Our data indicate that insufficient help of CD4(+) T cells may cause loss of IFN- gamma -producing CD8(+) T cells and loss of control of CMV dissemination. Increasing CMV-infected cell counts in the face of high CMV-specific perforin- and granzyme B-expressing CD8(+) T cell counts may explain the immune pathological characteristics of CMV disease.
Strong statistical associations between polymorphisms in HIV-1 population sequences and carriage of HLA class I alleles have been widely used to identify possible sites of CD8 T cell immune selection in vivo. However, there have been few attempts to prospectively and systematically test these genetic “hypotheses” arising from population-based studies at a cellular, functional level.
We assayed CD8 T cell epitope-specific IFNγ responses in 290 individuals from the same cohort which gave rise to 874 HLA-HIV associations in genetic analyses, taking into account autologous viral sequences and individual HLA genotypes. We found immunological evidence for 58% of 374 associations tested as sites of primary immune selection and identified up to 50 novel HIV-1 epitopes using this “reverse genomics” approach. Many HLA adapted epitopes elicited equivalent or higher magnitude IFNγ responses than the non-adapted epitopes, particularly in Nef. At a population level, inclusion of all the immunoreactive variant CD8 T cell epitopes in Gag, Pol, Nef and Env suggested that HIV adaptation leads to an inflation of Nef-directed immune responses relative to other proteins.
We conclude that HLA-HIV associations do mark viral epitopes subject to CD8 T cell selection. These results can be used to guide functional studies of specific epitopes and escape mutations as well as test, train and evaluate analytical models of viral escape and fitness. The inflation of Nef and HLA adapted variant responses may have negative effects on natural and vaccine immunity against HIV, and therefore has implications for diversity coverage approaches in HIV vaccine design.
Objective
To define the relative frequencies of different mechanisms of viral escape.
Design
A population-based approach to examine the distribution of HIV polymorphism associated with diverse population human leucocyte antigens (HLAs) at sites within and flanking CD8 T-cell epitopes as a correlate of likely mechanisms of viral escape.
Methods
Sequence windows surrounding 874 HLA allele-specific polymorphisms across the full HIV-1 proteomic consensus sequence were scanned by an epitope-prediction programme. Either already known or probable CD8 T-cell epitopes with HLA restriction matching that of the proximal HLA association were identified and synthesized. These peptides were used as stimulating antigens in automated enzyme-linked immunospot (ELISpot) assays. Peptide arrays were customized to each individual based on their HLA genotype.
Results
Among HLA-associated HIV polymorphisms detected in the viral sequences of a cohort of 800 individuals with chronic subtype B HIV infection, those which were likely to affect HLA peptide binding were significantly more common than polymorphisms at nonanchor HLA binding sites. HIV epitopes with such polymorphisms were associated with reduced IFNγ responses in ELISpot assays. HIV escape at sites affecting T-cell receptor (TCR) engagement and epitope processing were also evident.
Conclusion
HIV escape from HLA-peptide binding predominates as an effective viral evasion strategy and therefore has implications for inclusion of HLA-adapted epitopes in vaccine immunogens.
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