Browsing by Subject "Anti-HIV Agents"
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Item Excess mortality in treated HIV-infection(2015-11-20) Drechsler, Henning J.Item Improving the HIV care continuum in 2021(2021-06-25) Chow, JeremyItem Lethal Hypermutation Induced by the Innate Cellular Restriction Factor APOBEC Destroys HIV-1 in Infected Humanized Mice(2010-01-12) Krisko, John Frank; Garcia-Martinez, J. VictorTwenty eight years after the initial case reports of what would become known as AIDS, HIV-1 remains a major health issue both globally and locally. Current antiretroviral interventions are effective at suppressing virus replication; however, they must be maintained for life as the removal of these drugs resulting in the rapid return of viremia. Novel therapeutic approaches targeting HIV may be required to ultimately achieve a drug-free remission for infected individuals. Identification of the innate immune factor, APOBEC, has revealed one such approach. The cytidine deaminases APOBEC3G and 3F have potent antiretroviral activity; however, they are neutralized by the HIV-1 Vif protein. In vitro, the absence of Vif allows the enzymatic activity of APOBEC3G and 3F to induce hypermutation of the HIV-1 genome. These observations make the Vif/APOBEC axis a tantalizing therapeutic target. The ability of APOBEC to restrict HIV in vivo however remains to be addressed. The adaptive capability of HIV allows the virus to develop escape mutations to evade antiretroviral drugs and persist in infected individuals; thus the possibility that HIV will be able to evade APOBEC restriction in vivo exists. Humanized mice used as an in vivo model to study the capacity of APOBEC to restrict Vif-defective HIV revealed that the ability of the virus to replicate is severely crippled. HIV lacking Vif is heavily hypermutated by APOBEC, however, if the virus can restore Vif, the result is a fully replication competent virus that is resistant to APOBEC restriction. The goal of this dissertation project was to utilize a humanized mouse model to assess the ability of Vif-defective HIV to replicate, persist and ultimately escape restriction by APOBEC in vivo. My conclusions are that in the absence of Vif, restriction by APOBEC is absolute; however, this extreme selective pressure placed on the virus in some instances leads to the restoration of Vif, resulting in a fully APOBEC resistant pathogenic HIV. Thus, the Vif/APOBEC axis is an excellent candidate for antiretroviral intervention and furthermore, the humanized mouse will serve as a good model for assessing the in vivo efficacy of novel Vif-targeting compounds.Item Mucosal HIV-1 Transmission in Humanized Mice(2008-05-13) Denton, Paul Wesley; Garcia-Martinez, J. VictorHIV-1 infects ~6,800 people each and every day, transmitting predominantly through unprotected sexual contact. On a global scale, vaginal transmission now accounts for more than half of newly acquired HIV-1 infections. In developed countries intrarectal infection represents a major form of HIV-1 transmission. The social and economic toll of this disease has created an urgency to develop and implement novel approaches capable of preventing HIV-1 transmission. Yet this process has been hindered by the lack of adequate small animal models for pre-clinical efficacy and safety testing. Given the importance of mucosal HIV-1 transmission, the susceptibility of humanized mice to intrarectal and intravaginal HIV-1 infection was investigated. Human lymphocytes, including CD4+ T cells, generated in situ from hematopoietic stem cells reconstitute the gastrointestinal tract and the female reproductive tract of Bone marrow Liver Thymus (BLT) mice. The presence of human CD4+ T cells in these mucosal tissues renders BLT mice susceptible to both intrarectal and intravaginal HIV-1 transmission. Mucosally transmitted HIV-1 disseminates systemically in BLT mice. Effects of disseminated HIV-1 infection include a systemic loss of CD4+ T cells, particularly in gut associated lymphoid tissue, which closely mimics what happens in HIV-1 patients. The utility of humanized mice to study mucosal HIV-1 transmission is particularly highlighted by the demonstration herein that pre-exposure prophylaxis with antiretroviral drugs can prevent intravaginal HIV-1 transmission. This experimental finding has important implications for the clinical implementation of antiretroviral-based pre-exposure prophylactic measures to prevent the spread of AIDS. The goal of this dissertation project was to determine the suitability of the BLT mouse to serve as an animal model of HIV-1 transmission and as a model for assessing interventions aimed at preventing HIV-1 transmission. My conclusions are that BLT mice are susceptible to both intrarectal and intravaginal HIV-1 transmission and that pre-exposure prophylaxis with FDA approved antiretroviral drugs does prevent vaginal transmission in BLT mice. Thus, the BLT mouse system is an excellent candidate for pre-clinical evaluation of both microbicides and pre-exposure prophylactic regimens to prevent mucosal HIV-1 transmission.