In:
Journal of Virology, American Society for Microbiology, Vol. 81, No. 22 ( 2007-11-15), p. 12608-12618
Abstract:
Certain histocompatibility leukocyte antigen (HLA) alleles are associated with improved clinical outcomes for individuals infected with human immunodeficiency virus type 1 (HIV-1), but the mechanisms for their effects remain undefined. An early CD8 + T-cell escape mutation in the dominant HLA-B57-restricted Gag epitope TW10 (TSTLQEQIGW) has been shown to impair HIV-1 replication capacity in vitro. We demonstrate here that this T 242 N substitution in the capsid protein is associated with upstream mutations at residues H 219 , I 223 , and M 228 in the cyclophilin A (CypA)-binding loop in B57 + individuals with progressive disease. In an independent cohort of epidemiologically linked transmission pairs, the presence of these substitutions in viruses encoding T 242 N was associated with significantly higher plasma viremia in donors, further suggesting that these secondary mutations compensated for the replication defect of T 242 N. Using NL4-3 constructs, we illustrate the ability of these CypA loop changes to partially restore replication of the T 242 N variant in vitro. Notably, these mutations also enhanced viral resistance to the drug cyclosporine A, indicating a reduced dependence of the compensated virus on CypA that is normally essential for optimal infectivity. Therefore, mutations in TW10 allow HIV-1 to evade a dominant early CD8 + T-cell response, but the benefits of escape are offset by a defect in capsid function. These data suggest that TW10 escape variants undergo a postentry block that is partially overcome by changes in the CypA-binding loop and identify a mechanism for an HIV-1 fitness defect that may contribute to the slower disease progression associated with HLA-B57.
Type of Medium:
Online Resource
ISSN:
0022-538X
,
1098-5514
DOI:
10.1128/JVI.01369-07
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2007
detail.hit.zdb_id:
1495529-5
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