Document Detail


Individual contributions of mutant protease and reverse transcriptase to viral infectivity, replication, and protein maturation of antiretroviral drug-resistant human immunodeficiency virus type 1.
MedLine Citation:
PMID:  11238855     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Human immunodeficiency virus type 1 (HIV-1) variants resistant to protease (PR) and reverse transcriptase (RT) inhibitors may display impaired infectivity and replication capacity. The individual contributions of mutated HIV-1 PR and RT to infectivity, replication, RT activity, and protein maturation (herein referred to as "fitness") in recombinant viruses were investigated by separately cloning PR, RT, and PR-RT cassettes from drug-resistant mutant viral isolates into the wild-type NL4-3 background. Both mutant PR and RT contributed to measurable deficits in fitness of viral constructs. In peripheral blood mononuclear cells, replication rates (means +/- standard deviations) of RT recombinants were 72.5% +/- 27.3% and replication rates of PR recombinants were 60.5% +/- 33.6% of the rates of NL4-3. PR mutant deficits were enhanced in CEM T cells, with relative replication rates of PR recombinants decreasing to 15.8% +/- 23.5% of NL4-3 replication rates. Cloning of the cognate RT improved fitness of some PR mutant clones. For a multidrug-resistant virus transmitted through sexual contact, RT constructs displayed a marked infectivity and replication deficit and diminished packaging of Pol proteins (RT content in virions diminished by 56.3% +/- 10.7%, and integrase content diminished by 23.3% +/- 18.4%), a novel mechanism for a decreased-fitness phenotype. Despite the identified impairment of recombinant clones, fitness of two of the three drug-resistant isolates was comparable to that of wild-type, susceptible viruses, suggestive of extensive compensation by genomic regions away from PR and RT. Only limited reversion of mutated positions to wild-type amino acids was observed for the native isolates over 100 viral replication cycles in the absence of drug selective pressure. These data underscore the complex relationship between PR and RT adaptive changes and viral evolution in antiretroviral drug-resistant HIV-1.
Authors:
G Bleiber; M Munoz; A Ciuffi; P Meylan; A Telenti
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of virology     Volume:  75     ISSN:  0022-538X     ISO Abbreviation:  J. Virol.     Publication Date:  2001 Apr 
Date Detail:
Created Date:  2001-03-12     Completed Date:  2001-04-05     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3291-300     Citation Subset:  IM    
Affiliation:
Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/AF316831;  AF316837;  AF316838;  AF316844;  AF316845;  AF316851
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-HIV Agents / pharmacology*
Base Sequence
COS Cells
Drug Resistance, Microbial
Gene Products, gag / metabolism
Genome, Viral
HIV Protease / physiology*
HIV Reverse Transcriptase / physiology*
HIV-1 / enzymology*,  genetics,  physiology
Molecular Sequence Data
Mutation
Virus Replication*
Chemical
Reg. No./Substance:
0/Anti-HIV Agents; 0/Gene Products, gag; EC 2.7.7.49/HIV Reverse Transcriptase; EC 3.4.23.-/HIV Protease
Comments/Corrections

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