Comments

I. TRIGGERING EVENT
Transient immune dysfunction results in loss of viral containment of HHV-6 latency and thus reactivation. The immune dysfunction presumably relates to cell mediated immunity (CMI) and natural killer (NK) cell dysfunction. CMI (T cell immunity) entails antigen specific immunity and is major histocompatibility complex (MHC) restricted. In the genetically predisposed individual (see below – Genetic predisposition), MHC restricted antigen presentation and/or recognition may be ineffective in controlling the activated HHV-6. With altered T cell function for the virus, NK function becomes very important as a primary control mechanism for containing the activated virus. Thus, loss of NK function, coupled with T cell abnormalities, result in a major problem in containment of the virus for these individuals. This initial "loss of containment", may then lead to active HHV-6 infection. Examples of possible events, that may trigger transient immune dysfunction (thus viral reactivation) are: acute viral infection (mononucleosis – EBV or CMV, Hepatitis C, parvovirus, etc.), vaccination (post-vaccination neurologic syndromes, Gulf War syndrome), pregnancy, trauma, surgery, extreme stress, chemical immune suppression (chemotherapy, corticosteroids), HIV infection, Lyme disease, and leakage from silicone implants (1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17).
[See References – Group I]

II. GENETIC PREDISPOSITION
Genetics, particularly the specific MHC Class I and Class II determinants expressed by cells for any given individual, are associated with the effectiveness of the immune response for infections (18). Several reports have shown that viral infections, for which CMI (T cell response) is important, can vary widely in disease severity and clinical spectrum based on MHC type (18). Highly variable immune responses to infection related to MHC differences has been reported with a number of viruses including Herpes simplex virus (HSV), Varicella zoster virus (VZV), cytomegalovirus (CMV), Epstien-Barr virus (EBV), and Hepatitis C virus (HCV) (18, 19, 20). The same type of MHC dependent variation in response to infection likely occurs with HHV-6, as well. Genetically predisposed individuals presumably have inadequate or "lethargic" control and containment of either primary HHV-6 infection or reactivation. Genetic and epidemiologic data strongly suggests a genetic predisposition, especially with the prototypic example of multiple sclerosis (MS) (21, 22, 23). Clinical experience with both chronic fatigue syndrome (CFS) and fibromyalgia (FM) patients has suggested similar epidemiologic trends. We have observational data on patients with MS and CFS who have active HHV-6 viremia, in which we have done MHC Class II typing. The incidence of MHC Class II type DR 15, DQ 6 is approximately 65% (unpublished data). This is similar to what is reported in the MS genetic studies, which is significantly higher than the general population (22). There are likely problems involved with processing, presentation, or recognition of viral peptides. Certain MHC types (e.g. MHC Class II type DR 15 and DQ 6 in MS patients) may have a problem with MHC restricted antigen presentation and subsequent recognition by T cells. These problems with antigen presentation and/or recognition result in an inadequate CMI response for HHV-6.
[See References – Group II]

III. ACTIVE HHV-6 INFECTION
There is a growing body of information demonstrating active HHV-6 infection in patients with MS and CFS (24, 25, 26, 27, 28, 29). Albeit, virtually the entire population harbors latent HHV-6 (especially the B variant), it is very rare for the normal healthy individual to have active HHV-6 infection. Accurately differentiating between latent infection and active infection by laboratory testing has been a significant obstacle, however, newer methods have improved testing sensitivity and specificity for active infection (see HHV-6 Diagnosis). Until recently, the demonstration of HHV-6 reactivation has been predominately in the immune compromised host (30). However, studies using rapid viral culture or PCR detection (especially in the serum), have shown active HHV-6 infection in the bloodstream of both MS and CFS patients (26, 27, 28, 29). Such infection in these patients could be reactivation (usually the HHV-6B variant) or primary infection (usually the HHV-6A variant). Additionally, we have some limited but intriguing observational data demonstrating active HHV-6 viremia in FM, "post-Lyme disease" patients, certain syndromes in HIV patients (encephalopathy, FM, etc.) and Gulf War Syndrome (unpublished data).
[See References – Group III]

IV. IMMUNE DYSFUNCTION AS A RESULT OF CHRONIC ACTIVE HHV-6 INFECTION
Viral induced immune suppression has been documented with numerous viruses including virtually all of the members of the herpes virus family (31). The mechanisms of herpes virus induced immune suppression include: down regulation of MHC protein expression of both Class I and Class II proteins, altered cytokine production and activity, altered T cell recognition, and impaired NK function (31, 32). HHV-6 is immune suppressive, once activated (33). Cells involved in CMI (CD4, CD8 cytotoxic cells, NK cells) are affected either directly or indirectly by HHV-6 (33, 34). Laboratory analysis of immune function in MS and CFS patients has shown abnormal but variable results (35, 36, 37, 38, 39). In the literature, profound abnormality of NK function has been consistently demonstrated in both groups of patients(35, 36, 37, 38, 39). Furthermore, low NK function is inversely correlated with increased disease activity and severity (36, 39). Our group has shown severe NK dysfunction in both CFS and MS patients with active HHV-6 viremia (40). Reports of patients who have low or absent numbers of NK cells clearly demonstrate that these cells are very important for control of herpes virus infections, in that, these patients had severe, recurrent infections with several different herpes viruses (41). With chronic active HHV-6 infection, loss of NK cell activity results in lack of direct viral killing, loss of up regulation of MHC ClassII expression, diminished interferon gamma production, and loss of up regulation of CD4 cells and CD8 cytotoxic cells (34, 35). Thus, the HHV-6 induced immune suppression, of which the most consistent abnormality is marked decrease in NK function, gives rise to chronic ongoing HHV-6 reactivations.
[See References – Group IV]

V. IMMUNE CELL TROPISM
HHV-6 can infect and complete its replication in several different immune cells (42, 43). The virus is cytopathic for both T cells and NK cells (42, 43). Altered cytokine production by HHV-6 infected cells has also been demonstrated (44). As noted above in #4, immune dysfunction has been demonstrated in patients with active HHV-6 infection, and in clinical MS and CFS (particularly NK dysfunction). HHV-6 is then allowed to chronically reactivate. The resultant impairment of immune function, in turn, may lead to reactivation or emergence of other micro-organisms that persist chronically or in a latent state; in effect, opportunists (45, 46, 47, 48, 49). The most obvious example is reactivation of EBV, which has been reported in studies of CFS patients (45, 46). Since EBV is also immune suppressive, it may be playing an additional role in the immune effects on T cell function and NK function (10). Other persistent organisms that could potentially activate in the setting of defective immune functions (NK cell) are chlamydia, mycoplasma, Borrelia burgdorferi, and babesia, among others. Experimental studies have shown the importance of NK cells in immune control of several of these organisms (7, 47, 48, 49). Thus active HHV-6 and the related immune dysfunction may well be associated with "co-activations" of other persistent or latent organisms. The role of these co-infections in symptom production is not clear but raises some interesting questions.
[See References – Group V]

VI. ENDOTHELIAL CELL TROPISM / VASCULOPATHY
HHV-6 has been shown to infect endothelial cells and can establish chronic infection in these cells (50, 51). The infection of the cells can likely alter function of the endothelial cell and the cell surface, thus leading to activation of the coagulation pathways. Several members of the herpes family of viruses, particularly CMV, can infect endothelial cells and induce procoagulant activity (52, 53, 54). Presumably, the same applies to HHV-6, resulting in a hypercoaguable state. A hypercouaguable state has been clearly demonstrated by laboratory analysis of patients with a clinical diagnosis of CFS (55). Several of these patients also had antiphospholipid antibodies present (mainly anti-beta 2 GPI antibodies) (55). This is a curious finding since the antiphospholipid syndrome can be indistinguishable from MS in terms of neurological symptoms and clinical features (e.g. MRI scans) (56). Fibrin deposition, with or without thrombus formation, in turn, leads to various consequences. The resultant vasculopathy and coagulopathy can likely be either diffuse or focal, in terms of vessel involvement. Vascular stasis and impaired flow in the arterial circulation and the capillary bed result in decreased oxygen delivery and focal ischemia. Another consequence of fibrin deposition may be alteration in red blood cell (RBC) morphology and shape (nondiscocitic erythrocytes). Several studies have shown abnormal RBC morphologic changes in patients with CFS (57, 58). These changes are consistent with RBC surface alteration that may have been induced by flow through vessels in which fibrin has been deposited. The altered RBCs also have impaired oxygen carrying capacity and thus can accentuate impaired oxygen delivery (59). Another phenomenon that is commonly seen in CFS patients is a low erythrocyte sedimentation rate (ESR) (60). This may be the result of the fibrin formation and altered RBC surface changes, thereby slowing the rate of sedimentation of the erythrocytes. The endothelial cell involvement and vasculopathy may also give rise to focal vasospasm. Impaired oxygen delivery to tissues has been demonstrated by numerous studies in the CFS and FM literature (61, 62, 63). Muscle ischemia and impaired muscle oxygenation has been reported in several studies in both groups of patients (61, 62, 63). This could give rise to the symptoms of fatigue, decreased activity tolerance, increased symptoms after activity, and muscle pain (excess lactate production). Focal hypoperfusion demonstrated by SPECT scanning of the central nervous system (CNS) has been reported in CFS and FM (64, 65, 66). The diminished CNS perfusion could certainly relate to some of the neurologic and cognitive symptoms commonly reported by CFS and FM patients. Thus, there is ample clinical evidence of impaired oxygen delivery and focal hypoferfusion in these patients. In the venous circulation, the coagulopathy may give rise to venous pooling, stasis, and thrombosis. Clinically, venous flow abnormalities and increased thrombosis is seen with CFS patients (unpublished data). Hereditary coagulation abnormalities may also be involved in a subset of these patients. Several of the hereditary thrombophilias or hypofibrinolysis traits have been found in CFS patients (55). Lastly, it is interesting that vasculitis is one of the early histopathologic changes in the involved CNS tissue of MS patients (67). This entire process (vasculopathy, a hypercoaguable state, impaired oxygen delivery, and venous pooling) may be major factors in symptom production in the patients with the diseases described herein.
[See References – Group VI]

VII. NEUROTROPISM
HHV-6 is probably the most neurotropic of all the herpes viruses (33, 68). HHV-6 infects the CNS during primary infection in childhood (roseola) (68). The virus has been described in numerous reports of encephalitis in the literature (primary infection in children, immune compromised hosts, and individuals with a normal immune system) (69, 70, 71, 72). Several of these infections were fatal (70, 71, 72). Autopsy studies have shown HHV-6 infection in the CNS tissues of patients with MS (73, 74, 75, 76,). HHV-6 can infect oligodendrocytes and microglial cells (77). The virus may have a direct cytopathic effect on the cell or could cause damage by an immunopathogenic mechanism. Activated T cells directed at HHV-6 peptides could give rise to cellular damage and resultant demyelination. There may be a molecular mimicry mechanism involved as well (78). With any of the mechanisms, the associated inflammation and cytokine production probably plays an important role in the pathogenesis of tissue damage (i.e. demyelination) and the clinical consequences. Active HHV-6 infection of the CNS (either seeding from the periphery or reactivation in the CNS) may indeed be very important in MS, whether via a direct effect, an immune mechanism or both.
[See References – Group VII]