Virologic characterization of HIV type 1 with a codon 70 deletion in reverse transcriptase.
We identified a deletion at codon 70 (Delta70) of HIV-1 reverse transcriptase (RT) occurring together with L74V and Q151M mutations in a sample from a tenofovir (TFV)- and abacavir (ABC)-treated patient with extensive prior antiretroviral treatment. To investigate the characteristics of this mutant, we studied the drug susceptibility, relative infectivity, and fitness of viruses carrying Delta70 and associated RT mutations. The Delta70, L74V, and Q151M mutations were introduced into Hxb2 RT by site-directed mutagenesis and expressed in HIV-1 recombinants. The Delta70 mutation increased resistance to lamivudine and emtricitabine alone and in combination with various resistance mutations and augmented resistance to ABC and didanosine when present together with L74V. A recombinant virus expressing RT from the original clinical viral sample (Delta70-PRT) exhibited greater fitness than one in which the deletion had been repaired (K70-PRT). The Delta70 mutation also increased fitness of Hxb2 wild-type and 74V and Q151M mutants. Recombinants carrying Delta70-PRT showed greater relative infectivity in the presence of ABC (but not TFV) compared with K70-PRT recombinants. These results show that Delta70 enhances resistance to certain purine and pyrimidine analogues and contributes to multinucleoside resistance in the appropriate viral genetic background.
Hu
Zixin
Z
Section of Retroviral Therapeutics, Brigham and Women's Hospital, and Division of AIDS, Harvard Medical School, Boston, MA, USA.
Hatano
Hiroyu
H
Hammond
Sarah P
SP
Smith
Danielle
D
Wild
Mary
M
Gupta
Soumi
S
Whitcomb
Jeannette
J
Kalayjian
Robert C
RC
Gripshover
Barbara
B
Kuritzkes
Daniel R
DR
D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology; D002461:Cell Line, Transformed; D003062:Codon / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D016049:Didanosine / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D000068679:Emtricitabine; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D063065:Organophosphonates / Q000627:therapeutic use; D017354:Point Mutation; D016865:Reassortant Viruses / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000068698:Tenofovir; D000099227:Abacavir
D000225:Adenine; D000998:Antiviral Agents; D003062:Codon; D003841:Deoxycytidine; D016049:Didanosine; D015224:Dideoxynucleosides; D000068679:Emtricitabine; D054303:HIV Reverse Transcriptase; D019259:Lamivudine; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000099227:Abacavir