Progressive reversion of human immunodeficiency virus type 1 resistance mutations in vivo after transmission of a multiply drug-resistant virus.
Evolution and transmission of multiply drug-resistant human immunodeficiency virus type 1 (HIV-1) may limit therapeutic options as global treatment efforts expand. However, the stability of these mutants in the absence of drug selection pressure is not known. We performed a longitudinal analysis of plasma virus from a person who acquired HIV-1 that contained multiple reverse transcriptase (RT) and protease (PR) mutations. In the absence of therapy, 5 of 12 drug resistance mutations reverted in a stepwise fashion to wild type over the course of 52 weeks. Reversion of the M184V mutation alone did not change viral replicative capacity (RC), but it led to enhanced resistance to zidovudine and tenofovir. However, reversions of a second RT mutation and 3 PR mutations were associated with an increase in viral RC, and this was temporally correlated with a marked decrease in CD4 cell number. This study demonstrates the gradual stepwise back-mutation of certain drug resistance mutations in vivo in the absence of ongoing drug selection pressure. Moreover, it suggests that, despite initially impaired viral fitness, a transmitted HIV-1 isolate with multiple drug resistance mutations can evolve to develop increased RC and significant pathogenicity.
Gandhi
Rajesh T
RT
Infectious Diseases Unit, Massachusetts General Hospital, Boston, MA 02114, USA. rgandhi@partners.org
Wurcel
Alysse
A
Rosenberg
Eric S
ES
Johnston
Mary N
MN
Hellmann
Nicholas
N
Bates
Michael
M
Hirsch
Martin S
MS
Walker
Bruce D
BD
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology*; D005075:Biological Evolution; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D024882:Drug Resistance, Viral; D005838:Genotype; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation
D019380:Anti-HIV Agents