RESEARCH

Human Herpes Virus 6 (HHV-6) and Disease by Cort Johnson (June 2008)

HHV-6A and B: Two Variants or Two Viruses?

For years HHV-6A was believed to simply be a variant of HHV-6. Increasing evidence suggests, however, that not only does HHV-6A vary from HHV-6B but that it is very different indeed: differences in mode of transmission, prevalence, types of infection, types of cells infected etc. suggest to some researchers that it’s only a matter of time before these viruses are formally differentiated into different species. Most studies, however, still collapse the distinction between the two and simply study ‘HHV-6’ (Mirandola et. al 1998, Campadelli-Fiume 1999).

Types of Infection - Both HHV-6A and B are found throughout the brain but HHV-6A appears to have greater potential for central nervous system damage. HHV-6A, for instance, appears to be more commonly found in the cerebrospinal fluid (CSF) of AIDS and multiple sclerosis patients while HHV-6B is more frequently found in the cerebrospinal fluid (CSF) of healthy controls (Ahlqvist et al. 2005).

Several lab studies indicate HHV-6A is more effective at producing (re-)productive infections in immune and central nervous system (CNS) cells. An in vitro study found HHV-6A but not HHV-6B was able to infect, kill and establish a latent infection in nerve cells called oligodendrocytes (Ahlqvist et al. 2005). An ex vivo study found HHV-6A to be more effective in mounting productive infections in cytotoxic T-cells and was more able to easily infect natural killer cells (NK) (Grivel et al. 2003). Ablashi asserts that HHV-6A is the predominant strain in CFS, multiple sclerosis (MS) and AIDS patients.

HHV-6B is the strain most commonly reactivated during organ and stem cell transplantation and is also increased in virally derived encephalitic (central nervous system) conditions (Dewhurst 2004). A recent study employing real-time PCR found HHV-6B was found in most healthy controls, transplant and AIDS patients. HHV-6A was more commonly found in patients with central nervous system (CNS) dysfunctions (Boutolleau et.al. 2005). Primary Infection – HHV-6B is spread in the saliva and almost everyone carries the virus by their second year. Most primary HHV-6B infections in infants and children, while sometimes causing high fever and/or rash, are benign and resolve themselves without incident. Primary HHV-6B infection in children is, however, believed to cause febrile seizure and have severe CNS complications (encephalitis, meningitis, ataxia, learning disabilities) in rare cases. Febrile seizure is a seizure associated with high fever.

Latency - After the initial infection both HHV6A and B can persist in a latent state or in a state of chronic low-level replication for decades. HHV-6B is believed to hide out in its latent phase in PBMCs, monocytes and the bone marrow progenitor cells. The salivary glands and brain tissues appear to be sites of persistent HHV-6A infection.

A Widespread Infection - In vitro tests indicate HHV-6 can infect many different cell types including dendritic cells, NK cells and fibroblasts as well as liver, epithelial and endothelial cells and the glial cells in the brain (astrocytes, oligodendrocytes, microglia). The HHV6 genome has been detected in brain, liver, skin, lungs, kidneys, heart, tonsils, salivary glands, esophagus, etc. It is believed to make its way to the brain on board T lymphocytes able to penetrate the blood:brain barrier.

Although HHV-6 is able to infect many cells, in only a few is it able to progress to the ‘lytic phase’. (The lytic phase occurs when a virus enters the cells and uses its DNA to produce virions which usually end up killing the cell, allowing them to escape en masse.) HHV-6 can replicate in B cells and NK cells but productive HHV-6 infection is believed to be confined to T lymphocytes, in particular in T-helper (CD4+) cells, monocytes/macrophages, neurons, astrocytes and oligodendrocytes (Kakimoto et al. 2002, Grivel et al. 2003, Fotheringham et al. 2008)).

In even the most productive infections, however, viral yields are low compared to other infections (Campadelli-Fiume et al. 1999). This limits the amount of virus present in the bloodstream and has complicated efforts to characterize its effects. (See The Difficulties of Diagnosis).

Two central questions absorb HHV-6 researchers. Is the pathogen associated with a specific disease? If so is it an opportunistic invader or does it cause the disease? Controversy and dissatisfaction with the current testing methodologies suggests that the true extent of HHV-6 infection is unknown. A clear understanding of the effects of HHV-6A infection awaits better testing procedures.

HHV-6 and Disease (HHV-6 and Chronic Fatigue Syndrome (ME/CFS) is found in Part I)

Organ Transplantation – Several of the serious effects of HHV-6 infection are associated with the immunosuppression that occurs during organ transplantation (Campadelli-Fiume et al. 1999). HHV-6B reactivation commonly occurs (25-75%) during these procedures and much HHV-6 research is concentrated on organ transplantation (De Bolle et al. 2005). A recent study utilizing real-time PCR found 17% of samples from bone marrow transplant patients tested positive for HHV-6 (97% - HHV-6B) (Reddy and Manna 2005).

While reactivation during organ transplantation is common HHV-6’s effects - usually consisting of nothing more than a fever and rash (and often that not even visible) - are usually benign (Caserta et al. 2003, Ward 2005). Bone marrow suppression, transplant rejection, liver failure, pneumonitis and encephalitis may, however, be associated with HHV-6 reactivation in a small percentage of transplant patients. CNS complications were significantly more likely in liver transplant patients with evidence of HHV-6 reactivation than in those without it.

The case for HHV-6B in organ transplantation is clear. Most organ transplant patients in the U.S. are now given antiviral drugs (valganciclovir) to suppress the possibility of viral reactivation during this procedure (HHV-6 Foundation Disease Overview).

A Co-factor in other Diseases – HHV-6 may be a co-factor in a wide array of immunological disorders including infectious mononucleosis, hepatitis, multiple sclerosis, meningoencephalitis and pneumonitis (Flammond et al. 1993).

HIV-AIDS - The idea that HHV-6 is able to catalyze HIV activity and patients’ progression to AIDS was proposed early in the AIDS epidemic. HHV-6A is able to produce productive infections in T-helper cells, the same cells HIV targets, and it upregulates the expression of the primary HIV receptor CD 4. HHV-6 infection is commonly found in AIDS patients.

Epidemiological studies have not thus far, however, indicated that HHV-6 infection speeds the progression of AIDS. A report from the International 2007 HHV-6/7 Conference indicated, however, that primates infected with both HHV-6A and SIV (primate HIV) progressed to death faster and the subject remains open.

Herpesvirus Reactivation - In vitro studies indicate that HHV-6 infection of B-cells triggers the production of a nuclear protein (called Zebra) that turns on genes which are active early in the life cycle of the Epstein-Barr herpesvirus (EBV). Since one of the genes plays a crucial role in switching EBV from latency to activity, HHV-6 has been proposed to reactivate EBV (Flammand et al. 1993). HHV-6 also reactivates the cytomegalovirus herpesvirus (HCMV). As in AIDS, HCMV patients often exhibit HHV-6 reactivation but it does not appear to negatively affect the progression of their disease (Caserta et al. 2003). Nor does HHV-6 infection appear to increase the risk of mycoplasma or chlamydiae infection in chronic fatigue syndrome patients (Nicholson et al. 2003).

HHV-6 and the Central Nervous System - HHV-6’s dangers have long been thought to be primarily neurological. Found in many parts of the brain, HHV-6 has been proposed to be a co-factor in at least nine neurological diseases including Gullain-Barre Syndrome, Bell’s palsy and multiple sclerosis.

HHV-6 reactivation has been documented in small subsets of patients in several diseases. As noted earlier, most cases of HHV-6 reactivation are benign; even though the virus is present and replicating, patients remains asymptomatic in most cases. A PCR finding of HHV-6B DNA in the cerebrospinal fluid (CSF) does not, therefore, necessarily indicate a significant pathological process is occurring. HHV-6B DNA has been found in the CSF of immunocompromised patients who did not display neurological symptoms (Dewhurst 2004). Tavokoli suggests, however, that in patients with the appropriate clinical presentation positive PCR tests of the spinal fluid are highly significant (Tavokoli et al. 2007)

Seizures and encephalitis/meningitis  - HHV-6 is commonly found (20-40%) in febrile seizure patients. The incidence of HHV-6B infection in both febrile seizure patients and healthy controls is, however, the same and some febrile seizure patients show no evidence of HHV-6 CNS infection (Dewhurst 2004). Several recent studies have concluded, though, that HHV-6B is the likely cause of CNS damage (encephalopathy, etc.) in some children (Mannonen et al. 2007, Tavokoli et al. 2007).

PCR evidence of HHV-6 infection was found in approximately 2% of patients hospitalized with symptoms of encephalitis or meningitis. These patients generally demonstrated an abnormal cerebrospinal fluid profile (increased protein levels and white blood cell counts) (Tavokoli et al. 2007).

HHV-6A and Multiple Sclerosis - The strongest evidence of HHV-6’s potential to cause central nervous damage concerns HHV-6A and multiple sclerosis.

The detection of HHV-6 antigens in the oligodendrocytes, astrocytes, microglia and neurons in patients with MS and HHV-6 encephalopathy indicates HHV-6 reactivation may be associated with these diseases (Yoshikawa and Asano 2000). While both HHV-6A and B can infect astrocytes only HHV-6A is able to establish a productive infection in them. Astrocytes provide a protective function through their uptake of the amino acid glutamate, an excitatory neurotransmitter able to cause cell death (‘excitotoxicity’) at high levels. Reduced glutamate uptake in HHV-6A infected astrocytes suggests HHV-6A could cause central nervous system cell death.

Increased glutamate levels have been associated with symptom exacerbation in MS. High glutamate levels due to poorly performing HHV-6A infected astrocytes have been proposed to explain the lesions seen in MS. (Fotheringham et al. 2008). These lesions are formed by dead oligodendrocyte cells. A 2006 study finding that HHV-6A is able to induce oligodendrocytes to commit suicide provided another mechanism of HHV-6A induced cell death (Gardell et al. 2006)

Both oligodendrocytes and astrocytes originate from cells called glial precursor cells (GPCs) that appear to be underactive in demyelinating diseases such as MS. A recent in vitro study indicating HHV-6 is able to infect, replicate in and profoundly alter the morphology of GPCs suggested it may play a role in the demylinating process in MS (Dietrich et al. 2004).

HHV-6 also appears to tilt the production of a kind of oligodendrocyte that is particularly vulnerable to TNF-a, a pro-inflammatory cytokine found in MS lesions (Dietrich et al. 2004). Despite these effects HHV-6A infection did not result in increased GPC mortality. The authors noted, however, that several neurotropic viruses are able to disrupt cell functioning without altering cell survival.

HHV-6 and the Immune System – While most researchers have been concerned with HHV-6’s effects on the CNS, recent studies suggest several ways HHV-6 is able to alter immune functioning. HHV-6 enters cells through a ubiquitous protein called CD 46 that spans the outer membranes on almost all cells. This transmembrane protein protects them from being attacked during complement activation and plays a role in T-cell stimulation and nitric oxide (NO) production by macrophages.

Simply by binding to the CD 46 receptor HHV-6A appears able to down-regulate it possibly increasing the risk of tissue damage during immune activation. A parallel down regulation by HHV-6 of another receptor (CD3) involved in T-cell stimulation could result in immune suppression.

CD46 binding also inhibits the Th1 immune response (Smith et al. 2005). HHV-6 infected dendritic cells demonstrated a marked reduction in their ability to stimulate T cells and were associated with a ‘trend’ towards reduced TNF-a and increased IL-10 production (Smith et al. 2005). Dendritic cells are the main antigen presenting cells (APC’s) in the body. Several studies have found increased IL-10 production in ME/CFS.

HHV-6A and the Blood Vessels - HHV-6A infection of the endothelial cells lining the blood vessels could cause a central nervous system vasculitis. Vasculitis - the inflammation of a blood or lymph vessel - can cause reduced blood flow. Researchers proposed that the low blood flow to the basal ganglia in a case of HHV-6 encephalopathy was due to an HHV-6 caused vasculitis. Brain scans and other evidence suggest to Dr. Hyde that vasculitis of the CNS and other parts of the body plays a major role in CFS (Click here). In vitro studies that indicate HHV-6 can infect the endothelial cells which line the blood vessels suggest it could induce vasculitis.

HHV-6A induces T-cells to fuse together form giant polynucleate cells (Mori et al. 2002). A recent study indicated HHV-6A is able to induce cellular fusion simply by binding with the CD 46 protein. Since epithelial and endothelial cells appear most at risk from this process it is possible HHV-6 can alter blood vessel functioning as it travels through the blood stream.

Part I: HHV-6 and CFS - An Overview /  Part II: CFS and HHV-6 -The Difficulties of Diagnosis
_____________________________________
Ablashi, D. Balachandran,N., Josephs, S., Hung, C., Drueger, G. and B. Karansky. 1991. Genomic polymorphism, growth properties and immunologic variations in human herpes virus-6 isolates. Virology 184, 545-52.

Ablashi, D., Eastman, H., Owen, C., Roman, M., Friedman, J., Zabriskie, J., Peterson, D., Pearson, G. and J. Whitman. 2000. Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. Journal of Clinical Virology 36, 179-191.

Ahlqvist, J., Fotheringham, J., Akhyani, N., Yao, K., Fogdell-Hahn, A. and Steven Jacobsen. 2005. Differential tropism of human herpesvirus 6 (HHV-6) variants and induction of latency by HHV-6A in oligodendrocytes. Journal of NeuroVirology 11, 384-394.

Alvarez-Lafuente, R., De las Heras, V., Bartolome, M., Picazo, J. and R. Arroyo. 2004. Relapsing-remitting multiple sclerosis and human herpesvirus 6 active infection. Arch Neur. 61, 1523-1525.

Baraniuk, J., Casado, B., Maibach, H., Clauw, D., Pannell, L. and S. Hess. 2005. A chronic fatigue syndrome – related proteome in human cerebrospinal fluid. BMC Neurology,

Boutolleau, D., Duros, C., Bonnafous, P., Caiola, D., Karras, A., Castro, N., Ouachee, M., Narcy, P., Gueudin, M., Agut, H. and A. Gautheret-Dejean. 2005. Identification of human herpesvirus 6 variants A and B by primer-specific real-time PCR may help to revisit their respective role in pathology. Clin. Virol, Sept 21, (Epub ahead of print).

Buchwald, D., Cheney, P. and D. Peterson. 1992. A chronic illness characterized by fatigue, neurologic and immunologic disorders and active herpesvirus type 6 infection. Ann. Intern. Med. 116, 103-113.

Campadelli-Fiume, Mirandola, P. and L. Menotti. 1999. Human herpesvirus 6; an emerging pathogen. Emerging Infectious Diseases 5,

Caserta MT, Mock DJ, Dewhurst S. 2001. Human herpesvirus 6. Clin Infect Dis. 33(6):829-33.. Review.

Chapenko, S., Krumina, A., Kozireva, S., Nora, Z., Slutanova, A., Viksna, L. and M. Murovska. 2006. Activation of human herpesviruses 6 and 7 in patients with chronic fatigue syndrome. Journal of Clinical Virology 37 Suppl. 1 S47-S51.

De Bolle, L., Naesens, L. and E. De Clercq. 2005. Update on human herpesvirus 6 biology, clinical features and therapy. Clinical Microbiology Reviews 18, 217-245.

Derfuss, T., Hohlfiled, R and E. Meinl. 2005. Intrathecal antibody (IgG) production against human herpesvirus type 6 occurs in about 20% of MS patients and might be linked to a polyspecific B-cell response. J. Neurology 252, 968-77.

Dewhurst, S. 2004. Human herpesvirus type 6 and human herpesvirus type 7 infections of the central nervous system. Herpes 11, 105A-111A.

Dietrich, J., Blumberg, B. Roshal, M., Baker, J., Hurley, S., Mayer-Proschel, M. and D. Mock. 2004. Infection with an endemic human herpesvirus disrupts critical glial precursor cell properties. The Journal of Neuroscience 24, 4875-4883.

Flamand, L., Stefanescu, I., Ablashi, D. and J. Menezes. 1993. Activation of the Epstein-Barr virus replicative cycle by human herpesvirus 6. Journal of Virology 67, 6768-6777.

Fotheringham, J. and S. Jacobsen. 2005. Human herpesvirus 6 and multiple sclerosis: potential mechanisms for disease. Herpes 12, 1-9.

Fotheringham, J, Williams, E., Akhyani, N. and S. Jacobsen. 2008. Human herpesvirus 6 (HHV-6) induces dysregulation in glutamate uptake and transporter expression in astrocytes. J. Neuroimmune Pharmacol 3: 105-116.

Gardell, J., Dazin, P., Islar, J., Menge, T., Genain, C. and P. Lalive. 2006. Apoptotic effects of human herpesvirus -6A on glia and neurons as potential triggers for central nervous system autoimmunity. Journal of Clinical Virology 237 Supp. S11-S16.

Glaser R, Padgett DA, Litsky ML, Baiocchi RA, Yang EV, Chen M, Yeh PE, Klimas NG, Marshall GD, Whiteside T,

Herberman R, Kiecolt-Glaser J, Williams MV. 2005. Stress-associated changes in the steady-state expression of latent Epstein-Barr virus: implications for chronic fatigue syndrome and cancer. Brain Behav Immun. 19:91-103.

Grivel, J-C., Santoro, F., Chen, S., Faga, G., Malnati, M., Ito, Y., Margolis, L. and P. Lasso. 2003. Pathogenic effects of Human Herpesvirus 6 in human lymphoid tissue ex vivo. Journal of Virology 77, 8280-8289.

Koelle, D., Barcy, S., Huang, M., Ashley, R., Corey, L., Zeh, J., Ashton, S. and D. Buchwald. 2002. Markers of viral infection in monozygotic twins discordant for chronic fatigue syndrome. Clinical Infectious Diseases 35, 518-525.

Lerner AM, Beqaj SH, Deeter RG, Dworkin HJ, Zervos M, Chang CH, Fitzgerald JT, Goldstein J, O'Neill W. 2002. A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs Today (Barc).38(8):549-61

Lussso, P. 2006. HHV-6 and the immune system: mechanisms of immunomodulation and viral escape. Journal of Clinical Virology 37 Suppl. S4-S10.

Mannonen, L. et al. 2007. Primary human herpesvirus-6 infection in the central nervous system can cause severe disease. Pediatric Neurology 37, 186-191.

Meeuwsen, S., Persoon-Deen, C., Bsibsi, M., Bajramovic, J., Ravid, R., De Bolle, L. and J. van Noort. 2005. Modulation of the cytokine network in human adult astrocytes by human herpesvirus-6A. Journal of Neuroimmunology 164, 37-47.

Mirandola, P., Menegassi, P., Merighi, S., Ravaioli, T., Cassai, E. and D. DiLuca. 1998. Temporal mapping of transcripts in Herpesvirus 6 variants. Journal of Virology 72, 3837-3844.

Mori, Y., Seya, T., Huang, H., Akkapaiboon, P., Dhepakson, P. and K. Yamanishi. 2002. Human herpesvirus 6 variant A but not variant B induces fusion from without in a variety of human cells through a human herpesvirus 6 entry receptor, CD 46. Journal of Virology 76, 6750-6761.

Nicolson, G., Gan R. and J. Haier. 2003. Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS 111: 557–66.

Opsahl, M. and P. Kennedy. 2005. Early and late HHV-6 transcripts in multiple sclerosis lesions and normal appearing white matter. Brain 128, 516-527.

Reddy, S. and P. Manna. 2005. Quantitative detection and differentiation of human herpesvirus 6 subtypes in bone marrow transplant patients by using a single real-time polymerase chain reaction assay. Biol Blood Marrow Transplant 11, 530-541.

Reeves, W., Stamey, F.,Black, J., Mawle, A., Stewart, J. and P. Pellett. 2000. Human herpesviruses 6 and 7 in chronic fatigue syndrome: a case-control study. Clinical Infectious Diseases 31, 48-52.

Simmons, A. 2001. Herpesviruses and multiple sclerosis. Herpes 8, 60-63.

Smith, A., Paolucci, C., Di Lullo, G., Burastero, S., Santoro, F. and P. Lusso. 2005. Viral replication-independent blockade of dendritic cell maturation and interleukin-12 production by human herpesvirus 6. Journal of Virology 79, 2807-2813.

Soto, N. and S. Straus. 2000. Chronic fatigue syndrome and herpesviruses: fading evidence. Herpes 7, 46-51.
Stuve, Ol, Racke, M. and B. Hemmer. Viral pathogens in multiple Sclerosis; an intriguing history.Arch. Neurol. 61, 1500-1503.

Swanborg, R., Whittum-Hudson, J. and A. Hudson. 2002. Human herpesvirus 6 and Chlamydia pneumoniae as etiologic agents in multiple sclerosis – a critical review. Microbes and Infection 4, 1327-1333.

Tavakoli, N., Nattanmai, S, Hull, R., Fusco, H., Dzigua, L., Wang, H. and M. Dupuis. 2007. Detection and typing of HHV-6 by molecular methods in specimens from patients diagnosed with encephalitis or meningitis. Journal of Clinical Microbiology 45, 3972-3978.

Wallace, H., Natelson, B., Gause, W. and J. Hay. 1999. Human herpesviruses in chronic fatigue syndrome. Clinical and Diagnostic Laboratory Immunology 6, 216-222.

Ward, K. 2005. The natural history and laboratory diagnosis of human herpesvirus-6 and -7 infections in the immunocompetent. Journal of Virology 32, 183-193.

Yoshikawa, T and Y. Asano. 2000. Central nervous system complications in human herpesvirus-6 infection. Brain and Development 22, 307-314