APOBEC3 Restriction of Retroviral Infection in Small Animals

Hung Y. Fan, UC Irvine

The HIV Vif protein has been shown to counteract a system of host anti-viral defense mediated by the APOBEC family of proteins. Vif binds to human APOBEC3G (hA3G) and prevents its incorporation into virions. If hA3G is incorporated into HIV virions (e.g. in Vif- mutants), its cytosine deaminase activity converts C residues in reverse transcribed DNA to uracils; this leads to degredation of the DNA or G A mutations in viral DNA. Other possible mechanisms of A3G action have also been proposed, including restriction in the recipient cell, and deaminase-independent processes. We propose to study APOBEC restriction of retroviral infection in a small animal model, using the simple retrovirus murine leukemia virus and mice deficient in the murine APOBEC3 (mA3) gene. In preliminary experiments, we have found that mA3 -/- mice inoculated with Moloney murine leukemia virus (M-MuLV) establish substantially higher levels of infection at early times than do mice of the background C57/Bl6 strain. Thus mA3 restricts M-MuLV infection in mice, although not absolutely. In this IDEA proposal, we will distinguish between two possible mechanisms for the mA3 restriction: 1) low level incorporation of mA3 into M-MuLV particles, or 2) restriction by mA3 in the recipient cell. The biological consequences of M-MuLV infection in mA3 -/- mice will also be explored. Finally, we will test if the reduced infectivity of M-MuLV in rats and rat cells is related to more efficient incorporation of rat APOBEC3 into M-MuLV virions.