Molecular Mechanisms of HIV Disease Pathogenesis

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] HIV-1Nef is a 27-34 kDa myristoylated protein that has multiple activities defined in vitro. These include: alterations in signaling with disruption of pro-apoptotic pathways [1-5]; increased viral infectivity; T cell activation; CD28, CD4 and MHC-I downmodulation and protection of infected primary T cells form CTL lysis (for review see [6]). Based on in vivo studies, it is known that an intact nef gene is necessary for the timely development of AIDS [7-9], and in infected monkeys, the ability of Nef to downmodulate MHC-I is an important component of Nef's in vivo activities [10]. In infected people, there have been many reports that MHC-I genotype influences the rate of HIV disease progression (for review see [11]), but to date, this has not been linked to Nef's effects on MHC-I molecules. Preliminary data presented here suggest that polymorphisms in the extracellular domain of MHC-I molecules influence the activity of Nef, and indicate that differential effects of Nef could help explain the genetic data. In addition to Nef's effects on CTL killing, we have also found that CTLs are very sensitive to viral protein expression levels. Specifically changes in Rev that attenuate its activity influence CTL killing by reducing viral protein expression levels and epitope density. The effect of attenuating mutations in rev are apparent even in cells that express Nef and downmodulate MHC-I, so the effects of Nef and an attenuated rev are independent and confer additive protection from CTLs. Studies are proposed to understand the role of MHC-I genetics in HIV disease progression and to demonstrate a clear role for Rev in HIV immune evasion. A complete understanding of the variables that affect CTL recognition of infected cells should help facilitate the development a vaccine and new approaches to the treatment of AIDS. [unreadable] [unreadable]