In vivo Consequences of VIf anatgonism

Mansfield, Keith

Abstract

In this application we propose the development of small molecule inhibitors of the HIV Vif protein.While Vif has been recognized as an important gene for viral infectivity, the cellular mechanismresponsible for this effect has only recently been elucidated. Vif functions to inactivate the cellulardefense protein APOBEC 3G which otherwise induces deamination of viral DNA rendering itnoninfectious. Our previous work in vaccine development has demonstrated the crucial in vivosignificance of Vif to viral replication in the rhesus macaque and supports the relevance of this drugtarget. The University of Massachusetts Medical School (UMMS) established a high throughput drugscreening facility in order to identify lead compounds with activity against HIV/SIV Vif. As part of thisventure, a large chemical library has been screened for anti-Vif compounds using a cell-based inhibitorscreen and a number of lead compounds have been identified that have the potential to target peripheraland CNS reservoirs of HIV-1 replication and persistence. The proposed work will facilitate the furtherdevelopment of these Vif inhibiting agents. The application brings together a collaborative team withdiverse expertise in medicinal chemistry, molecular virology, and in vivo systems to examine the clinicalpotential of such inhibitors.Our objective is to utilize pharmacokinetic and efficacy studies in rodent species in a leadoptimization approach reserving proof-of-principal studies in nonhuman primates to the most promisingdrug candidates. Long term efficacy studies will allow us to examine the effect of Vif inhibitors on plasmaviral load and markers of immunodeficiency as well as to evaluate the effect of drug treatment on SIVencephalitis, a lentiviral specific disease process. To accomplish these goals we propose the followingspecific aims:
Specific aim 1 : To define the pharmacokinetic and safety profile of novel Vif inhibitors in rodentsand rhesus macaques.
Specific aim 2 : To examine the short term in vivo effect of Vif inhibitors on viral replication andcellular reservoirs in rodent and rhesus macaque models of HIV infection.
Specific aim 3 : To examine the efficacy of Vif inhibitors on biomarkers of CNS inflammation andmorphologic evidence of CNS pathology in an SIV-macaque model of neuroAIDS.