May 12, 2006
Mechanisms of HIV Neuropathogenesis: Emerging Domestic and Global Issues
NAMHC Concept Clearance
Jeymohan Joseph, Ph.D.
Chief, Mechanisms of HIV Neuropathogenesis Program
Chief, Viral and Host Genetics Program
Center for Mental Health Research on AIDS
Division of AIDS and Health and Behavior Research
As treatment with HAART (highly active anti-retroviral therapy) enables people with HIV to live longer, the nature of associated central nervous system (CNS) disease is changing; for example, frequency of milder, more chronic forms is rising. Emerging data also suggest genetic differences in HIV's ability to cause dementia in different regions of the world. One component of this initiative would focus on mechanisms that regulate the pathogenesis of milder and chronic forms of HIV-associated CNS disease resulting from long-term treatment and associated confounding factors. A second component would focus on viral and host genetic factors that may account for possible worldwide differences in the incidence of HIV-associated dementia. Data from this proposed initiative are intended to provide opportunities for developing novel treatments that target the CNS, by increasing understanding of these issues.
Examples of research topics in the first area of focus would include impact of low CNS levels of viral replication and immune activation on HIV neuropathogenesis, in the context of high CD4 counts in periphery; identification of novel biomarkers in milder and chronic forms of HIV dementia; factors that regulate the fluctuating patterns of CNS symptomatology that are occurring in the HAART era; mechanisms that regulate hepatitis C-associated neurocognitive impairments in HIV/hepatitis C co-infection; the role of aging-associated events, such as hyperlipidemia and increased β-amyloid levels; effects of antiretrovirals on CNS functions, including the role of mitochondrial toxicity; and mechanisms that regulate development of CNS-associated immune reconstitution syndromes. Research topics in the second area of focus would include incidence and prevalence of HIV-associated dementia in different regions of the world where distinct clades predominate, as well as potential involvement of host genetic factors in these regions, and identification of unique molecular motifs associated with the virus that may contribute to clade differences in induction of HIV dementia.