HIV lacking Vif is susceptible to human APOBEC3 (A3)-mediated restriction, rendering the virus non-infectious. The archetypal family member, A3G, has a well-defined role in HIV restriction in T cells. Other A3s have been implicated but despite nearly a decade of study, no consensus has been reached regarding the restrictive repertoire. Following reverse transcription, nascent viral cDNA transcripts are deaminated by A3 proteins resulting in transition mutations that inhibit HIV replication. To counteract this, Vif targets A3s for proteolytic degradation. However, sequences derived from infected patients exhibit G-to-A hypermutation, a hallmark of A3 activity, suggesting Vif neutralization in vivo is incomplete. I hypothesize that these mutations promote HIV genetic variation and underlie beneficial phenotypes such as the acquisition of drug resistance. In the following proposal, I will define three vital characteristics of the A3 family: (i) which A3s are relevant to HIV restriction,(ii) the extent to which they contribute to the HIV mutation rate, and, (iii) whether drug-resistant virl isolates emerge following A3-mediated sub-lethal mutagenesis. I anticipate that when taken together these studies will supply definitive conclusions to the innate host-defense field while prioritizing efforts to develop future HIV/AIDS therapies especially for HIV infected substance abusers.
HIV has an intrinsically high mutation rate that can result in a virus that is resistant to currently available anti- retroviral therapies. A better understanding o the mechanisms of HIV mutation will lead to more effective treatment options for disproportionately affected populations, including those suffering from chemical dependency.
|Refsland, Eric W; Hultquist, Judd F; Luengas, Elizabeth M et al. (2014) Natural polymorphisms in human APOBEC3H and HIV-1 Vif combine in primary T lymphocytes to affect viral G-to-A mutation levels and infectivity. PLoS Genet 10:e1004761|
|Refsland, Eric W; Harris, Reuben S (2013) The APOBEC3 family of retroelement restriction factors. Curr Top Microbiol Immunol 371:1-27|
|Burns, Michael B; Lackey, Lela; Carpenter, Michael A et al. (2013) APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494:366-70|