Antiretroviral drug resistance in HIV-2: three amino acid changes are sufficient for classwide nucleoside analogue resistance.
Genotypic surveys suggest that human immunodeficiency virus type 1 (HIV-1) and HIV-2 evolve different sets of mutations in response to nucleoside reverse-transcriptase inhibitors (NRTIs). We used site-directed mutagenesis, culture-based phenotyping, and cell-free assays to determine the resistance profiles conferred by specific amino acid replacements in HIV-2 reverse transcriptase. Although thymidine analogue mutations had no effect on zidovudine sensitivity, the addition of Q151M together with K65R or M184V was sufficient for high-level resistance to both lamivudine and zidovudine in HIV-2, and the combination of K65R, Q151M, and M184V conferred classwide NRTI resistance. These data suggest that current NRTI-based regimens are suboptimal for treating HIV-2 infection.
Department of Pathology, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98133, USA. smithra@u.washington.edu
Robert A
RA
Smith
Donovan J
DJ
Anderson
Crystal L
CL
Pyrak
Bradley D
BD
Preston
Geoffrey S
GS
Gottlieb
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000354:Africa, Western / Q000453:epidemiology; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D015498:HIV-2 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D012194:RNA-Directed DNA Polymerase / Q000187:drug effects / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D012194:RNA-Directed DNA Polymerase