Vicriviroc resistance decay and relative replicative fitness in HIV-1 clinical isolates under sequential drug selection pressures.

TitleVicriviroc resistance decay and relative replicative fitness in HIV-1 clinical isolates under sequential drug selection pressures.
Publication TypeJournal Article
Year of Publication2012
AuthorsTsibris AMN, Hu Z, Paredes R, Leopold KE, Putcharoen O, Schure AL, Mazur N, Coakley E, Su Z, Gulick RM, Kuritzkes DR
JournalJ Virol
Volume86
Issue12
Pagination6416-26
Date Published2012 Jun
ISSN1098-5514
KeywordsAnti-HIV Agents, Cell Line, Drug Resistance, Viral, HIV Envelope Protein gp120, HIV Envelope Protein gp41, HIV Infections, HIV-1, Humans, Molecular Sequence Data, Mutation, Peptide Fragments, Phylogeny, Piperazines, Pyrimidines, Virus Internalization, Virus Replication
Abstract

We previously described an HIV-1-infected individual who developed resistance to vicriviroc (VCV), an investigational CCR5 antagonist, during 28 weeks of therapy (Tsibris AM et al., J. Virol. 82:8210-8214, 2008). To investigate the decay of VCV resistance mutations, a standard clonal analysis of full-length env (gp160) was performed on plasma HIV-1 samples obtained at week 28 (the time of VCV discontinuation) and at three subsequent time points (weeks 30, 42, and 48). During 132 days, VCV-resistant HIV-1 was replaced by VCV-sensitive viruses whose V3 loop sequences differed from the dominant pretreatment forms. A deep-sequencing analysis showed that the week 48 VCV-sensitive V3 loop form emerged from a preexisting viral variant. Enfuvirtide was added to the antiretroviral regimen at week 30; by week 48, enfuvirtide treatment selected for either the G36D or N43D HR-1 mutation. Growth competition experiments demonstrated that viruses incorporating the dominant week 28 VCV-resistant env were less fit than week 0 viruses in the absence of VCV but more fit than week 48 viruses. This week 48 fitness deficit persisted when G36D was corrected by either site-directed mutagenesis or week 48 gp41 domain swapping. The correction of N43D, in contrast, restored fitness relative to that of week 28, but not week 0, viruses. Virus entry kinetics correlated with observed fitness differences; the slower entry of enfuvirtide-resistant viruses corrected to wild-type rates in the presence of enfuvirtide. These findings suggest that while VCV and enfuvirtide select for resistance mutations in only one env subunit, gp120 and gp41 coevolve to maximize viral fitness under sequential drug selection pressures.

DOI10.1128/JVI.00286-12
Alternate JournalJ. Virol.
PubMed ID22491471
PubMed Central IDPMC3393533
Grant ListAI051966 / AI / NIAID NIH HHS / United States
AI055357 / AI / NIAID NIH HHS / United States
AI068636 / AI / NIAID NIH HHS / United States
AI069419 / AI / NIAID NIH HHS / United States
K08 AI081547 / AI / NIAID NIH HHS / United States
P30 AI060354 / AI / NIAID NIH HHS / United States
R37 AI055357 / AI / NIAID NIH HHS / United States
RR016482 / RR / NCRR NIH HHS / United States
RR024996 / RR / NCRR NIH HHS / United States