Since it has proven difficult to develop a vaccine against HIV-1, the major cause of the AIDS pandemic, the research community has shifted some of its focus to the development of topical microbicides. Since both the vaginal and rectal tract are portals of HIV-1 entry, topical microbicides suitable to protect both sites need to be developed. In this grant, we focus on a novel mechanism that has not previously been explored for HIV prevention. In 2002, it was found that the cellular target of the HIV-1 protein Vif is APOBEC3G (A3G). A3G is an enzyme of the AID/APOBEC family, characterized by the targeted deamination of cytosine to generate uracil within DNA. APOBEC3G plays an important role in retroviral defense by acting on viral reverse transcripts and mediates numerous critical immune responses. We believe that A3G is an important innate retroviral defense mechanism in the vaginal and rectal tract. By using inhibitors of the viral protein Vif, the Vif-APOBEC3G interaction is blocked and APOBEC3G is not degraded by the proteosome. As a consequence, fatal hypermutations are introduced into the viral cDNA transcripts and HIV is rendered incompetent for replication. Our grant has four specific aims:
Specific Aim 1 : Explore the role of the restriction factor A3G in mucosal tissues of the vaginal and rectal tract Specific Aim 2: Examine whether RN18 and its analogs are active in microbicide cell-based assays and ex vivo explant HIV transmission models Specific Aim 3: Vaginal humanized BLT mouse model testing of promising Vif inhibitor candidates Specific Aim 4: Macaque microbicide model testing of promising Vif inhibitor candidates It is expected that these studies will define the role of A3G in the vaginal and rectal tract and whether inhibitors of the viral Vif protein can prevent sexual transmission of HIV.
The majority of new human immunodeficiency virus type 1 (HIV-1) infections occur in sub- Saharan Africa and Asia, and of the people infected, the majority are women. Women are at a risk for acquiring HIV-1 due to exposure to infectious seminal fluid during consensual or nonconsensual intercourse with high-risk sex partners. Effective topical microbicides products with anti-HIV-1 activity, inserted into the vagina or rectum prior to sexual intercourse, would offer an alternative to condom use that would be controlled by the receptive partner.
|Mohammed, Idrees; Kummetha, Indrasena Reddy; Singh, Gatikrushna et al. (2016) 1,2,3-Triazoles as Amide Bioisosteres: Discovery of a New Class of Potent HIV-1 Vif Antagonists. J Med Chem 59:7677-82|
|Stevenson, Mario (2015) Role of myeloid cells in HIV-1-host interplay. J Neurovirol 21:242-8|
|Mohammed, Idrees; Parai, Maloy K; Jiang, Xinpeng et al. (2012) SAR and Lead Optimization of an HIV-1 Vif-APOBEC3G Axis Inhibitor. ACS Med Chem Lett 3:465-469|
|Ali, Akbar; Wang, Jinhua; Nathans, Robin S et al. (2012) Synthesis and structure-activity relationship studies of HIV-1 virion infectivity factor (Vif) inhibitors that block viral replication. ChemMedChem 7:1217-29|
|Ali, Akbar; Ghosh, Animesh; Nathans, Robin S et al. (2009) Identification of flavopiridol analogues that selectively inhibit positive transcription elongation factor (P-TEFb) and block HIV-1 replication. Chembiochem 10:2072-80|