Preferential CTL targeting of Gag is associated with relative viral control in long-term surviving HIV-1 infected former plasma donors from China

Abstract

It is generally believed that CD8(+) cytotoxic T lymphocytes (CTLs) play a critical role in limiting the replication of human immunodeficiency virus type 1 (HIV-1) and in determining the outcome of the infection, and this effect may partly depend on which HIV product is preferentially targeted. To address the correlation between HIV-1-specific CTL responses and virus replication in a cohort of former plasma donors (FPDs), 143 antiretroviral therapy naive FPDs infected with HIV-1 clade B' strains were assessed for HIV-1-specific CTL responses with an IFN-γ Elispot assay at single peptide level by using overlapping peptides (OLPs) covering the whole consensus clade B proteome. By using a Spearman's rank correlation analysis, we found that the proportion of Gag-specific CTL responses among the total virus-specific CTL activity was inversely correlated with viral loads while being positively correlated to CD4 counts, as opposed to Pol- and Env-specific responses that were associated with increased viral loads and decreased CD4 counts. In addition, Vpr-specifc CTL responses showed a similar protective effect with Gag responses, but with a much lower frequency of recognition. Significantly, we also observed an association between HLA-A*30/B*13/Cw*06 haplotype and lower viral loads that was probably due to restricted Gag-specific CTL responses. Thus, our data demonstrate the prominent role of Gag-specific CTL responses in disease control. The advantage of HLA-A*30/B*13/Cw*06 haplotype in viral control may be associated with the contribution of Gag-specific CTL responses in the studied individuals.

Figure 1

The overall CTL responses are distributed over the HIV proteome and cluster in immunodominant regions. A total of 143 FPDs infected with HIV-1 B' were tested by using an OLP set of 413 peptides. The figure shows the frequency of recognition for each single peptide among the 143 subjects tested (y axis). The words under x axis indicate the HIV proteins spanned by the OLPs.

Figure 2

Correlation of the magnitude and contribution of HIV-1-specific CTL responses with plasma viral loads. (A) For the 143 untreated and chronically infected subjects, the magnitude of responses was compared to individuals' viral loads. (B) Relative magnitude was calculated for the proportion of the HIV-1 Gag-, Pol- and Env-specific response among the total response, and compared to individuals' viral loads. The numbers on the y axis represent the log₁₀ viral load. P-values (two-sided) and r_s values are based on Spearman's rank test. The solid lines represent the linear trend.

Figure 3

Correlation of the breadth and contribution of HIV-1-specific CTL responses with plasma viral loads. (A) For the 143 untreated and chronically infected subjects, the breadth of responses was compared to individuals' viral loads. (B) Relative breadth was calculated for the proportion of the HIV-1 Gag-, Pol- and Env-specific response among the total response, and compared to individuals' viral loads. The numbers on the y axis represent the log₁₀ viral load. P-values (two-sided) and r_s values are based on Spearman's rank test. The solid lines represent the linear trend.

Figure 4

Distribution of HIV-1-specific CTL responses among different disease progression groups. (A) Distribution of HIV-1-specific CTL responses within 14 elite controllers and 17 AIDS patients to nine HIV-1 proteins. CTL responses to each HIV-1 protein in color coding are illustrated for each subject. (B) A detailed illustration shows the recognition for each single OLP among the two groups. The red bars indicate the OLPs with a higher frequency of recognition within AIDS patients than elite controllers, while the green bars indicate the OLPs with a higher frequency of recognition within elite controllers. Left y axis indicates the individuals. Right y axis represents the HLA typing results of the individuals. The x axis indicates the nine HIV proteins spanned by the OLPs.

Figure 5

The association of HLA-I molecules with the control of viral replication. (A) The difference of viral loads between the individuals with and without HLA-A^*30, B^*13, Cw^*06 and the HLA-A^*30/B^*13/Cw^*06 haplotype. The red bars show the median with interquartile range. ^*Represents a P-value < 0.05. (B) Comparison of the HIV-1 protein-specific CTL responses between the individuals with and without the HLA-A^*30/B^*13/Cw^*06 haplotype. The box plots show the median (horizontal line), interquartile range (box), the 10th and 90th percentiles (whiskers), and the 5th and 95th percentiles (points). ^*Represents a P-value < 0.05. (C) The associations between viral loads and Gag- and Env-specific CTL responses in the individuals with the HLA-A^*30/B^*13/Cw^*06 haplotype. (D) The associations between viral loads and Gag- and Env-specific CTL responses in the individuals without the HLA-A^*30/B^*13/Cw^*06 haplotype.