CCR5 expression, haplotype and immune activation in protection from infection in HIV-exposed uninfected individuals in HIV-serodiscordant relationships

Abstract

Several host factors have been implicated in resistance to HIV infection in individuals who remain HIV-seronegative despite exposure. In a cohort of HIV-serodiscordant heterosexual couples, we investigated interactions between systemic inflammation and T-cell activation in resistance to HIV infection. Males and females in stable long-term relationships with either HIV-infected or uninfected partners were recruited, blood T-cell activation (CD38, HLA-DR, CCR5 and Ki67) and plasma cytokine concentrations were evaluated. The HIV-negative exposed individuals had significantly lower frequencies of CCR5⁺ CD4⁺ and CD8⁺ T cells than unexposed individuals. Mean fluorescence intensity of CCR5 expression on CD4⁺ T cells was significantly lower in HIV-negative exposed than unexposed individuals. Protective CCR5 haplotypes (HHA/HHF*2, HHF*2/HHF*2, HHC/HHF*2, HHA/HHA, HHA/HHC and HHA/HHD) tended to be over-represented in exposed compared with unexposed individuals (38% versus 28%, P = 0·58) whereas deleterious genotypes (HHC/HHD, HHC/HHE, HHD/HHE, HHD/HHD and HHE/HHE) were under-represented (26% versus 44%; P = 0·16). Plasma concentrations of interleukin-2 (P = 0·02), interferon-γ (P = 0·05) and granulocyte-macrophage colony-stimulating factor (P = 0·006) were lower in exposed compared with unexposed individuals. Activation marker expression and systemic cytokine concentrations were not influenced by gender. We conclude that the dominant signature of resistance to HIV infection in this cohort of exposed but uninfected individuals was lower T-cell CCR5 expression and plasma cytokine concentrations.

Keywords: CCR5; HIV; immune activation; resistance.

Figure 1

Impact of partner HIV status on specific T‐cell activation (expression of CD38, HLA‐DR, or Ki67) and CCR5 expression in HIV‐unexposed (open) versus HIV exposed–uninfected (shaded) individuals. Frequency of specific activation marker expression (Ki67, HLA‐DR, CD38) and CCR5 expression on CD4⁺ (a and c) and CD8⁺ (b and d) T cells derived from the blood of HIV‐exposed (n = 30) and unexposed (n = 38) was assayed. The % of T cells in each group of individuals is depicted by box‐and‐whisker plots indicating the median (middle line), 25th (bottom line) and 75th centiles (top line), and the range (whiskers) of the frequencies of T cells expressing the respective activation markers. Assessments of differences between exposed and unexposed participants were carried out using the Mann–Whitney U‐test.

Figure 2

Impact of partner HIV status on density of CCR5 expression by T cells (measured by mean fluorescence intensity). The cumulative MFI in each group of individuals is depicted by box‐and‐whisker plots indicating the median (middle line), 25th (bottom line) and 75th centiles (top line), and the range (whiskers). Assessments of differences between exposed and unexposed participants were carried out using the Mann–Whitney U‐test.

Figure 3

Impact of gender on specific T‐cell activation (expression of CD38, HLA‐DR, or Ki67) and CCR5 expression. Frequency of specific activation marker expression (Ki67, HLA‐DR, CD38) and CCR5 expression on CD4⁺ (a and c) and CD8⁺ (b and d) T cells derived from the blood of men and women was assayed. The % of T cells in each group of individuals is depicted by box‐and‐whisker plots indicating the median (middle line), 25th (bottom line) and 75th centiles (top line), and the range (whiskers) of the frequencies of T cells expressing the respective activation markers. Assessments of differences between men and women was carried out using the Mann–Whitney U‐test.

Figure 4

Distribution of CCR5 haplotypes and potential phenotypes across HIV‐exposed and unexposed individuals and their association with CCR5 expression level. (a) Distribution of CCR5 haplotypes previously described.24 (b) Distribution of phenotypes based on pre‐established sets of genotypes24, 33 conferring protection (Protective), increased risks (Deleterious) or no effect (Neutral) in the context of HIV‐1 infection and AIDS disease. (c) Influence of HHA and HHE haplotypes on CCR5 expression within CD4⁺ and CD8⁺ T‐cell subsets. Individuals with or without an HHA allele were designated as HHA+ and HHA− respectively. Individuals with or without an HHE allele were designated as HHE+ and HHE−, respectively. Matching CCR5 expression data and CCR5 haplotypes was available for 33 participants (n = 14 for HHA+, 19 for HHA−, 16 for HHE+ and 17 for HHE−). (d) Influence of protective, deleterious, or neutral CCR5 genotypes on CCR5 expression by CD4⁺ and CD8⁺ T‐cell subsets.