Document Detail


Polymorphism of HIV type 1 gag p7/p1 and p1/p6 cleavage sites: clinical significance and implications for resistance to protease inhibitors.
MedLine Citation:
PMID:  10957718     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
F Bally; R Martinez; S Peters; P Sudre; A Telenti
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  AIDS research and human retroviruses     Volume:  16     ISSN:  0889-2229     ISO Abbreviation:  AIDS Res. Hum. Retroviruses     Publication Date:  2000 Sep 
Date Detail:
Created Date:  2000-09-27     Completed Date:  2000-09-27     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  8709376     Medline TA:  AIDS Res Hum Retroviruses     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1209-13     Citation Subset:  IM; X    
Affiliation:
Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
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*
gag Gene Products, Human Immunodeficiency Virus
Chemical
Reg. No./Substance:
0/Capsid Proteins; 0/Fusion Proteins, gag-pol; 0/Gene Products, gag; 0/HIV Protease Inhibitors; 0/NCP7 protein, Human immunodeficiency virus 1; 0/RNA, Viral; 0/Reverse Transcriptase Inhibitors; 0/Viral Proteins; 0/gag Gene Products, Human Immunodeficiency Virus; 0/gag protein p1, Human immunodeficiency virus; EC 3.4.23.-/HIV Protease

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