Relative fitness and replication capacity of a multinucleoside analogue-resistant clinical human immunodeficiency virus type 1 isolate with a deletion of codon 69 in the reverse transcriptase coding region.
Deletions, insertions, and amino acid substitutions in the beta3-beta4 hairpin loop-coding region of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have been associated with resistance to nucleoside RT inhibitors when appearing in combination with other mutations in the RT-coding region. In this work, we have measured the in vivo fitness of HIV-1 variants containing a deletion of 3 nucleotides affecting codon 69 (Delta69) of the viral RT as well as the replication capacity (RC) ex vivo of a series of recombinant HIV-1 variants carrying an RT bearing the Delta69 deletion or the T69A mutation in a multidrug-resistant (MDR) sequence background, including the Q151M complex and substitutions M184V, K103N, Y181C, and G190A. Patient-derived viral clones having RTs with Delta69 together with S163I showed increased RCs under drug pressure. These data were consistent with the viral population dynamics observed in a long-term-treated HIV-1-infected patient. In the absence of drugs, viral clones containing T69A replicated more efficiently than those having Delta69, but only when patient-derived sequences corresponding to RT residues 248 to 527 were present. These effects could be attributed to a functional interaction between the C-terminal domain of the p66 subunit (RNase H domain) and the DNA polymerase domain of the RT. Finally, recombinant HIV-1 clones bearing RTs with MDR-associated mutations, including deletions at codon 69, showed increased susceptibilities to protease inhibitors in phenotypic assays. These effects correlated with impaired Gag cleavage and could be attributed to delayed maturation and decreased production of active protease in those variants.
Villena
Cristina
C
irsiCaixa Foundation, Hospital Germans Trias i Pujol, Ctra. de Canyet s/n, 08916 Badalona, Spain.
Prado
Julia G
JG
Puertas
Maria Carmen
MC
Martínez
Miguel Angel
MA
Clotet
Bonaventura
B
Ruiz
Lidia
L
Parkin
Neil T
NT
Menéndez-Arias
Luis
L
Martinez-Picado
Javier
J
D000595:Amino Acid Sequence / Q000235:genetics*; D001483:Base Sequence; D003062:Codon / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D016296:Mutagenesis; D012150:Polymorphism, Restriction Fragment Length; D011480:Protease Inhibitors / Q000633:toxicity; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics / Q000502:physiology*
D003062:Codon; D011480:Protease Inhibitors; D054303:HIV Reverse Transcriptase