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. 2012;7(8):e43690.
doi: 10.1371/journal.pone.0043690. Epub 2012 Aug 22.

Ex Vivo SIV-specific CD8 T Cell Responses in Heterozygous Animals Are Primarily Directed Against Peptides Presented by a Single MHC Haplotype

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Free PMC article

Ex Vivo SIV-specific CD8 T Cell Responses in Heterozygous Animals Are Primarily Directed Against Peptides Presented by a Single MHC Haplotype

Justin M Greene et al. PLoS One. .
Free PMC article

Abstract

The presence of certain MHC class I alleles is correlated with remarkable control of HIV and SIV, indicating that specific CD8 T cell responses can effectively reduce viral replication. It remains unclear whether epitopic breadth is an important feature of this control. Previous studies have suggested that individuals heterozygous at the MHC class I loci survive longer and/or progress more slowly than those who are homozygous at these loci, perhaps due to increased breadth of the CD8 T cell response. We used Mauritian cynomolgus macaques with defined MHC haplotypes and viral inhibition assays to directly compare CD8 T cell efficacy in MHC-heterozygous and homozygous individuals. Surprisingly, we found that cells from heterozygotes suppress viral replication most effectively on target cells from animals homozygous for only one of two potential haplotypes. The same heterozygous effector cells did not effectively inhibit viral replication as effectively on the target cells homozygous for the other haplotype. These results indicate that the greater potential breadth of CD8 T cell responses present in heterozygous animals does not necessarily lead to greater antiviral efficacy and suggest that SIV-specific CD8 T cell responses in heterozygous animals have a skewed focus toward epitopes restricted by a single haplotype.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Viral suppression assay schematic.
Target cells are prepared on Day 1 by CD8 depleting PBMC and stimulating cells with ConA. Cells are washed on Day 2. On Day 4 target cells are superinfected in vitro with SIVmac239 and plated in a 96 well plate. Effector cells are prepared by isolating CD8β T cells from PBMC. Effector cells are added to target cells in a 1∶1 ratio. Each combination of effector and target cells was compared in this assay.
Figure 2
Figure 2. Viral load does not correlate with CD8 T cell efficacy in vitro.
A) Plasma viral loads were plotted against the percentage of p27+ cells after eight days in culture in wells where cells were not superinfected in vitro. These results display the growth of autologous virus. B) Viral loads were plotted against the normalized percent suppression on autologous target cells. C) Viral loads were plotted against the percentage of target cells that were p27+ after in vitro superinfection in the no effector control wells. D) The normalized % suppresion was plotted against the percentage of p27+ targets in the no infection control wells. E) Normalized percent suppression was plotted against the percent of p27+ targets in the no effector control wells. F) The percent of p27+ targets in the no infection wells was plotted against the percent of p27+ targets in the no effector control wells.
Figure 3
Figure 3. Viral suppression by effector cells from homozygous animals.
A) Each plot represents the results from an individual M3/M3 effector animal on each target animal. Each column in the graph displays a different target animal haplotype. B) Table showing the Tukey’s Multiple Comparison Test of the columns in each of the graphs (*p<0.05; **p<0.01; ***p<0.001). C) Each plot represents the results from an individual M1/M1 effector animal on each target animal. Each column in the graph displays a different target animal haplotype. D) Table showing the Tukey’s Multiple Comparison Test of the columns in each of the graphs (*p<0.05; **p<0.01; ***p<0.001).
Figure 4
Figure 4. Viral suppression by effector cells from heterozygous animals.
A) Each plot represents the results from an individual M1/M3 effector animal on each target animal. Each column in the graph displays a different target animal haplotype. B) Table showing the Tukey’s Multiple Comparison Test of the columns in each of the graphs (*p<0.05; **p<0.01; ***p<0.001).

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References

    1. Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, et al. (2010) Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 329: 1168–1174. - PMC - PubMed
    1. Pitisuttithum P, Gilbert P, Gurwith M, Heyward W, Martin M, et al. (2006) Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J Infect Dis 194: 1661–1671. - PubMed
    1. Ogg GS, Jin X, Bonhoeffer S, Dunbar PR, Nowak MA, et al. (1998) Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279: 2103–2106. - PubMed
    1. Yasutomi Y, Reimann KA, Lord CI, Miller MD, Letvin NL (1993) Simian immunodeficiency virus-specific CD8+ lymphocyte response in acutely infected rhesus monkeys. J Virol 67: 1707–1711. - PMC - PubMed
    1. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB (1994) Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 68: 6103–6110. - PMC - PubMed

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