Herpes Viruses Implicated in Alzheimer’s Disease

The brains of Alzheimer’s disease patients have an abnormal build up of amyloid-β proteins and tau tangles, which, according to many researchers, drives the ultimately fatal cognitive disease. This theory is being amended to a newer one, which posits that microbes may trigger Alzheimer’s pathology. Two new studies, using different approaches, further bolster this pathogen theory. Analyzing the transcriptomes of post-mortem brain samples from patients with Alzheimer’s disease, one group of researchers finds that two strains of human herpes virus (Roseoloviruses HHV-6 and HHV-7) are significantly more abundant than in the brains of people of the same age without Alzheimer’s disease. Gene networks in the brains of Alzheimer’s patients with these strains are also rewired such that disease-related genes are differentially expressed compared to controls.

In the other study, another team of investigators observed in mouse models and in a three-dimensional human neuronal cell culture that a Herpesviridae infection could seed amyloid-β plaques.

Activation of Human Herpesvirus Replication by Apoptosis.

 A central feature of herpesvirus biology is the ability of herpesviruses to remain latent within host cells. Classically, exposure to inducing agents like activating cytokines or phorbol esters that stimulate host cell signal transduction events, and epigenetic agents (e.g. butyrate) were thought to end latency. We recently showed that Kaposi's Sarcoma-associated Herpesvirus (KSHV, or Human herpesvirus-8, HHV-8) has another, alternative emergency escape replication pathway that is triggered when KSHV's host cell undergoes apoptosis, characterized by the lack of a requirement for the RTA transcriptional activator, accelerated late gene kinetics, and production of virus with decreased infectivity. Caspase-3 is necessary and sufficient to initiate the alternative replication program. HSV-1 was also recently shown to initiate replication in response to host cell apoptosis. These observations suggested that an alternative apoptosis-triggered replication program might be a general feature of herpesvirus biology and that apoptosis-initiated herpesvirus replication may have clinical implications, particularly for herpesviruses that almost universally infect humans. To explore whether an alternative apoptosis-initiated replication program is a common feature of herpesvirus biology we studied cell lines latently infected with Epstein-Barr Virus/HHV-4, HHV-6A, HHV-6B, HHV-7, and KSHV. We found that apoptosis triggers replication for each HHV studied, with caspase-3 being necessary and sufficient for HHV replication. An alternative apoptosis-initiated replication program appears to be a common feature of HHV biology. We also found that commonly used cytotoxic chemotherapeutic agents activate HHV replication, suggesting that treatments that promote apoptosis may lead to activation of latent herpesviruses, with potential clinical significance.

Association of active human herpesvirus-6, -7 and parvovirus b19 infection with clinical outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome.

Frequency of active human herpesvirus-6, -7 (HHV-6, HHV-7) and parvovirus B19 (B19) infection/coinfection and its association with clinical course of ME/CFS was evaluated. 108 ME/CFS patients and 90 practically healthy persons were enrolled in the study. Viral genomic sequences were detected by PCR, virus-specific antibodies and cytokine levels-by ELISA, HHV-6 variants-by restriction analysis. Active viral infection including concurrent infection was found in 64.8% (70/108) of patients and in 13.3% (12/90) of practically healthy persons. Increase in peripheral blood leukocyte DNA HHV-6 load as well as in proinflammatory cytokines' levels was detected in patients during active viral infection. Definite relationship was observed between active betaherpesvirus infection and subfebrility, lymphadenopathy and malaise after exertion, and between active B19 infection and multijoint pain. Neuropsychological disturbances were detected in all patients. The manifestation of symptoms was of more frequent occurrence in patients with concurrent infection. The high rate of active HHV-6, HHV-7 and B19 infection/coinfection with the simultaneous increase in plasma proinflammatory cytokines' level as well as the association between active viral infection and distinctive types of clinical symptoms shows necessity of simultaneous study of these viral infections for identification of possible subsets of ME/CFS.

Childhood virus infection linked to prolonged seizures with fever

New research shows that human herpesviruses (HHV)-6B and HHV-7, commonly know as roseola virus), account for one third of febrile status epilepticus (FSE) cases. Results of the FEBSTAT prospective study now available in Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy (ILAE), suggest that HHV-6B may be involved in the development of epilepsy and further research is urgently needed.