Many recent studies have highlighted the significance of the human host defense genes APOBEC3B, APOBEC3F, and APOBEC3G as part of a potent anti-viral cellular response against HIV-1 infection. However, HIV-1 has evolved a counter-response to this cellular defense. The HIV-1 Vif protein directly binds both 3F and 3G and directs their proteasomal degradation. Preliminary studies have indicated that elevating and/or stabilizing the levels of APOBEC3G is sufficient to overcome this Vif mediated effect and allows for significant suppression of infectivity of wildtype HIV-1. Additionally, it is of interest that APOBEC3B can suppress wildtype HIV-1 and its expression is unaffected by the presence of Vif. However, APOBEC3B is expressed at very low levels in lymphocytes, the natural target cells for HIV- 1. Taken together, this preliminary information suggests that manipulating these genes to increase APOBEC3F and APOBEC3G expression and induce APOBEC3B expression in lymphocytes may provide a novel point of therapeutic intervention. Additionally, the Vif mediated ubiquitination and subsequent proteasomal degradation of APOBEC3G have recently been highlighted as critical steps in the viral life cycle. However, the specific residues of APOBEC3G that are modified have yet to be identified. Also, the role of monoubiquitinated APOBEC3G in the viral counter response pathway has not been explored. This proposal aims to determine the regulatory sequence and corresponding proteins that control APOBEC3B, APOBEC3F, and APOBEC3G expression and to elucidate the role of monoubiquitinated APOBEC3G during the viral life cycle. This information could then be utilized to design therapies that would allow effective manipulation of APOBEC3B, APOBEC3F, and APOBEC3G expression and post-translational modification.
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