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. 2012 Jan;86(2):1166-80.
doi: 10.1128/JVI.05721-11. Epub 2011 Nov 9.

For protection from HIV-1 infection, more might not be better: a systematic analysis of HIV Gag epitopes of two alleles associated with different outcomes of HIV-1 infection

Ma Luo  1 , Christina A Daniuk, Tamsir O Diallo, Rupert E Capina, Joshua Kimani, Charles Wachihi, Makubo Kimani, Thomas Bielawny, Trevor Peterson, Mark G R Mendoza, Sandra Kiazyk, T Blake Ball, Francis A Plummer
Affiliations

For protection from HIV-1 infection, more might not be better: a systematic analysis of HIV Gag epitopes of two alleles associated with different outcomes of HIV-1 infection

Ma Luo et al. J Virol. 2012 Jan.

Abstract

A subset of women in the Pumwani Sex Worker Cohort, established in 1985 in Nairobi, Kenya, remains uninfected despite repeated high-risk exposure (HIV-exposed, seronegative [HESN]) through active sex work. This HESN phenotype is associated with several alleles of human leukocyte antigens (HLAs) and specific CD8(+) and CD4(+) T cell responses to HIV-1. The associations of HLA alleles with differential HIV-1 infection are most likely due to their different abilities to present antigen and the different immune responses they induce. The characteristics of epitopes of HLA alleles associated with different outcomes of HIV-1 infection might therefore point to a vital clue for developing an effective vaccine. In this study, we systematically analyzed HIV-1 clade A and D Gag CD8(+) T cell epitopes of two HLA class I alleles associated with different outcomes of HIV-1 infection. Binding affinity and off-rates of the identified epitopes were determined. Gamma interferon (IFN-γ) enzyme-linked immunospot (ELISpot) assays with patient peripheral blood mononuclear cells (PBMCs) validated the epitopes. Epitope-specific CD8(+) T cells were further phenotyped for memory markers with tetramer staining. Our study showed that the protective allele A*01:01 recognizes only three Gag epitopes. By contrast, B*07:02, the allele associated with susceptibility, binds 30 epitope variants. These two alleles differ most importantly in the spectrum of Gag epitopes they can present and not in affinity, off-rates, the location of the epitopes, or epitope-specific Tem/Tcm frequencies. The binding of more epitopes and strong IFN-gamma ELISpot responses are associated with susceptibility to HIV-1 infection, while more focused antigen recognition of multiple subtypes is protective. Rational vaccine design should take these observations into account.

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Figures

Fig 1
Fig 1
Kaplan-Meier analysis of seroconversion in the Pumwani Sex Worker Cohort. (A) Women with A*01:01 were significantly less likely to seroconvert than individuals without A*01. Solid line, with A*01; dashed line, without A*01. (B) Women with B*07:02 were significantly more likely to seroconvert than individuals without B*07:02. Solid line, with B*07:02; dashed line, without B*07:02.
Fig 2
Fig 2
The binding, affinity, and off-rates of A*01:01 HIV-1 Gag epitopes. (A) The level of binding of Gag epitopes to A*01:01. (B) The binding affinity of A*01:01 Gag epitopes. (C) The off-rates of A*01:01 Gag epitopes. (D) The binding of variant peptides of A*01:01 epitope NSSKVSQNY. (E) The binding affinity of epitope variants to A*01:01. (F) The off-rates of A*01:01 epitope variants.
Fig 3
Fig 3
The binding, affinity, and off-rates of B*07:02 HIV-1 Gag epitopes. (A) The level of binding of Gag epitopes to B*07:02. (B to D) The binding affinity of B*07:02 Gag epitopes. (E to G) The off-rates of B*07:02 Gag epitopes.
Fig 4
Fig 4
The location of HIV-1 Gag epitopes of A*01:01 and B*07:02. A*01:01 epitopes are highlighted in yellow, and B*07:02 epitopes are highlighted in red. The epitope variants are shaded in gray. PRC, protease cleavage sites. The clade A Gag consensus is at the top of the alignment, and the clade D consensus is at the bottom.
Fig 5
Fig 5
Comparison of the HIV-1 Gag epitopes of A*01:01 and B*07:02. (A) Binding affinities of HIV-1 Gag epitopes and epitope variants of A*01:01 and B*07:02. (B) Off-rates of HIV-1 Gag epitopes and epitope variants of A*01:01 and B*07:02. (C) IFN-γ ELISpot responses of HIV-1 Gag epitopes and epitope variants of A*01:01 and B*07:02. (D) Comparison of ELISpot responses to the A*01:01 and B*07:02 peptides among HESN, NSN, and POS.
Fig 6
Fig 6
Phenotype analysis of A*01:01 and B*07:02 epitope-specific CD8+ T cells. (A) Identification of circulating HIV-specific CD8+ T cells with Gag HLA peptide tetrameric complex. Results represent analyses of samples from representative HIV-1-seropositive subjects. (B) Visualization of virus-specific CD8+ T cells by staining ex vivo with MHC-I tetramers and surface expression of memory/effector phenotypic markers. All cells shown are a result of a gate on the specific CD8 subset to a tetramer. (Top) Representative figure showing surface expression of CCR7 and CD45-RA on specific HIV-1 CD8-T cells to A*01:01-NSSKVSQNY and B*07:02-APRKKGCWK tetramers. Numbers in the quadrants indicate percentages of cells. (Bottom) Comparison of percentages of markers expressed by CCR7 and CD45-RA (NC, naive cells; CM, central memory; EM, effector memory; TD: terminal differential) on specific HIV-1 CD8-T cells to A*01:01-NSSKVSQNY, B*07:02-APRKKGCWK, and B*07:02-SPRTLNAWV tetramers. Data are from the participants with HIV-1 tetramer reactivity (n = 3 for A*01:01-NSSKVSQNY and for B*07:02-APRKKGCWK and B*07:02-SPRTLNAWV). (C) Comparison of CD27 and CD28 expression in CD8+ T cells of A*01:01-NSSKVSQNY, B*07:02-APRKKGCWK, and B*07:02-SPRTLNAWV tetramers. Representative figure showing surface expression of CD28+ CD27− (left) and surface expression of CD28− CD27− (right) on specific HIV-1 CD8-T cells to each tetramer. Data are from participants with HIV-1 tetramer reactivity (n = 3 for A*01:01-NSSKVSQNY and for B*07:02-APRKKGCWK and B*07:02-SPRTLNAWV).
Fig 7
Fig 7
Confirmation of epitopes identified using the iTopia epitope discovery system by IFN-γ ELISpot assays. (A) Percent responders among all subjects with A*01:01 or B*07:02 tested using either fresh PBMCs or PBMCs that were stored in liquid nitrogen. (B) Percent responders among subjects with A*01:01 or B*07:02 tested using fresh PBMCs.
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References

    1. Abrahams MR, et al. 2009. Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-poisson distribution of transmitted variants. J. Virol. 83:3556–3567 - PMC - PubMed
    1. Ahlers JD, Belyakov IM. Lessons learned from natural infection: focusing on the design of protective T cell vaccines for HIV/AIDS. Trends Immunol. 31:120–130 - PubMed
    1. AIDS Vaccine Advocacy Coalition 2004. Support for the RV144 HIV vaccine trial. Science 305:177–180; author reply 177–180 - PubMed
    1. Alimonti JB, et al. 2006. Characterization of CD8 T-cell responses in HIV-1-exposed seronegative commercial sex workers from Nairobi, Kenya. Immunol. Cell Biol. 84:482–485 - PubMed
    1. Alimonti JB, et al. 2005. CD4+ T cell responses in HIV-exposed seronegative women are qualitatively distinct from those in HIV-infected women. J. Infect. Dis. 191:20–24 - PubMed

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