Polymorphism of HIV type 1 gag p7/p1 and p1/p6 cleavage sites: clinical significance and implications for resistance to protease inhibitors

Details

Serval ID
serval:BIB_A98506B54078
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Polymorphism of HIV type 1 gag p7/p1 and p1/p6 cleavage sites: clinical significance and implications for resistance to protease inhibitors
Journal
AIDS Research and Human Retroviruses
Author(s)
Bally  F., Martinez  R., Peters  S., Sudre  P., Telenti  A.
ISSN
0889-2229 (Print)
Publication state
Published
Issued date
09/2000
Volume
16
Number
13
Pages
1209-13
Notes
Journal Article --- Old month value: Sep 1
Abstract
Amino acid substitutions at HIV-1 Gag p7/p1 and p1/p6 cleavage sites may be selected under antiretroviral pressure or represent natural polymorphisms. Whether changes are associated with specific protease (PR) mutation patterns and different clinical evolution has not been investigated. p7/p1 and p1/p6 cleavage site sequences from sera from 110 patients infected with HIV-1 were compared by regression analysis, using clinical, laboratory, and sequence variables, and the evolution of CD4(+) cell counts and viral load over time. Sixteen of 35 (46%) individuals naive to PR inhibitors (PIs), and 49 of 75 (65%) receiving PI-containing regimens had a p7/p1 and/or p1/p6 cleavage site polymorphism (p = 0.06). A431V and/or L449F were present exclusively among individuals failing PI treatment (17 of 75 [23%] and 3 of 75 [3%], respectively). There was a significant association between A431V and PR M46I,L (OR 13.7; 95% CI 4.2-44.3) and V82A,F,T (OR 8.8; 95% CI 2.7-27.8). Natural polymorphism P453L was strongly associated with the selection of PR I84V (OR 49.5; 95% CI 12-212) and selected against V82 mutation (OR 0.15; 95% CI 0.02-1. 2). After a median followup of 15 months, no polymorphism was associated with parameters of disease progression among individuals failing treatment. Only a limited set of amino acid substitutions can be tolerated at p7/p1 and p1/p6 cleavage sites. A431V is selected in association with specific PR inhibitor mutations. Natural polymorphism P453L might direct the PR resistance pathway through I84V instead of V82 mutation. No short-term clinical impact of cleavage site substitutions was documented.
Keywords
Capsid/genetics *Capsid Proteins Disease Progression Drug Resistance, Microbial/genetics Drug Therapy, Combination Fusion Proteins, gag-pol/genetics/metabolism Gene Products, gag/*genetics HIV Infections/drug therapy/physiopathology/*virology HIV Protease/genetics HIV Protease Inhibitors/*pharmacology/therapeutic use HIV-1/*drug effects/genetics/physiology Humans Mutation Polymorphism, Genetic/*genetics RNA, Viral/blood Reverse Transcriptase Inhibitors/therapeutic use *Viral Proteins
Pubmed
Web of science
Create date
25/01/2008 15:45
Last modification date
20/08/2019 16:13
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