Human immunodeficiency virus type 1-specific CD8+ T-cell responses during primary infection are major determinants of the viral set point and loss of CD4+ T cells

Abstract

Primary HIV-1 infection (PHI) is marked by a flu-like syndrome and high levels of viremia that decrease to a viral set point with the first emergence of virus-specific CD8+ T-cell responses. Here, we investigated in a large cohort of 527 subjects the immunodominance pattern of the first virus-specific cytotoxic T-lymphocyte (CTL) responses developed during PHI in comparison to CTL responses in chronic infection and demonstrated a distinct relationship between the early virus-specific CTL responses and the viral set point, as well as the slope of CD4+ T-cell decline. CTL responses during PHI followed clear hierarchical immunodominance patterns that were lost during the transition to chronic infection. Importantly, the immunodominance patterns of human immunodeficiency virus type 1 (HIV-1)-specific CTL responses detected in primary, but not in chronic, HIV-1 infection were significantly associated with the subsequent set point of viral replication. Moreover, the preservation of the initial CD8+ T-cell immunodominance patterns from the acute into the chronic phase of infection was significantly associated with slower CD4+ T-cell decline. Taken together, these data show that the specificity of the initial CTL response to HIV is critical for the subsequent control of viremia and have important implications for the rational selection of antigens for future HIV-1 vaccines.

FIG. 1.

Immunodominance pattern of CD8⁺ T-cell responses targeted during PHI (A) and chronic HIV-1 infection (B). (A) The recognition of described HLA class I matched HIV-1-specific CD8⁺ T-cell epitopes is shown ranked based on the frequencies of recognition of these epitopes by CD8⁺ T cells in subjects (n = 428) expressing the respective HLA alleles ([%] fraction of responders) during PHI. The order of recognition, HLA class I restrictions, protein locations, and sequences of these optimal epitopes (1 to 222) are listed in Table S1 in the supplemental material. (B) Frequencies of recognition by CD8⁺ T cells during chronic infection for the same optimal epitopes (n = 99).

FIG. 2.

Correlation between immunodominance patterns of HIV-1-specific CD8⁺ T-cell responses and the viral set point. The early viral set points 6 months after infection were determined for 110 subjects identified during PHI who remained treatment naïve. (A) Correlation between the contributions of the immunodominant HIV-1-specific CD8⁺ T-cell responses restricted by each HLA class I allele to the total virus-specific CD8⁺ T-cell responses and the average viral set point for the respective HLA class I allele (n = 110). The average viral load showed a significant inverse correlation (R = −0.39; P = 0.03) with the percent contribution of immunodominant HIV-1-specific immune responses restricted by the respective HLA class I allele to the total response, and it became more prominent (P = 0.007) after removal of the outlier B8-FL8 (Nef) (▪) based on Cook's outlier analysis (R = −0.49). (B) Correlation between the frequencies of recognition ([%] fraction of responders expressing the respective HLA allele) of the most immunodominant HIV-1-specific CD8⁺ T-cell epitope restricted by each HLA class I allele and the average viral set point for subjects (n = 110) expressing the respective HLA class I allele. The average viral load showed an inverse correlation (P = 0.07) with the (%) recognition of the immunodominant CD8⁺ T-cell epitope restricted by the respective HLA class I allele (R = −0.33) and became statistically significant (R = −0.43; P = 0.03) after removal of the outlier B8-FL8 (Nef) (▪) based on Cook's outlier analysis.

FIG. 3.

Correlation of the frequency and contribution of HIV-1-specific CD8⁺ T-cell responses during primary infection and the viral set point derived from the MACS cohort. The fraction of responders to the immunodominant epitope detected during PHI for each HLA class I allele was calculated for the 428 subjects during PHI (A) and the 99 subjects during chronic HIV-1 infection (B) and correlated with the mean log₁₀ viral set point derived from the MACS cohort for each HLA class I allele. The numbers on the x axes represent the average mean log₁₀ viral loads, ranging from 3.8 to 4.8. The individual immunodominant epitopes for each HLA class I allele and their frequencies of recognition in primary and chronic infection are shown in Table S2 in the supplemental material. We observed a significant inverse correlation between the fraction of responders and the plasma viral set point for the subjects expressing the respective HLA class I allele (determined 1.5 to 3 years after infection) (R = −0.42; P = 0.009), while no correlation was observed with the frequency of epitope recognition determined in the chronic phase of HIV-1 infection and the mean log₁₀ viral set point derived from the MACS cohort (R = −0.2; P = 0.22). (C) Correlation between the contribution of the immunodominant HIV-1-specific CD8⁺ T-cell responses restricted by each HLA class I allele to the total virus-specific CD8⁺ T-cell responses and the average viral set point for the respective HLA class I allele derived from the MACS cohort. (D) The average viral load showed an inverse correlation (R = −0.37; P = 0.03) with the (%) contribution of HIV-1-specific immune responses restricted by the respective HLA class I allele to the total number of responses, while no correlation was observed with the frequency of epitope recognition of the early immunodominant CD8⁺ T-cell responses determined in the chronic phase of HIV-1 infection and the mean log₁₀ viral set point derived from the MACS cohort (R = −0.14; P = 0.4).

FIG. 4.

Correlation between the frequency of HIV-1-specific CD8⁺ T-cell response during primary infection and the slope of CD4 decline derived from the MACS cohort. The fraction of responders to the immunodominant epitope detected during PHI for each HLA class I allele was calculated during PHI (n = 428) (A) and chronic HIV-1 infection (n = 99) (B) and correlated with the slope of CD4 decline derived from the MACS cohort for each respective HLA class I allele. The numbers on the x axes represent the average slopes of CD4 decline, ranging from −1.8 (representing a faster loss of CD4 cells) to −1 (representing a slower loss of CD4 cells). The individual immunodominant epitopes for each HLA class I allele and their frequencies of recognition in primary and chronic infection are shown in Table S2 in the supplemental material.