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Updated: May 19, 2026
A Restriction Enzyme Based Cloning Method to Assess the In vitro Replication Capacity of HIV-1 Subtype C Gag-MJ4 Chimeric Viruses
Published on: August 31, 2014
Temporal association of HLA-B*81:01- and HLA-B*39:10-mediated HIV-1 p24 sequence evolution with disease progression
R S Ntale1, D R Chopera, N K Ngandu
1Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Insights
Human Leukocyte Antigen (HLA)-B*81:01 alleles influence HIV-1 subtype C evolution. Escape mutations in the TL9 epitope impact viral load control, demonstrating HLA-B*81:01
Area of Science:
- Immunogenetics
- Virology
- HIV Pathogenesis
Background:
- Certain Human Leukocyte Antigen (HLA) alleles, including HLA-B*81:01 and HLA-B*39:10, are linked to controlling HIV-1 subtype C.
- These HLA alleles restrict the p24 Gag TL9 epitope, and escape mutations are associated with a viral fitness cost.
Purpose of the Study:
- To investigate the timing and impact of mutations within the TL9 epitope on disease progression in individuals with HIV-1 subtype C carrying HLA-B*81:01 or HLA-B*39:10.
Main Methods:
- Analysis of viral sequences from HIV-1 subtype C infected individuals (n=7) with specific HLA alleles (HLA-B*81:01 and HLA-B*39:10).
- Tracking of escape mutations in the TL9 epitope over time post-infection.
- Correlation of escape mutations with viral load and coevolving residues in Gag.
Main Results:
- HLA-B*39:10 participants showed early TL9 escape mutations (within 2 months post-infection).
- HLA-B*81:01 participants exhibited variable timing of TL9 escape mutations, with some showing late escape (10 months post-infection) or no detectable escape.
- Escape mutations were linked to Gag coevolution and, in some cases, late increases in viral load, particularly in HLA-B*81:01 individuals.
Conclusions:
- The timing of TL9 escape mutations varies between HLA-B*39:10 and HLA-B*81:01 alleles in HIV-1 subtype C.
- Late escape mutations in the TL9 epitope, coupled with compensatory mutations, can detrimentally impact viral load control in individuals with HLA-B*81:01.
- This study provides in vivo evidence for HLA-B*81:01-driven viral evolution affecting viremia control through a single Gag p24 epitope.
Abstract:
HLA-B*81:01 and HLA-B*39:10 alleles have been associated with viremic control in HIV-1 subtype C infection. Both alleles restrict the TL9 epitope in p24 Gag, and cytotoxic-T-lymphocyte (CTL)-mediated escape mutations in this epitope have been associated with an in vitro fitness cost to the virus. We investigated the timing and impact of mutations in the TL9 epitope on disease progression in five B*81:01- and two B*39:10-positive subtype C-infected individuals. Whereas both B*39:10 participants sampled at 2 months postinfection had viruses with mutations in the TL9 epitope, in three of the five (3/5) B*81:01 participants, TL9 escape mutations were only detected 10 months after infection, taking an additional 10 to 15 months to reach fixation. In the two remaining B*81:01 individuals, one carried a TL9 escape variant at 2 weeks postinfection, whereas no escape mutations were detected in the virus from the other participant for up to 33 months postinfection, despite CTL targeting of the epitope. In all participants, escape mutations in TL9 were linked to coevolving residues in the region of Gag known to be associated with host tropism. Late escape in TL9, together with coevolution of putative compensatory mutations, coincided with a spontaneous increase in viral loads in two individuals who were otherwise controlling the infection. These results provide in vivo evidence of the detrimental impact of B*81:01-mediated viral evolution, in a single Gag p24 epitope, on the control of viremia.
