more complicated in 1986 when moves by the editors and other writers to reunite the original X-Men, for the new title "X-Factor", resulted in Jean Grey's resurrection and Scott leaving his wife and son. This deeply compromised the character of Cyclops and left little room for Madelyne, and Cyclops' actions then—and towards even Jean Grey much later—have been controversial ever since. Marvel avoided addressing these problems, instead resorting to a "deus ex machina", in the 1989 "Inferno" crossover (co-scripted by Louise Simonson, with Claremont), in which Madelyne is retconned to be a clone of Jean Grey created by Mr. Sinister to produce a child with Scott Summers, and corrupted by her anger and demonic influence into the Goblin Queen, leading to her elimination and into an object of "damnatio memoriae" (and "nonperson" status) for several years.

Asked about his intended plans for Madelyne's character, Claremont said:
Madelyne Pryor was brought back in 1995 as a supporting character in "X-Man", a marginal X-Men related title. Though by around 2001 (along with the cancellation of the "X-Man" title), this became a false start at reviving the character, as Pryor would again cease being featured in any Marvel titles, except when Chris Claremont included the character in his non-canon limited-series, "" (2004-2006).

In 2008, exactly 25 years since the character's debut in "Uncanny X-Men", Madelyne Pryor was brought back in the flagship X-Men title for the first time since 1989. By 2009, after less than 12 issues, Pryor would be declared ""apparently destroyed"", and would not be featured in another story again until 2014 (exactly 25 years since the "Inferno" storyline) in the secondary title, "X-Men" (Vol. 4).

Madelyne Pryor was a cargo pilot in Anchorage, Alaska working for Scott Summers' grandparents when she and Scott meet during a Summers family reunion. A romantic relationship quickly begins between them; however, Scott is disturbed at her striking resemblance to his dead lover, Jean Grey/Phoenix. Also, she was the sole survivor of an airplane crash that occurred the same day Phoenix died on the moon. In addition, Professor X is unable to scan her mind (which, he notes, is occasionally the case with normal humans). Scott, still recovering from Jean's death, becomes obsessed with the idea that Madelyne is her reincarnation, eventually confronting her with his suspicions. Madelyne, furious and hurt, punches Scott and runs from him. As soon as she is alone, she is abducted by Mastermind, who had been manipulating the X-Men for months — as revenge for being driven temporarily insane by Phoenix due to his involvement in her corruption. To defeat him, Storm summons a violent storm which nearly kills Madelyne, but Scott resuscitates her. After the conflict, Scott comes to terms with the fact that Jean Grey is dead and that Madelyne is not her, and that he loves her all the same. The two are married, and Scott retires from active duty with the X-Men.

Giving up the life of an adventurer proves harder for Scott than imagined. Early in Madelyne and Scott's marriage, they (along with Alpha Flight and the rest of the X-Men) are taken to an abandoned city by the Asgardian trickster-god Loki. Entirely for his own purposes, Loki endows mystical powers on a small group of non-powered humans, including Madelyne, transforming her into a healer of virtually any injury, illness, psychological issue, or physical defect. She adopts the name "Anodyne" and cures Scott's childhood head injury, enabling him to control his optic blasts without the use of ruby-quartz lenses. She also removes Aurora's DID and Wolverine's berserker rage. When it is discovered that Loki's gifts are extremely flawed, and fatal to some, everyone assembled reject the gift. Madelyne and the other beneficiaries are reverted to their original states, as are all those who had been healed by Madelyne. During this adventure Madelyne reveals that she is pregnant.

Going into premature labor, Madelyne gives birth to a baby boy (Nathan Christopher Charles Summers) alone in the X-Mansion. Sensing a reluctance on Scott's part to retire to family life, a powerless Storm challenges him to a duel for leadership of the team, which Storm wins. This in effect forces Scott to accept his new role as a husband and father.

Although Scott tries to live a normal family life in Alaska, he often thinks of Jean Grey, and of his life with the X-Men. Maddie tries her best to make Scott happy, but her efforts seem wasted. Finally Scott receives a call from his former teammate Angel that Jean Grey has been found alive. Without explaining himself, Scott abandons Madelyne and their son to reunite with his lost love, and forms X-Factor with his old friends from the original X-Men. Madelyne and Nathan are then attacked by the Marauders; Nathan is kidnapped and Madelyne left for dead, but survives and is hospitalized as a "Jane Doe". A guilt-wracked and increasingly unstable Scott returned home to find his house empty, and all records of his family's existence erased.

Alone and threatened, Madelyne calls the X-Men for help; they arrive and fight off another attack by the Marauders. Despairing from Scott's absence and of her son's fate, she contemplates suicide. Madelyne's brother-in-law, Alex Summers (Havok), talks her out of it, and the two of them grow closer. With the Marauders still after her, she stays with the X-Men, and they sacrifice their lives to stop the Adversary from remaking the world in "Fall of the Mutants". A reporter video-interviews them before their death, and Maddie uses this to deliver a message to Scott, pleading that he find their child. With the world thinking them dead, Madelyne and the X-Men are resurrected by the Omniversal Guardian Roma and begin working secretly out of an abandoned Reavers base in Australia. Madelyne serves as the team's technical support.

Monitoring news transmissions, Madelyne learns that Jean Grey is alive and with Scott. She punches the computer monitor's screen, breaking it and causing electrical feedback that renders her unconscious. The Limbo demon S'ym invades Madelyne's mind during her unconscious state, and tempts her to take on the power that would make her the Goblin Queen. Believing to be dreaming, Madelyne accepts.

Madelyne keeps the existence of the original X-Men as X-Factor secret from the others, filtering in only information and news showing X-Factor as an anti-mutant group. Later abducted by the Genoshans and taken to their island-nation, Madelyne is subjected to psychic torture intended to transform her into a docile slave of the state. Madelyne instinctively lashes out with her developing abilities, which cause the deaths of her torturers. In the recorded images of the psychic probe performed on Madelyne, her appearance reflects her change into the Goblin Queen. Shortly after being rescued by the X-Men, Madelyne strikes a bargain with another demon, N'astirh, to find the Marauders and return her son to her. During this time, she and Alex become lovers.
To keep his end of their bargain, N'astirh takes Madelyne to the orphanage in Nebraska where Scott grew up, actually a front for Mr. Sinister's genetic laboratory. Sinister appears and tells Madelyne about her origins. When he learnt about Jean Grey, he planned to eliminate her parents and take the girl to his orphanage. Fortuantely for them, Charles Xavier had already approached them and started to work with the young girl. Sinister only managed to acquire a blood and tissue sample which he then created a clone of her. However, the clone failed to develop any mutant powers. When Phoenix took her own life, a part of the Phoenix Force entered and awakened the clone, giving her sentience. Sinister then conceived a plan to use the clone to facilitate selective breeding between her and Scott. Sinister named her "Madelyne Pryor", and created a false background, implanted memories, and a personality designed to attract Summers. He then planted her with Scott's grandparents' company, thus ensuring the two would eventually meet. As Jean Grey's return might cause the truth about Madelyne to be uncovered if the two were to meet, Sinister tasked his Marauders with killing Madelyne and bringing him Nathan, the fruits of his scheme.

Broken in spirit to insanity by the revelations, although Madelyne then regains her son, she now willingly aids N'astirh in his demonic invasion of Earth. Returning to New York City, where the demonic invasion is already in full swing, she confronts X-Factor with the revelation that she is alive. When the X-Men arrive, Madelyne steers the teams against each other at first, and convinces Alex to join her. X-Factor and the other X-Men work together to defeat N'astirh. Madelyne refuses to stop, forcing the heroes to overwhelm her. Cyclops rescues his son, but Madelyne commits suicide in an attempt to telepathically take Jean with her. The Phoenix Force appears to Jean and offers to save her, but in order to survive Jean has to integrate the essence of both the Phoenix and Madelyne, gaining their memories and personalities. Mr. Sinister attempts to entrap all of the X-Men and X-Factor in Madelyne's dying mind, but forced to choose between having revenge either on the X-Men or Mr. Sinister, Madelyne ejects Mr. Sinister from her mind. With her personality influencing Jean's, she then prompts the X-Men and X-Factor to attempt lethal retribution against him.

Jean, having inherited Madelyne's maternal feelings for Nathan Christopher, becomes his proxy mother. They would raise Nathan Christopher until Apocalypse, seeing the potential threat in the child, infected him with a techno-organic virus. Dying, the child was taken 2,000 years into the future by Askani to be saved.

Madelyne mysteriously reappears years later as an amnesiac to Nate Grey (X-Man) — the "genetic offspring" of Scott Summers and Jean Grey from the alternate reality known as the "Age of Apocalypse" — when he comes to Earth-616. Under the tutelage of Selene, Madelyne eventually becomes the Hellfire Club's "Black Rook" (even becoming Sebastian Shaw's mistress), has her memories of her previous life restored by Tessa, and meets her aged son Cable in an uneasy truce.

It is revealed that Madelyne is a "psionic construct" inadvertently resurrected by Nate Grey's psionic powers. Antagonistic for a time after this revelation, eventually she and Nate become companions, until an attack by Strikesquad: Gauntlet, a group of operatives wearing psi-shielded armor, Madelyne was buried alive by one of them. She managed to escape by teleporting, yet, as the battle had taken a lot out of X-Man, she looked drained and withered. In no shape to continue whatever plans she had with Nate, she left.

Soon after, Nate Grey is accompanied again by Madelyne alive and well, but she turns out to be a Jean Grey from another alternate reality (Earth-9575). This woman seems to have taken advantage of Madelyne's absence and replaced her, to then worm her way into Nate's head. The exact details of the encounter between Madelyne and this Jean have yet to be revealed, but obviously the latter either destroyed the body Nate Grey had created for Madelyne or at least severed her consciousness’ connection to it, since Cyclops and Cable would eventually encounter Madelyne within the telepathic astral plane, describing herself as now only a "ghost" and unable to return to the physical world.

Some years later, the X-Men investigate an anti-mutant group calling itself the "Hellfire Cult", being led by Empath. Empath is secretly being controlled and taking orders from a mysterious woman calling herself the "Red Queen", who is particularly interested in learning about Cyclops' new lover Emma Frost. (Scott and Jean's marriage had fallen apart, and Grey then died during a mission soon afterward.) The X-Men take down the Cult and capture Empath, while the Red Queen slips away unseen. She then psionically impersonates Frost and has virtual sex with Scott, without him realizing the deception. Afterward, the Red Queen travels to Madripoor where she recruits Chimera into a new group called the "Sisterhood of Mutants" and reveals herself to be Madelyne Pryor returned to the living somehow. Later during a concert of Dazzler, Scott is surprised at the sight of Madelyne observing him from a distance before losing her amongst the crowd.

With Martinique Jason (recruited before the Cult's exposure) and Chimera accompanying her, Madelyne recruits Spiral and Lady Deathstrike into the Sisterhood as well. Madelyne then recruits Martinique's half-sister, Lady Mastermind, who accepts membership on Madelyne's peculiar (and ironic) promise to bring back the half-sisters' late father, the original Mastermind. Carrying out Madelyne's orders, the Sisterhood retrieved the corpse of Revanche and performed an elaborate set of procedures on Revanche and a captured Psylocke, fully restoring the body and transferring Psylocke's mind into it. Madelyne's true priority was to restore herself back into flesh-and-blood. In the time since the encounter in the astral plane, Pryor had eventually managed to manifest back in the physical world as an intangible entity of psionic energy, and needed to find a body to inhabit that could contain her disembodied form and psionic powers. The experiment on Psylocke served as a test run for Pryor.

The Sisterhood commences a surprise raid on the X-Men's base, quickly neutralizing several of the main X-members. Recovering from the initial attacks, the X-Men force the Sisterhood (now including a brainwashed Psylocke) to retreat. But the battle was only a distraction, as the real purpose was for Madelyne to locate Jean Grey's gravesite. (As Madelyne's own body had been cremated after her suicide, Grey's seemed the only option available to her.) At Jean's grave, Madelyne attempts to repeat the ritual with her corpse. However, Cyclops had correctly guessed Madelyne's goal and had arranged for Grey's body to be replaced with another, which Madelyne only learned after it was too late. The second she bound herself to the corpse, she perished, as the decayed body could not contain her vast psionic energies.

During the 2012 "Avengers vs. X-Men" storyline, Mister Sinister had created a group of six Madelyne Pryor clones in order to take the Phoenix Force energies from the Phoenix Five (consisting of the Phoenix Force-empowered Cyclops, Colossus, Emma Frost, Magik, and Namor). Unlike the original Madelyne, none of the six clones showed indications of having individual personalities or free will, but instead appeared to follow Sinister completely. The Madelyne Pryor clones joined Sinister's other clone creations in fighting the Phoenix Five and managed to defeat each one. They also were able to siphon some of the energy from the Phoenix Force, but they all were immediately killed by the entity itself.

Lady Deathstrike, whose consciousness had taken possession of a Colombian girl named Ana Cortes, formed an all new Sisterhood initially composed of her, the mutant Typhoid Mary, and the exiled Asgardian Amora (the Enchantress). The sentient bacteria Arkea possessed Lady Deathstrike's assistant Reiko and joined. As Arkea feared being opposed by the X-Men, she wanted powerhouses with the Sisterhood, so she had Enchantress use her magicks to restore Selene and also planned to resurrect Madelyne Pryor. Ana Cortes managed to turn against Deathstrike, contact the X-Men and alert them of the Sisterhood's location, and then committed suicide in an attempt to prevent Arkea's plans. Arkea was able to place Deathstrike's consciousness into Reiko also, and seeing an opportunity, spliced Jean Grey's DNA to Ana's body, making it a fully compatible host for Madelyne Pryor. Enchantress then used her magicks to retrieve Pryor's consciousness, place it into the body and revive Madelyne (in the process, seemingly reshaping Cortes' physical appearance into Pryor's), making her flesh-and-blood again for the first time since her own suicide. When the X-Men arrived and attacked, Madelyne fought and telepathically defeated the more experienced telepath Rachel Grey. Storm offered Madelyne and Selene a deal, essentially letting them go free as the X-Men were only after Arkea at the moment. As Madelyne and the other members of the Sisterhood didn't particularly care for Arkea, they deserted her, allowing all of the Arkea bacteria to be destroyed. Accompanied by Selene, Madelyne declared that she would create an all new Sisterhood.

As a clone of Jean Grey, Madelyne Pryor also possesses mutant abilities of telepathy and telekinesis. These powers were completely dormant while she was believed to be a baseline human, but later manifested in ways that Jean's never had.

During her brief time as Anodyne, when still believed to be human, Madelyne was endowed with Asgardian magic that manifested as eldritch flames which granted her the power to heal and cure. Among her beneficial actions were fixing the childhood brain injury that prevented Cyclops from controlling his optic blasts, curing Puck of his mystically induced dwarfism, unifying Aurora's multiple personalities, and giving Rogue the ability to control her mutant power. Madelyne also seemed to gain the physical stature of an Asgardian.

As the Goblin Queen, demonic eldritch magic activated Pryor's long-dormant mutant powers, and also exponentially enhanced them to the point where she could warp reality (equivalent to the abilities of Proteus) within a localized area, possibly over an entire city.

After her apparent resurrection by Nate Grey, Madelyne regained her natural mutant abilities. Without the demonic enhancements, her powers are still considerable. Her telepathy enables her to read minds, broadcast her thoughts, create illusions, change or erase memories, and defend herself against other telepaths. With her telekinesis, Madelyne can lift and manipulate large objects, levitate, fire powerful mental force-blasts, form protective shields, and even rearrange small objects on a molecular level. Madelyne has also utilized her powers to augment her physical strength and agility, making her formidable in hand-to-hand combat.

Madelyne also learnt how to use her powers to teleport over long distances by psychokinetically shifting in and out of the astral plane (and was shown to be able to carry along at least one other person with her when teleporting), and also able to channel psionic energies from other psionic-powered mutants to boost her own abilities or those of another (usually Nate Grey, and on occasion Cable). It is speculated that Selene's tutelage made these added abilities possible by Madelyne.

As the Red Queen, Madelyne was again a non-physical entity of psionic energy (similar to the Shadow King). Along with her usual powers, Madelyne had demonstrated other abilities of a mysterious nature which she referred to as "magic", which were probably related to the eldritch magics she had previously wielded. She was shown to heal wounds, locate spirits interdimensionally, and work in conjunction with science to restore life to the dead.

In one alternate reality (Earth-89112), Madelyne Pryor and S'ym were successful in opening a portal between Limbo and Earth (having killed baby Nathan Christopher) and demons overran the planet. The X-Men and X-Factor were dead (with the exception of a possessed Wolverine), and the only resistance left was led by Doctor Strange, who attempted to summon the Phoenix Force through Rachel Summers, the reality-hopping daughter of Scott Summers and Jean Grey. Madelyne however was successful in quelling the resistance and wresting control of the Phoenix Force from Rachel, but was ultimately betrayed and killed by S'ym, using Wolverine's reanimated adamantium skeleton. Rachel, reassuming the mantle of the Phoenix, used the Force to cleanse the planet of the demon plague.

On Earth-9250, most mutants in the city of Manhattan are vampires ruled by Wolverine. Madelyne was not infected, but became the Goblyn Queen and planned on releasing a demon army to wipe out the vampire mutants and dominate the world. Madelyne made contact with the lord of the Dark Dimension, Dormammu, who became her ally. However, the vampiric Marvel Girl (Jean Grey) bonded with the Phoenix Force, became Dark Phoenix, and killed Madelyne and Dormammu.

Another reality saw Madelyne Pryor as a member of an "X-Men" team formed by Mr. Sinister alongside Cyclops (Scott Summers), Havok (Alex Summers), and Sabretooth. However this version of Madelyne had never been awakened by the Phoenix Force, so she was simply a mindless shell inhabited by the psychic entity Malice. Scott noticed his physical attraction to Madelyne, but could not respond to her advances; when he encountered Professor Xavier's X-Men and their leader Jean Grey, however, much deeper emotions were stirred. Sinister called for their deaths, and under his orders Cyclops and Havok infiltrated Xavier's X-Men as double agents.

In the alternate reality known as the Mutant X universe, young Scott Summers was abducted into space along with his father Christopher and mother Kate, leaving his brother Alex to become one of the founders of the X-Men as Havok. This reality's Madelyne Pryor marries Alex and has a son, named Scotty, with him. Just like in Earth-616, Madelyne also makes a deal with Limbo's demons, unlocking her latent psionic abilities, and initiates the "Inferno Crisis". In this instance however, Madelyne survives the crisis; and, using the alias "Marvel Woman", leaves the X-Men team with her husband when he forms the splinter group called "The Six". Her evil side resurfaces a number of times, first as the "Goblyn Queen" and later as the "Goblyn Force". When it returns a second time, it merges with the Beyonder to form a nigh-omnipotent being. Havok supposedly saves Madelyne by placing the "Nexus of Realities" in her body, purging her of the malevolent Goblyn Force and reuniting her with her son Scotty, before Havok returns once more to the void.

In the Marvel Mangaverse title "Legacy of Fire", Madelyne Pryor was reinvented as Madelyne Pyre, a powerful sorceress and possessor of the Phoenix Sword, who was training her sister Jena to be her successor.

Madelyne Pryor plays an important role in "", Chris Claremont's limited series about an alternate future. In the story, Madelyne — through circumstances left unexplained — makes a surprise return. Mysteriously joined with the X-Men's alien enemies (the Skrulls and the Shi'ar), Madelyne affected a disguise to infiltrate the X-Men, planting herself near Cyclops for the rest of the series. Still seeking revenge against her former husband, Madelyne wavered however and protected him instead, after eavesdropping on Scott expressing remorse for everything that happened to her, and even implied that he genuinely loved her after all. Cyclops later admitted to having recognized her at some point, and an understanding and peace was finally reached between them, for the sake of aiding their son Cable in battle. When Cable's effort leaves him dying, a grief-stricken Madelyne is accepted back with the X-Men again. After Cyclops and Jean Grey are also killed, Madelyne cryptically reveals that, since the very beginning, she was always both Madelyne Pryor and a crucial portion of Jean Grey herself (and even hinted to being the Dark Phoenix), explaining that she was the part of Jean that truly and completely loved Scott, and that was why Jean and Scott's marriage failed. Madelyne then sacrifices herself by turning into energy and fusing with Jean Grey, who is once again resurrected. Jean is able to use her power to its fullest again, which allows her and all the dead X-Men to merge with the Phoenix and transcend to a new level of existence. In the story's final panel, Madelyne's image is present next to Cyclops' among the X-Men who died heroically.

When Doctor Doom became the God Emperor Doom and saved remnants of the destroyed Multiverse to form Battleworld, among the salvaged worlds was a reality where the X-Men failed to stop the "Inferno" event instigated by the Darkchilde and the Goblin Queen. Contrary to all assumptions, Madelyne Pryor never committed the sacrificial prolicide of her baby son, and had been raising Nathan in the years since.

Doom had made Pryor the ruling Baroness of the "Domain of Limbo" at first, until the X-Men entrapped the demonic invasion within Manhattan and war broke out between Madelyne and Illyana, leading to Cyclops being appointed Limbo's Baron. Colossus would be forced into an alliance with Madelyne to deal with Illyana, only for Darkchilde to breach the containment and unleash Inferno on the rest of the domain. When Sinister emerged to coerce the defeated X-Men to ally with him against Darkchilde, Madelyne killed Sinister in overdue revenge. Colossus then had to kill Illyana after she massacred all the last remaining X-Men. In the aftermath, Pryor took possession of Darkchilde's demonic magic, making Madelyne the next demonic sorceress and ruler of Limbo domain, with Nathan alongside her.

Doom himself acknowledged Pryor's re-ascendence to Baroness. Pryor then became one of four Barons (among the others, an alternate version of Sinister) Doom chose as his "Generals" and ordered to field their armies to crush an uprising against the God Emperor. The Goblin Queen followed Doom's wishes, until betrayed and then beaten-down by Sinister and Captain Marvel.

Following the events of the "Secret Wars" and the restoration of Earth-616, this version of Madelyne Pryor was able to survive the destruction of Battleworld along with her pet dragon Bamfy and a horde of goblins. They opened a portal to a storage facility in Florida, from which they planned to invade Prime Earth, however, their mustering was interrupted by Wolverine and Angel, forcing the horde to withdraw. She later opened another portal to gain access to Earth in Miami and her hordes of demons descended to wreak chaos all over the place. She also revealed that when Battleworld began collapsing, twelve hell gates inexplicably opened near the area she was and she along with Bamfy entered one that took them to Limbo where they remained in the shadows. Now once again on Earth she had her horde of demons capture the small team of X-Men that were taking a break there and was on the verge of using them for her final sacrifice until her plans were interrupted by the arrival of the mystical infused time-displace Hank McCoy which forced her to withdraw by using Bamfy to teleport her to some unknown place.

Madelyne has since been training the time-displaced Hank on how to hone his mystical capabilities. While training him, she travels across the multiverse collecting supernatural X-Men from alternate realities and promised to give them what they wanted if they help her. Madelyne then has Hank cast a ritual that summons her and her new team of supernatural X-Men, calling them her "Hex Men", and ambushes Magneto's team of X-Men in Madripoor. Her goal is to use the ritual that Beast started to summon alternate versions of herself trapped in the underworld and bring them to the surface to help her gain power. Bloodstorm sees how Madelyne has used them as a means to her own goal and knows that she will throw the Hex Men to the wolves when her main goal is accomplished. Bloodstorm convinces Beast to betray Madelyne and in doing so interrupts the ritual. Because of the interruption the alternate versions of Madelyne drag all of the Hex Men to the underworld with them except for Bloodstorm and Beast.

A limited series that does an abridged and condensed retelling of four decades of X-Men related canon from the 1960s debut onward, Pryor's introduction and early storylines are included but substantially rewritten in the "Second Genesis" chapter. Pryor debuts and participates in stories which originally featured Lee Forrester (who is entirely excluded in this retelling), is not a pilot Cyclops meets in Alaska, her plane crash survivor story told as having happened when Phoenix first emerged instead of when she died on the moon, and Mastermind's actions on Pryor never happening.

A story (by Claremont again), included as an addition with the main story in "The Exterminated" one-shot, appears as if to be a flashback from just after Cyclops and Storm's leadership duel and his moving back to Alaska with Pryor. Circumstances shown here lead to Scott and Madelyne happily reconciling, before the discovery and return of Grey. This and other differences from canon seem to place this story in the setting of Claremont's "X-Men Forever" universe.