Likely Role of APOBEC3G-Mediated G-to-A Mutations in HIV-1 Evolution and Drug Resistance

Abstract

The role of APOBEC3 (A3) protein family members in inhibiting retrovirus infection and mobile element retrotransposition is well established. However, the evolutionary effects these restriction factors may have had on active retroviruses such as HIV-1 are less well understood. An HIV-1 variant that has been highly G-to-A mutated is unlikely to be transmitted due to accumulation of deleterious mutations. However, G-to-A mutated hA3G target sequences within which the mutations are the least deleterious are more likely to survive selection pressure. Thus, among hA3G targets in HIV-1, the ratio of nonsynonymous to synonymous changes will increase with virus generations, leaving a footprint of past activity. To study such footprints in HIV-1 evolution, we developed an in silico model based on calculated hA3G target probabilities derived from G-to-A mutation sequence contexts in the literature. We simulated G-to-A changes iteratively in independent sequential HIV-1 infections until a stop codon was introduced into any gene. In addition to our simulation results, we observed higher ratios of nonsynonymous to synonymous mutation at hA3G targets in extant HIV-1 genomes than in their putative ancestral genomes, compared to random controls, implying that moderate levels of A3G-mediated G-to-A mutation have been a factor in HIV-1 evolution. Results from in vitro passaging experiments of HIV-1 modified to be highly susceptible to hA3G mutagenesis verified our simulation accuracy. We also used our simulation to examine the possible role of A3G-induced mutations in the origin of drug resistance. We found that hA3G activity could have been responsible for only a small increase in mutations at known drug resistance sites and propose that concerns for increased resistance to other antiviral drugs should not prevent Vif from being considered a suitable target for development of new drugs.

Human APOBEC3G-Mediated Editing Can Promote HIV-1 Sequence Diversification and Accelerate Adaptation to Selective Pressure

“…These data further support a model wherein physiological concentrations of A3G contribute to the extent of diversity and the rate of evolution of HIV-1 by enhancing the generation of mutations that enable the virus to evolve and adapt to changing conditions during the course of infection (5,6,19). Though difficult to prove unambiguously, it is plausible that A3G contributes to the rapid emergence of mutations in HIV-1 RT that confer 3TC resistance in people on therapy with 3TC alone (12,20). Thus, the high rates of sequence change that characterize HIV-1 infection can be influenced not only by the poor fidelity of the virus replicating enzymes, but also by the host-encoded antiviral factor A3G.…”

N -Linked Glycosylation Protects Gammaretroviruses against Deamination by APOBEC3 Proteins

“…As such, permitting sublethal mA3 mutations could help these gammaretroviruses persist in their murine host and thereby increase their chances of becoming endogenized in the mouse germ line. This concept that sublethal levels of A3-induced deamination could be a driving force behind retroviral/HIV evolution, drug resistance, and immune escape has been raised several times before (63)(64)(65)(66)(67)(68).…”

Identification of Two APOBEC3F Splice Variants Displaying HIV-1 Antiviral Activity and Contrasting Sensitivity to Vif*

“…A3F⌬2 and A3F⌬2-4 contain intact CD2 regions; however, their lower enzymatic activities likely reflect conformational changes in the proteins that compromise deoxycytidine deaminase activity. It has been hypothesized that cytidine deaminase-driven viral defense mechanisms may introduces inherent mutagenic risks to the host and could potentially generates mutations that are beneficial to the virus (42,43). Expression of A3F isoforms with reduced enzymatic activity in multi-FIGURE 5.…”