Identification and structural characterization of I84C and I84A mutations that are associated with high-level resistance to human immunodeficiency virus protease inhibitors and impair viral replication.
Two novel human immunodeficiency virus protease mutations, I84C and I84A, were identified in patient isolates. The mutants with I84C displayed high-level resistance (median, at least 56-fold) to nelfinavir and saquinavir, but the majority remained susceptible to lopinavir. In contrast, isolates with the I84A mutation exhibited>or=33-fold median increased levels of resistance to nelfinavir, indinavir, amprenavir, ritonavir, lopinavir, saquinavir, and atazanavir. Isolates with the I84A or I84C mutation tended to be more resistant than the isolates with the I84V mutation. Modeling of the structure of the mutant proteases indicated that the I84V, I84C, and I84A mutations all create unoccupied volume in the active site, with I84A introducing the greatest change in the accessible surface area from that of the wild-type structure.
Mo
Hongmei
H
Global Pharmaceutical Research and Development, Department R4CQ, Building AP52N, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, IL 60064-6217, USA.
Parkin
Neil
N
Stewart
Kent D
KD
Lu
Liangjun
L
Dekhtyar
Tatyana
T
Kempf
Dale J
DJ
Molla
Akhteruzzaman
A
D019380:Anti-HIV Agents / Q000494:pharmacology; D000069446:Atazanavir Sulfate; D024882:Drug Resistance, Viral / Q000235:genetics*; D015750:Genes, gag; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D009154:Mutation; D019888:Nelfinavir / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology; D014779:Virus Replication / Q000235:genetics
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D019469:Indinavir; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir