Prevention of HIV-induced T cell killing by autophagy

University Of New Mexico Health Scis Ctr, Albuquerque NM

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Abstract

SUMMARY HIV pathogenesis is mediated by non-protective inflammatory responses to viral infection. This is true of the primary manifestation of HIV infection that leads to AIDS, CD4+ T cell depletion, and also of certain co- morbidities such as premature aging or neurodegeneration that remain challenges for HIV patients in spite of viral suppression by antiretroviral therapy. As such, in addition to limiting viral replication, there is also a need to suppress the inflammatory cascade triggered by viral infection. The purpose of this application is to test whether autophagy, a cellular waste management pathway, could be engaged to counteract HIV-induced inflammation. Autophagy has the potential to protect against HIV pathogenesis in two ways. First, autophagy is reported to have direct antiviral activities against several viruses, including HIV. Second, autophagy can protect against inflammatory processes through multiple complimentary mechanisms. Our hypothesis is that autophagy, when ?turned on? by existing drugs, can act as an anti-HIV effector mechanism and also prevent HIV-induced CD4+ T cell depletion through its anti-inflammatory activities. The understanding of inflammation?s role in HIV pathogenesis has emerged recently as a result of improved models of HIV infection. Whereas most HIV infection and inflammation takes place in lymphoid tissue in vivo, most cell culture models of HIV infection use cell lines or isolated blood-derived immune cells. While these models have been useful in many respects, they are not representative of what happens in the complex setting of lymphoid tissue. Thus, we will use a previously published ex vivo model of lymphoid tissue that will allow us to monitor the effect of autophagy induction on HIV infection and spread as well as the inflammatory depletion of CD4+ T cells under physiologically relevant conditions. We will also determine if viral or host factors implicated in initiating or transducing inflammatory responses to HIV are targets of selective autophagy as this would be one mechanism whereby autophagy could exert is anti-inflammatory effects. Completion of these aims will: i) determine if the reported anti-HIV actions of autophagy are active in a physiologically relevant model of infection, and ii) assess whether autophagy?s anti-inflammatory properties can counteract HIV-induced inflammation and T cell depletion. This work may lead to approaches to enable or enhance autophagy in ways that would mitigate HIV pathogenesis in a clinical setting. Our expertise in autophagy and in HIV will ensure a successful outcome of these studies.