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Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients

Journal Article · · Journal of Experimental Medicine
DOI:https://doi.org/10.1084/jem.20072457· OSTI ID:1625193
 [1];  [2];  [2];  [3];  [3];  [4];  [2];  [2];  [5];  [5];  [6];  [4];  [7];  [2];  [8];  [2]
  1. University of Alabama, Birmingham, AL (United States); DOE/OSTI
  2. Emory University, Atlanta, GA (United States)
  3. University of Oxford (United Kingdom)
  4. Microsoft Research, Redmond, WA (United States)
  5. University of Alabama, Birmingham, AL (United States)
  6. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  7. Zambia-Emory HIV Research Group, Lusaka (Zambia)
  8. Emory University, Atlanta, GA (United States); University of KwaZulu-Natal, Durban (South Africa); Massachusetts General Hospital, Charlestown, MA (United States)
+ Show Author Affiliations
In a study of 114 epidemiologically linked Zambian transmission pairs, we evaluated the impact of human leukocyte antigen class I (HLA-I)–associated amino acid polymorphisms, presumed to reflect cytotoxic T lymphocyte (CTL) escape in Gag and Nef of the virus transmitted from the chronically infected donor, on the plasma viral load (VL) in matched recipients 6 mo after infection. CTL escape mutations in Gag and Nef were seen in the donors, which were subsequently transmitted to recipients, largely unchanged soon after infection. We observed a significant correlation between the number of Gag escape mutations targeted by specific HLA-B allele–restricted CTLs and reduced VLs in the recipients. This negative correlation was most evident in newly infected individuals, whose HLA alleles were unable to effectively target Gag and select for CTL escape mutations in this gene. Nef mutations in the donor had no impact on VL in the recipient. Thus, broad Gag-specific CTL responses capable of driving virus escape in the donor may be of clinical benefit to both the donor and recipient. In addition to their direct implications for HIV-1 vaccine design, these data suggest that CTL-induced viral polymorphisms and their associated in vivo viral fitness costs could have a significant impact on HIV-1 pathogenesis.
Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
International AIDS Vaccine Initiative; Medical Research Fund UK; Microsoft Research; 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:
1625193
Journal Information:
Journal of Experimental Medicine, Journal Name: Journal of Experimental Medicine Journal Issue: 5 Vol. 205; ISSN 0022-1007
Publisher:
Rockefeller University PressCopyright Statement
Country of Publication:
United States
Language:
English

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Human Leukocyte Antigens and HIV Type 1 Viral Load in Early and Chronic Infection: Predominance of Evolving Relationships journal March 2010
HLA-Associated Immune Pressure on Gag Protein in CRF01_AE-Infected Individuals and Its Association with Plasma Viral Load journal June 2010
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Progression to AIDS in South Africa Is Associated with both Reverting and Compensatory Viral Mutations journal April 2011
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Reversion and T Cell Escape Mutations Compensate the Fitness Loss of a CD8+ T Cell Escape Mutant in Their Cognate Transmitted/Founder Virus journal July 2014
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Modelling the Evolution and Spread of HIV Immune Escape Mutants journal November 2010
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Whole Genome Deep Sequencing of HIV-1 Reveals the Impact of Early Minor Variants Upon Immune Recognition During Acute Infection journal March 2012
HLA-Cw*0102-Restricted HIV-1 p24 Epitope Variants Can Modulate the Binding of the Inhibitory KIR2DL2 Receptor and Primary NK Cell Function journal July 2012
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Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease posted_content January 2019
Specific antibody-dependent cellular cytotoxicity responses associated with slow progression of HIV infection journal January 2013
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