Partially active HIV-1 Vif alleles facilitate viral escape from specific antiretrovirals.
BACKGROUND
The HIV-1 Vif protein counteracts the antiviral activity of the cytidine deaminases APOBEC3G and APOBEC3F. Natural variation in Vif may result in reduced efficacy against APOBEC3 proteins and in increased HIV-1 diversity. We speculated that this mechanism could facilitate viral escape from certain antiretroviral drugs.


RESULTS
We analyzed the protease, reverse transcriptase and Vif sequences of viruses from plasma obtained from 92 HIV-1-infected individuals failing antiretroviral treatment and 65 antiretroviral-naive patients. Mutation K22H in Vif was more frequent in patients failing to antiretroviral compared to antiretroviral-naive patients. In-vitro experiments showed that mutant K22H failed to completely neutralize APOBEC3G. Upon infection of MT-2 cells, most of the K22H proviral clones encoded increased numbers of G-to-A mutations. Among these mutations, the lamivudine drug-resistance-associated mutation M184I in reverse transcriptase was detected in 25% of clones in the absence of any lamivudine exposure. In our population, among pretreated patients, 72% of K22H viruses versus 42% in WT K22 viruses harbored at least two drug-resistance-associated mutations in a GA/GG dinucleotide context. More specifically, K22H viruses harbored significantly more G16E and M36I in protease than in those isolated from pretreated patients harboring WT K22 viruses.


CONCLUSIONS
This study provides evidence that patients experiencing virological failure frequently harbor Vif point mutants (i.e. K22H). Such Vif alleles lose their ability to counteract APOBEC3 proteins, leading to an increase of G-to-A viral mutations that can facilitate the emergence of some antiretroviral resistance mutations.
Fourati
Slim
S
UMR 943, Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Virologie, Paris France. slim.fourati@psl.aphp.fr
Malet
Isabelle
I
Binka
Mawuena
M
Boukobza
Stephanie
S
Wirden
Marc
M
Sayon
Sophie
S
Simon
Anne
A
Katlama
Christine
C
Simon
Viviana
V
Calvez
Vincent
V
Marcelin
Anne-Geneviève
AG
D000071480:APOBEC-3G Deaminase; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D023241:Antiretroviral Therapy, Highly Active; D015153:Blotting, Western; D003564:Cytidine Deaminase / Q000235:genetics; D043525:Cytosine Deaminase / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D055815:Young Adult; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D019259:Lamivudine; D054303:HIV Reverse Transcriptase; C492906:APOBEC3F protein, human; D043525:Cytosine Deaminase; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase