Human herpesvirus 6 and epilepsy.

We investigated the association between human herpesvirus 6 (HHV-6) and mesial temporal sclerosis (MTS) in 87 patients who had surgery for drug-resistant epilepsy. Fifty-four had MTS, 22 focal cortical dysplasia (FCD), four tumors, three vascular malformations, and three a history of encephalitis. We extracted DNA from fresh brain tissue immediately after surgery and performed viral detection with quantitative real-time polymerase chain reaction (PCR) or digital droplet PCR specific for HHV-6A and HHV-6B. Tissue was studied with standard clinical techniques, including hematoxylin and eosin, glial fibrillary acidic protein, and NeuN stains. Twenty-nine of 54 patients with MTS, six of 23 with focal cortical dysplasia (FCD), and one of three with a history of encephalitis were positive for HHV-6 (P < .02). Febrile seizure history was not associated with HHV-6 detection. Patients with MTS had significantly lower seizure onset age than those with other pathologies. Thirteen patients had positron emission tomography with [11C]PBR28, a marker for reactive astrocytes and activated microglia; there was a trend for HHV-6-positive patients to have higher binding in their seizure foci, suggesting inflammation. Our study supports a potential role for HHV-6 in the etiology of MTS.

Prevalence of salivary human herpesviruses in pediatric multiple sclerosis cases and controls.

BACKGROUND: Multiple sclerosis (MS) is a multifactorial disease of unknown origin. The current paradigm is that disease develops in genetically susceptible individuals, influenced by environmental factors. Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have particularly strong associations with the disease. Both viruses are typically acquired during childhood, decades before MS presents. However, in patients with pediatric MS, the temporal window between viral acquisition and disease onset is shortened, which may provide insights into the association of herpesviruses with MS. OBJECTIVE: To compare the frequency of EBV and HHV-6 in the saliva of a cohort of pediatric MS patients and age-matched controls. METHODS: The study enrolled 32 pediatric MS patients and 42 controls and evaluated saliva for HHV-6 u57 and EBV lmp-1 amplification by droplet digital polymerase chain reaction (ddPCR). RESULTS: Pediatric MS patients did not differ from controls in the frequency or magnitude of salivary viral shedding. During the assessment of EBV positivity, distinct profiles emerged that correlated with target amplicon mutations. CONCLUSIONS: None of these mutations were evident in EBV-positive samples from pediatric MS patients, whereas they were present in pediatric controls, in addition to MS and control adults, suggesting differential host-immune control of EBV in this pediatric MS cohort.

Herpesvirus trigger accelerates neuroinflammation in a nonhuman primate model of multiple sclerosis.

Pathogens, particularly human herpesviruses (HHVs), are implicated as triggers of disease onset/progression in multiple sclerosis (MS) and other neuroinflammatory disorders. However, the time between viral acquisition in childhood and disease onset in adulthood complicates the study of this association. Using nonhuman primates, we demonstrate that intranasal inoculations with HHV-6A and HHV-6B accelerate an MS-like neuroinflammatory disease, experimental autoimmune encephalomyelitis (EAE). Although animals inoculated intranasally with HHV-6 (virus/EAE marmosets) were asymptomatic, they exhibited significantly accelerated clinical EAE compared with control animals. Expansion of a proinflammatory CD8 subset correlated with post-EAE survival in virus/EAE marmosets, suggesting that a peripheral (viral?) antigen-driven expansion may have occurred post-EAE induction. HHV-6 viral antigen in virus/EAE marmosets was markedly elevated and concentrated in brain lesions, similar to previously reported localizations of HHV-6 in MS brain lesions. Collectively, we demonstrate that asymptomatic intranasal viral acquisition accelerates subsequent neuroinflammation in a nonhuman primate model of MS.

Development of neurologic diseases in a patient with primate T lymphotropic virus type 1 (PTLV-1).

BACKGROUND: Virus transmission from various wild and domestic animals contributes to an increased risk of emerging infectious diseases in human populations. HTLV-1 is a human retrovirus associated with acute T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 originated from ancient zoonotic transmission from nonhuman primates, although cases of zoonotic infections continue to occur. Similar to HTLV-1, the simian counterpart, STLV-1, causes chronic infection and leukemia and lymphoma in naturally infected monkeys, and combined are called primate T-lymphotropic viruses (PTLV-1). However, other clinical syndromes typically seen in humans such as a chronic progressive myelopathy have not been observed in nonhuman primates. Little is known about the development of neurologic and inflammatory diseases in human populations infected with STLV-1-like viruses following nonhuman primate exposure. RESULTS: We performed detailed laboratory analyses on an HTLV-1 seropositive patient with typical HAM/TSP who was born in Liberia and now resides in the United States. Using a novel droplet digital PCR for the detection of the HTLV-1 tax gene, the proviral load in PBMC and cerebrospinal fluid cells was 12.98 and 51.68 %, respectively; however, we observed a distinct difference in fluorescence amplitude of the positive droplet population suggesting possible mutations in proviral DNA. A complete PTLV-1 proviral genome was amplified from the patient's PBMC DNA using an overlapping PCR strategy. Phylogenetic analysis of the envelope and LTR sequences showed the virus was highly related to PTLV-1 from sooty mangabey monkeys (smm) and humans exposed via nonhuman primates in West Africa. CONCLUSIONS: These results demonstrate the patient is infected with a simian variant of PTLV-1, suggesting for the first time that PTLV-1smm infection in humans may be associated with a chronic progressive neurologic disease.