Showing papers by "Brian Wigdahl published in 2013"

Immunological control of herpes simplex virus infections

Abstract: Herpes simplex virus type 1 (HSV-1) is capable of causing a latent infection in sensory neurons that lasts for the lifetime of the host. The primary infection is resolved following the induction of the innate immune response that controls replication of the virus until the adaptive immune response can clear the active infection. HSV-1-specific CD8+ T cells survey the ganglionic regions containing latently infected neurons and participate in preventing reactivation of HSV from latency. The long-term residence and migration dynamics of the T cells in the trigeminal ganglia appear to distinguish them from the traditional memory T cell subsets. Recently described tissue resident memory (TRM) T cells establish residence and survive for long periods in peripheral tissue compartments following antigen exposure. This review focuses on the immune system response to HSV-1 infection. Particular emphasis is placed on the evidence pointing to the HSV-1-specific CD8+ T cells in the trigeminal belonging to the TRM class of memory T cells and the role of TRM cells in virus infection, pathogenesis, latency, and disease.

Extracellular HIV-1 viral protein R affects astrocytic glyceraldehyde 3-phosphate dehydrogenase activity and neuronal survival

Abstract: Extracellular human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) is a pleiotropic protein accomplishing several functions within the viral life cycle. While Vpr has been described extensively as an intracellular protein, very little is known about its role as an extracellular protein. In fact, HIV-1 Vpr has been detected in the blood, serum, and cerebrospinal fluid of HIV-1-infected patients, with concentrations increasingly higher in late-stage disease. To determine the role exogenous Vpr plays in HIV-associated central nervous system dysfunction, primary human fetal astrocytes were exposed to recombinant Vpr and a time- and dose-dependent decrease was demonstrated in two fundamental intracellular metabolites (adenosine-5′-triphosphate (ATP) and glutathione (GSH)). Additionally, exposure to exogenous Vpr led to increased caspase activity and secretion of proinflammatory cytokines IL-6 and IL-8 and chemoattractants, monocyte chemotactic protein-1, and migration inhibition factor. Extracellular Vpr also dampened the glycolytic pathway through impairment of glyceraldehyde 3-phosphate dehydrogenase activity, causing a decline in the levels of ATP. The reduction in intracellular ATP increased reactive oxygen species buildup, decreasing GSH concentrations, which affected several genes in the oxidative stress pathway. In addition, exposure of the SK-N-SH neuroblastoma cell line to conditioned medium from exogenous Vpr-treated astrocytes decreased synthesis of GSH, leading to their apoptosis. These observations point to a role that Vpr plays in altering astrocytic metabolism and indirectly affecting neuronal survival. We propose a model that may explain some of the neurological damage and therefore neurocognitive impairment observed during the course of HIV-1 disease.

Global NeuroAIDS roundtable

Abstract: In May 2012, the Division of AIDS Research at the National Institute of Mental Health (NIMH) organized the "Global NeuroAIDS Roundtable" in conjunction with the 11th International Symposium on Neurovirology and the 2012 Conference on HIV in the Nervous System. The meeting was held in New York, NY, USA and brought together NIMH-funded investigators who are currently working on projects related to the neurological complications of AIDS (NeuroAIDS) in Africa, Asia, Eastern Europe, and Latin America in order to provide an opportunity to share their recent findings and discuss the challenges encountered within each country. The major goals of the roundtable were to evaluate HIV-associated neurocognitive impairment and determine if it may be directly attributable to distinct HIV subtypes or clades and to discuss the future priorities for global NeuroAIDS research. At the "Global NeuroAIDS Roundtable", presentations of preliminary research indicated that HIV-associated neurocognitive impairment is prevalent in all countries examined regardless of which HIV clade is present in the region. The only clear-cut difference between HIV-1 clades was in relation to subtypes A and D in Uganda. However, a key point that emerged from the discussions was that there is an urgent need to standardize neurocognitive assessment methodologies across the globe before definitive conclusions can be drawn regarding the relationship between HIV clade diversity and neuropathogenesis. Future research directions were also discussed at the roundtable with particular emphasis on the potential of viral and host factor molecular interactions to impact the pathophysiology of HIV-associated neurocognitive disorders (HAND) from a global perspective.

Genetic variation and HIV-associated neurologic disease.

Abstract: HIV-associated neurologic disease continues to be a significant complication in the era of highly active antiretroviral therapy. A substantial subset of the HIV-infected population shows impaired neuropsychological performance as a result of HIV-mediated neuroinflammation and eventual central nervous system (CNS) injury. CNS compartmentalization of HIV, coupled with the evolution of genetically isolated populations in the CNS, is responsible for poor prognosis in patients with AIDS, warranting further investigation and possible additions to the current therapeutic strategy. This chapter reviews key advances in the field of neuropathogenesis and studies that have highlighted how molecular diversity within the HIV genome may impact HIV-associated neurologic disease. We also discuss the possible functional implications of genetic variation within the viral promoter and possibly other regions of the viral genome, especially in the cells of monocyte–macrophage lineage, which are arguably key cellular players in HIV-associated CNS disease.

Epigenetics, drugs of abuse, and the retroviral promoter.

Abstract: Drug abuse alone has been shown to cause epigenetic changes in brain tissue that have been shown to play roles in addictive behaviors. In conjunction with HIV-1 infection, it can cause epigenetic changes at the viral promoter that can result in altered gene expression, and exacerbate disease progression overall. This review entails an in-depth look at research conducted on the epigenetic effects of three of the most widely abused drugs (cannabinoids, opioids, and cocaine), with a particular focus on the mechanisms through which these drugs interact with HIV-1 infection at the viral promoter. Here we discuss the impact of this interplay on disease progression from the point of view of the nature of gene regulation at the level of chromatin accessibility, chromatin remodeling, and nucleosome repositioning. Given the importance of chromatin remodeling and DNA methylation in controlling the retroviral promoter, and the high susceptibility of the drug abusing population of individuals to HIV infection, it would be beneficial to understand the way in which the host genome is modified and regulated by drugs of abuse.

Impact of age on markers of HIV-1 disease.

Abstract: Aging is a complicated process characterized by a progressive loss of homeostasis, which results in an increased vulnerability to multiple diseases. HIV-1-infected patients demonstrate a premature aging phenotype and develop certain age-related diseases earlier in their lifespan than what is seen in the general population. Age-related comorbidities may include the development of bone disease, metabolic disorders, neurologic impairment and immunosenescence. Age also appears to have an effect on traditional markers of HIV-1 disease progression, including CD4+ T-cell count and viral load. These effects are not only a consequence of HIV-1 infection, but in many cases, are also linked to antiretroviral therapy. This review summarizes the complex interplay between HIV-1 infection and aging, and the impact that aging has on markers of HIV-1 disease.