Research

A Multi-Systems Study of HIV Neuropathogenesis: Genetics-Neuropathology-Behavior

Agency: NIH/NIMH/UCLA

Agency Award Number: R01MH096648

All studies of HAND-related genetic susceptibility loci have relied solely on clinical outcomes; nothing is known of what pathophysiological changes these genetic variants cause. An innovative approach for determining the pathophysiological mechanisms through which genetic susceptibility loci influence HAND is to examine their influence on neuropathological intermediate phenotypes, or NIPs. At its most basic level, HAND is believed to be the end result of a sequence of physiological events that commences with HIV-induced cellular changes that are modified by genetic factors. In the context of the present study, we deem quantifiable neuropathological changes that occur proximal to the beginning of this causal chain of HAND pathogenesis as the NIPs necessary for the behavioral impairments characteristic of HAND. There exist a number of candidate NIPs that are associated with HAND, including synaptodendritic simplification; macrophage infiltration; microglial and astrocyte activation, and beta-amyloid deposition. Through examining the relationship between genetic susceptibility loci and NIPs in brain tissue derived from a clinically well-characterized cohort, it will be possible t determine 1) which genetic variants are biologically relevant to HAND, 2) the pathophysiological mechanisms through which they exert their effect on the neurobehavioral phenotypes, and 3) the relative importance of NIPs as underlying causative factors of HAND.