N88D facilitates the co-occurrence of D30N and L90M and the development of multidrug resistance in HIV type 1 protease following nelfinavir treatment failure.

TitleN88D facilitates the co-occurrence of D30N and L90M and the development of multidrug resistance in HIV type 1 protease following nelfinavir treatment failure.
Publication TypeJournal Article
Year of Publication2006
AuthorsMitsuya Y, Winters MA, W Fessel J, Rhee S-Y, Hurley L, Horberg M, Schiffer CA, Zolopa AR, Shafer RW
JournalAIDS Res Hum Retroviruses
Volume22
Issue12
Pagination1300-5
Date Published2006 Dec
ISSN0889-2229
KeywordsBase Sequence, California, Drug Resistance, Multiple, Viral, Evolution, Molecular, HIV Infections, HIV Protease, HIV Protease Inhibitors, HIV-1, Humans, Molecular Sequence Data, Nelfinavir
Abstract

Nelfinavir was once one of the most commonly used protease inhibitors (PIs). To investigate the genetic mechanisms of multidrug resistance in protease isolates with the primary nelfinavir resistance mutation D30N, we analyzed patterns of protease mutations in 582 viruses with D30N from 460 persons undergoing HIV-1 genotypic resistance testing at Stanford University Hospital from 1997 to 2005. Three patterns of mutational associations were identified. First, D30N was positively associated with N88D but negatively associated with N88S. Second, D30N and L90M were negatively associated except in the presence of N88D, which facilitated the co-occurrence of D30N and L90M. Third, D30N+N88D+L90M formed a stable genetic backbone for the accumulation of additional protease inhibitor (PI) resistance mutations. In 16 patients having isolates with more than one combination of mutations at positions 30, 88, and 90, all exhibited one of the steps in the following progression: D30N-->D30N+N88D-->D30N+N88D+L90M-->D30N+N88D+L90M+(L33F+/-I84V or M46I/L+/-I54V). Although nelfinavir is now used less frequently than other PIs, the well-delineated mutational pathway we describe is likely to influence patterns of cross-resistance in viruses from persons who experience virologic failure while receiving this PI.

DOI10.1089/aid.2006.22.1300
Alternate JournalAIDS Res. Hum. Retroviruses
PubMed ID17209774
PubMed Central IDPMC2573402
Grant ListAI46148-01 / AI / NIAID NIH HHS / United States
GM66524 / GM / NIGMS NIH HHS / United States
P01 GM066524 / GM / NIGMS NIH HHS / United States
P01 GM066524-06 / GM / NIGMS NIH HHS / United States
R01 AI046148 / AI / NIAID NIH HHS / United States
R01 AI046148-08 / AI / NIAID NIH HHS / United States