Lethal Hypermutation Induced by the Innate Cellular Restriction Factor APOBEC Destroys HIV-1 in Infected Humanized Mice




Krisko, John Frank

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Twenty 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.

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