The relative ability of cell autonomous HIV-1 restriction factors to interfere with the viral life cycle contributes to a host?s level of susceptibility to infection. Pharmacological enhancement of restriction factor efficacy would be a novel approach to treating HIV infection. However, the mechanistic basis for HIV blockage by restriction factors is not completely understood hampering efforts to employ restriction factor-based host directed therapies. The tripartite motif (TRIM) family of proteins consists of more than 70 members in humans, several of which have been identified as antiviral restriction factors. In this role, TRIMs can diminish viral replication directly by interfering with the viral life cycle or indirectly by fine tuning cellular innate immune responses. TRIM family member TRIM5? accomplishes both of these: first, it prevents retroviral infection of cells by a hitherto unexplained mechanism. Second, TRIM5? also acts as a pattern recognition receptor, promoting the establishment of an antiviral cellular state via the activation of inflammatory signaling pathways upon retroviral recognition. Although TRIMs appear to employ multiple approaches in antiretroviral defense, one strikingly common feature among the TRIM family is that many if not all TRIMs are involved in the regulation and execution of autophagy. In addition to its role as a known defense mechanism against intracellular pathogens (including HIV-1), autophagy is also increasingly recognized as a means of reducing or fine tuning inflammation. Here, we propose to test the hypothesis that autophagy underlies TRIM action in protecting cells against HIV-1 infection and in modulating the TRIM-dependent inflammatory signaling. The studies proposed here have several overarching goals. First, they seek to improve our understanding of the molecular mechanism whereby rhesus TRIM5? both regulates autophagy and directs the autophagic degradation of incoming HIV-1 capsids (Aim 1). Second, they will determine if modulations of the autophagy pathway affect TRIM5?-dependent activation of pro-inflammatory signaling upon lentiviral infection. Finally, they will address whether human TRIMs other than TRIM5? that restrict HIV also employ autophagy in their antiviral actions (Aim 2). We have assembled a team of autophagy and HIV experts to address these questions. Our studies have the potential to uncover the mode of action of several known antiretroviral proteins and lay the groundwork for our understanding of how TRIMs as a family can both positively and negatively affect inflammation. We expect these studies to show that autophagy is a unifying aspect of diverse TRIM actions in HIV defense. Since autophagy can be pharmacologically manipulated, our findings may indicate that modulations of autophagy could be a therapeutic approach to dealing with TRIM-related diseases including HIV/AIDS. Our expertise in TRIMs and autophagy, along with the financial and institutional support to be provided should the COBRE application be funded will ensure successful completion of these aims.
Members of the TRIM family of proteins have been identified as being capable of limiting the ability of HIV to infect and replicate within cells, but the mechanism(s) underlying their action have not been fully uncovered. In this proposal, we test the hypothesis that autophagy, a pathway that can be manipulated with existing drugs, underlies the action of TRIM proteins in antiviral defense. These studies will further our understanding of the cellular functions of TRIM proteins at a molecular level and may provide the groundwork for therapeutic approaches to the diverse diseases, including HIV/AIDS, in which TRIMs play a role.
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