Cytidine deamination induced HIV-1 drug resistance

Abstract

The HIV-1 Vif protein is essential for overcoming the antiviral activity of DNA-editing apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) cytidine deaminases. We show that naturally occurring HIV-1 Vif point mutants with suboptimal anti-APOBEC3G activity induce the appearance of proviruses with lamivudine (3TC) drug resistance-associated mutations before any drug exposure. These mutations, ensuing from cytidine deamination events, were detected in >40% of proviruses with partially defective Vif mutants. Transfer of drug resistance from hypermutated proviruses via recombination allowed for 3TC escape under culture conditions prohibitive for any WT viral growth. These results demonstrate that defective hypermutated genomes can shape the phenotype of the circulating viral population. Partially active Vif alleles resulting in incomplete neutralization of cytoplasmic APOBEC3 molecules are directly responsible for the generation of a highly diverse, yet G-to-A biased, proviral reservoir, which can be exploited by HIV-1 to generate viable and drug-resistant progenies.hypermutation ͉ reservoir ͉ diversity ͉ reverse transcription

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.…”

“…When 3TC is used as a single drug for people infected with HIV-1, drug-resistant virus outcompetes wild-type virus within a few weeks (3), suggesting that the required sequence changes commonly preexist in the virus population. Given that the M184I mutation is caused by a change in the previously reported consensus target for A3G-mediated editing (specifically, AUG-GAT to AUA-GAT) (1, 10, 29), we hypothesized that A3G has the potential to facilitate this particular adaptation to 3TC (9,20). Using the presence of 3TC as a means of applying selection pressure, we therefore used modified CEM-SS cell lines that express or lack A3G (Fig.…”

Large-scale DNA editing of retrotransposons accelerates mammalian genome evolution

“…Therefore, DNA editing can explain how some retrotransposons have acquired such a diverse collection of functions. Indeed, accelerated evolution due to editing has been demonstrated in the exogenous HIV virus, in which editing can result in drug resistance 46 . Another consequence of our results arises in the field of phylogenetics.…”

Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis

“…(30). Hepatitis C virus (Jc1FLAG2[p7-nsGluc2a]) was kindly provided by Charles Rice (Rockefeller University, New York, NY) and grown as described previously (31).…”