This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this proposal is to test the hypothesis that estrogen can decrease HIV viral load by decreasing viral replication. As AIDS is now the third leading cause of death among women ages 25-44, understanding the role that female sex hormones might play in the physiology of HIV-1 infection is especially critical. Many manifestations of HIV differ in women, including that women generally have lower HIV viral loads compared to men at similar stages of disease, and have attenuated or absent disease progression during pregnancy. Conversely, while studies suggest that women may be more vulnerable to certain AIDS-related illnesses, such as HIV dementia and lipodystrophy, there is data strongly suggesting that an estrogen deficient state can be associated with HIV infection. Evaluated as a whole, this clinical evidence indicates that female hormones such as estrogen could act to maintain low viral titers, and suggest that maintenance of serum estradiol levels could decrease the incidence of AIDS-related syndromes. While the mechanisms whereby estrogen modulates HIV infection are still very poorly understood, data from our labs show that estrogen attenuates Tat-induceed transcription at the long-term repeat (LTR) domain of the HIV-1 promoter. These studies are thus designed to use novel molecular, pharmacological, and proteomic tools to determine the mechanisms whereby estrogen modulates HIV replication, with specific emphasis on the role of the multicatalytic proteasome as a convergence point for estrogen and Tat in HIV regulation.
The specific aims are to 1: To test the hypothesis that estrogen has specific negative effects on Tat-induced LTR activation; 2: To test the hypothesis that the effects of estrogen on the HIV-1 LTR are proteasome dependent; and 3: To determine the full proteomic mechanisms whereby estrogen modulates the HIV-1 LTR. Realization of these goals could lead to identification of novel and pertinent protein regulators of HIV-1 replication, the manipulation of which might allow for more precise control over HIV infection in humans.
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