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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
HIV control through a single nucleotide on the HLA-B locus
Henrik N Kløverpris1, Mikkel Harndahl, Alasdair J Leslie
1Department of Paediatrics, University of Oxford, Oxford, United Kingdom. henrik.kloverpris@paediatrics.ox.ac.uk
Journal of Virology
|August 17, 2012
Summary
A single amino acid change in the HLA-B gene significantly impacts HIV progression by altering T cell responses. This finding clarifies how specific human leukocyte antigen (HLA) variations influence viral load and disease control in HIV infection.
Area of Science:
- Immunogenetics
- Human Virology
- Molecular Biology
Background:
- Genetic variations in the Human Leukocyte Antigen (HLA)-B locus are strongly associated with HIV disease progression.
- Distinguishing individual HLA allele effects is challenging due to linkage disequilibrium and complex interactions with NK and CD8 T cells.
Purpose of the Study:
- To investigate the precise mechanism by which a single amino acid difference between two closely related HLA-B alleles (HLA-B*42:01 and HLA-B*42:02) affects HIV disease progression.
- To elucidate the role of specific cytotoxic T lymphocyte (CTL) epitopes presented by these alleles in controlling viral load.
Main Methods:
- Utilized a natural experiment comparing HLA-B*42:01 and HLA-B*42:02 in an HIV C-clade infected cohort (n=2,093).
- Assessed peptide binding and CTL epitope presentation ex vivo using gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assays.
- Analyzed CTL escape mutations and viral load set points in relation to HLA allele type.
Main Results:
- A single amino acid change at position 9 of HLA-B critically altered peptide binding and targeted CTL epitopes.
- HLA-B*42:01, presenting multiple Gag epitopes, was associated with significantly lower viral load set points compared to HLA-B*42:02, which presented no p24 Gag epitopes (P = 0.02).
- The observed effect size for this single amino acid difference was substantial, comparable to that of the highly protective HLA-B*57:03 allele.
Conclusions:
- This study provides clear evidence that a single amino acid substitution in HLA-B can profoundly impact HIV-specific CTL responses and disease control.
- The findings highlight the critical role of specific CTL epitopes in managing HIV infection and underscore the power of naturally controlled experiments in immunogenetics.
