Journal
JOURNAL OF VIROLOGY
Volume 86, Issue 24, Pages 13423-13433Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.02171-12
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Funding
- Canadian Institutes for Health Research (CIHR) [MOP-93536, HOP-115700]
- Microsoft Research
- National Institute of Allergy and Infectious Diseases (NIAID)
- National Institutes of Health (NIH)
- U.S. Department of Health and Human Services grant [U19 A151794]
- NIAID International Research in Infectious Diseases (IRID) [1R01AI078936]
- Technology Innovation Agency, South Africa (TIA)
- Centre for the AIDS Program of Research in South Africa (CAPRISA)
- Canada-HOPE fellowship from CIHR
- Sanofi-Aventis
- Clinical Infectious Diseases Research Initiative (CIDRI) fellowship
- Sydney Brenner fellowship
- National Research Foundation
- Ragon Institute of Massachusetts General Hospital
- Massachusetts Institute of Technology
- Harvard University
- Howard Hughes Medical Institute (HHMI)
- CIHR New Investigator Award
- Michael Smith Foundation for Health Research (MSFHR) Scholar Award
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Certain immune-driven mutations in HIV-1, such as those arising in p24(Gag), decrease viral replicative capacity. However, the intersubtype differences in the replicative consequences of such mutations have not been explored. In HIV-1 subtype B, the p24(Gag) M250I mutation is a rare variant (0.6%) that is enriched among elite controllers (7.2%) (P = 0.0005) and appears to be a rare escape variant selected by HLA-B58 supertype alleles (P < 0.01). In contrast, in subtype C, it is a relatively common minor polymorphic variant (10 to 15%) whose appearance is not associated with a particular HLA allele. Using site-directed mutant viruses, we demonstrate that M250I reduces in vitro viral replicative capacity in both subtype B and subtype C sequences. However, whereas in subtype C downstream compensatory mutations at p24(Gag) codons 252 and 260 reduce the adverse effects of M250I, fitness costs in subtype B appear difficult to restore. Indeed, patient-derived subtype B sequences harboring M250I exhibited in vitro replicative defects, while those from subtype C did not. The structural implications of M250I were predicted by protein modeling to be greater in subtype B versus C, providing a potential explanation for its lower frequency and enhanced replicative defects in subtype B. In addition to accounting for genetic differences between HIV-1 subtypes, the design of cytotoxic-T-lymphocyte-based vaccines may need to account for differential effects of host-driven viral evolution on viral fitness.
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