This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Cell membranes form a mosaic of specialized lipid domains. Among them, sphingolipid and cholesterol enriched domains, called lipid rafts, have received much attention due to the role they play in membrane trafficking, cell morphogenesis, signal transduction and particularly in entry of various pathogens including bacteria and their toxins as well as viruses. Although the role of lipid rafts in HIV infection is still unclear, it seems likely that rafts represent privileged sites for virus binding to CD4 receptors concentrated in these domains. Thus, my research goals have focused on A) understanding the significance of localization of HIV-1 receptors in lipid rafts in HIV entry and B) elucidating the molecular mechanism(s) targeting the primary HIV-1 receptor, CD4, into lipid rafts.Extensive mutagenesis of the CD4 receptor identified a raft-localizing marker, consisting of a short sequence of positively charged amino acid residues, RHRRR, and present in the membrane-proximal cytoplasmic domain of CD4. Substitution of the RHRRR sequence with alanine residues redirected CD4 to non-rafts. Surprisingly, the mutant CD4 supported productive HIV-1 entry to levels equivalent to that of wild type CD4, suggesting that raft localization of CD4 might not be required for virus entry. However, we cannot exclude the possibility that HIV binding to CD4 receptors localized outside rafts could stimulate raft assembly before or after engaging coreceptors or during fusion/entry process. Further studies are aimed to answer these questions.We and others have demonstrated that antiretroviral activity of APOBEC3G requires its packaging into assembling HIV virions through interaction with the Gag nucleocapsid protein NC. However, this process is severely limited in the presence of the viral accessory protein Vif, which binds to and target APOBEC3G for degradation by proteasomes. Thus, finding means of escaping of Vif-mediated degradation has become a challenge to developing an effective APOBEC3G-based antiretroviral therapy. Recently, we have found that APOBEC3G can be efficiently packaged into exosomes, cell-derived nanovesicles that showed promissing potential in cancer therapy clinical trials. Our current research is focused on the elucidation of the molecular mechanism(s) for targeting APOBEC3G into exosomes and evaluating the potential of exosome-encapsidated APOBEC3G as a novel approach in anti-HIV therapy.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZRR1-RCMI-2 (01))
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Meharry Medical College
Internal Medicine/Medicine
Schools of Medicine
United States
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