HIV-1 Protease and reverse-transcriptase mutations: correlations with antiretroviral therapy in subtype B isolates and implications for drug-resistance surveillance.
Background. It is important, for drug-resistance surveillance, to identify human immunodeficiency virus type 1 (HIV-1) strains that have undergone antiretroviral drug selection.Methods. We compared the prevalence of protease and reverse-transcriptase (RT) mutations in HIV-1 sequences from persons with and without previous treatment with protease inhibitors (PIs), nucleoside RT inhibitors (NRTIs), and nonnucleoside RT inhibitors (NNRTIs). Treatment-associated mutations in protease isolates from 5867 persons and RT isolates from 6247 persons were categorized by whether they were polymorphic (prevalence, >0.5%) in untreated individuals and whether they were established drug-resistance mutations. New methods were introduced to minimize misclassification from transmitted resistance, population stratification, sequencing artifacts, and multiple hypothesis testing.Results. Some 36 established and 24 additional nonpolymorphic protease mutations at 34 positions were related to PI treatment, 21 established and 22 additional nonpolymorphic RT mutations at 24 positions with NRTI treatment, and 15 established and 11 additional nonpolymorphic RT mutations at 15 positions with NNRTI treatment. In addition, 11 PI-associated and 1 NRTI-associated established mutations were polymorphic in viruses from untreated persons.Conclusions. Established drug-resistance mutations encompass only a subset of treatment-associated mutations; some of these are polymorphic in untreated persons. In contrast, nonpolymorphic treatment-associated mutations may be more sensitive and specific markers of transmitted HIV-1 drug resistance.
Division of Infectious Diseases, Department of Medicine, Stanford University, CA 94301, USA.
Soo-Yon
SY
Rhee
W Jeffrey
WJ
Fessel
Andrew R
AR
Zolopa
Leo
L
Hurley
Tommy
T
Liu
Jonathan
J
Taylor
Dong Phuong
DP
Nguyen
Sally
S
Slome
Daniel
D
Klein
Michael
M
Horberg
Jason
J
Flamm
Stephen
S
Follansbee
Jonathan M
JM
Schapiro
Robert W
RW
Shafer
D019380:Anti-HIV Agents / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000635:transmission; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D016333:HIV Protease