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Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA

Journal Article · · Journal of Experimental Medicine
DOI:https://doi.org/10.1084/jem.20041455· OSTI ID:1625186
 [1];  [2];  [3];  [4];  [4];  [4];  [4];  [3];  [3];  [2];  [2];  [5];  [6];  [2];  [4];  [7];  [7];  [8];  [8];  [2] more »;  [9];  [4];  [4];  [9];  [3];  [10];  [11] « less
  1. University of Oxford (United Kingdom); DOE/OSTI
  2. Massachusetts General Hospital, Charlestown, MA (United States)
  3. University of Natal, Durban (South Africa)
  4. University of Oxford (United Kingdom)
  5. High Wycombe General Hospital, Buckinghamshire (United Kingdom)
  6. Radcliffe Infirmary, Oxford (United Kingdom)
  7. University of Washington, Seattle, WA (United States)
  8. Royal Perth Hospital, Perth, WA (Australia)
  9. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
  10. Massachusetts General Hospital, Charlestown, MA (United States); University of Natal, Durban (South Africa)
  11. University of Oxford (United Kingdom); Massachusetts General Hospital, Charlestown, MA (United States); University of Natal, Durban (South Africa)
+ Show Author Affiliations
Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of “negatively associated” or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.
Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
Doris Duke Charitable Foundation; Elizabeth Glaser Pediatric AIDS Foundation; National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; Wellcome Trust
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1625186
Journal Information:
Journal of Experimental Medicine, Journal Name: Journal of Experimental Medicine Journal Issue: 6 Vol. 201; ISSN 0022-1007
Publisher:
Rockefeller University PressCopyright Statement
Country of Publication:
United States
Language:
English

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Early immune adaptation in HIV-1 revealed by population-level approaches journal August 2014
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Frequent Toggling between Alternative Amino Acids Is Driven by Selection in HIV-1 journal December 2008
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59 BASIC BIOLOGICAL SCIENCES
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