HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8(+) T Cell Response against HIV-1

Abstract

Background: Very little is known about the immunodominance patterns of HIV-1-specific T cell responses during primary HIV-1 infection and the reasons for human lymphocyte antigen (HLA) modulation of disease progression.

Methods and findings: In a cohort of 104 individuals with primary HIV-1 infection, we demonstrate that a subset of CD8(+) T cell epitopes within HIV-1 are consistently targeted early after infection, while other epitopes subsequently targeted through the same HLA class I alleles are rarely recognized. Certain HLA alleles consistently contributed more than others to the total virus-specific CD8(+) T cell response during primary infection, and also reduced the absolute magnitude of responses restricted by other alleles if coexpressed in the same individual, consistent with immunodomination. Furthermore, individual HLA class I alleles that have been associated with slower HIV-1 disease progression contributed strongly to the total HIV-1-specific CD8(+) T cell response during primary infection.

Conclusions: These data demonstrate consistent immunodominance patterns of HIV-1-specific CD8(+) T cell responses during primary infection and provide a mechanistic explanation for the protective effect of specific HLA class I alleles on HIV-1 disease progression.

Figure 1

Immunodominance Patterns for HIV-1-Specific CD8⁺ T Cell Responses Restricted by Individual HLA Class I Alleles Peptides corresponding to described optimal HIV-1-specific CD8⁺ T cell epitopes were tested in all study participants expressing the respective HLA class I allele. The average magnitude of CD8⁺ T cell responses specific for each tested peptide, given as SFCs per million input PBMCs (SFC/Mill PBMC), are shown as bars in the left part of each graph. The percentage of participants expressing the respective allele that had a detectable peptide-specific CD8⁺ T cell response are shown as bars on the right part of each graph. Epitopes are aligned for each HLA class I allele according to their frequency of recognition from top to bottom. The peptide number corresponds to the peptide sequence listed for each HLA allele and number in Table 2. Data are shown only for HLA class I alleles that were expressed in at least three individuals, and for which at least three HIV-1-specific optimal CD8⁺ T cell epitopes had been defined.

Figure 2. CD8⁺ T Cell responses Directed against the Most Frequently Recognized CD8⁺ T Cell Epitopes Were Also of the Highest Magnitude

(A) For each HLA class I allele studied, the four most frequently targeted HIV-1-specific CD8⁺ T cell epitopes were listed according to their hierarchy (for HLA class I alleles with only three described epitopes, the fourth value was excluded from the analysis). The average magnitudes of CD8⁺ T cell responses directed against the 1st, 2nd, 3rd, and 4th most frequently targeted epitope for each allele were calculated (given as SFCs per million input PBMCs [SFC/Mill PBMC]) and are shown as box plots. The average magnitude of the most frequently targeted HIV-1-specific CD8⁺ T cell epitopes restricted by each allele were significantly higher than the average magnitude of the 3rd and 4th most frequently targeted epitopes, and the respective p-values are provided above the box plot. (B) The sequence conservation within targeted CD8⁺ T cell epitopes does not contribute significantly to the observed immunodominance patterns of HIV-1-specific CD8⁺ T cell response in primary infection. For each HLA class I alleles studied, the four most frequently targeted HIV-1-specific CD8⁺ T cell epitopes were listed according to their hierarchy (for HLA class I alleles with only three described epitopes; the fourth value was excluded from the analysis). The average sequence conservations, in comparison to HIV-1 clade B sequences published in the Los Alamos Database, of the 1st, 2nd, 3rd, and 4th most frequently targeted epitope for each allele were calculated (given as percent sequence conservation) and are shown as box plots. The average percentage of sequence conservation of the four most frequently targeted HIV-1-specific CD8⁺ T cell epitopes restricted by each allele did not differ significantly.

Figure 3. Different HLA Class I Alleles Differ in Their Contribution to the Total HIV-1-Specific CD8⁺ T Cell Response

The percentage contribution of HIV-1-specific CD8⁺ T cell responses restricted by each individual HLA class I allele to the total HIV-1-specific CD8⁺ T cell response in individuals expressing the respective allele is shown. HLA class I alleles are listed according to their contribution from left to right. HLA-B57 and HLA-B27 contributed 66% and 65.4%, respectively, to the total HIV-1-specific CD8⁺ T cell response in individuals expressing these alleles.

Figure 4. Immunodomination of HLA-B57- and HLA-B27-Restricted HIV-1-Specific CD8⁺ T Cell Responses

The percent contribution (left graphs) and the absolute magnitude (right graphs, given as SFCs per million input PBMCs [SFC/Mill PBMC]) of HLA-A1-, -A2-, -A3-, and -A24-restricted HIV-1-specific CD8⁺ T cell responses in individuals expressing these HLA class I alleles alone, or in conjunction with HLA-B57 or HLA-B27, are shown. Each dot represents data for one individual. The contribution, as well as the absolute magnitude, of HIV-1-specific CD8⁺ T cell responses directed against HLA-A1-, -A2-, and -A24-restricted CD8⁺ T cell epitopes was significantly lower in participants that also coexpressed HLA-B57 or HLA-B27. The same trend was observed for HLA-A3, but did not reach statistical significance. HLA-A1-, -A2-, -A3-, and -A24-restricted HIV-1-specific CD8⁺ T cell response did not differ between individuals expressing other frequent HLA class B alleles, such as HLA-B7, -B8, -B35, or -B44 (unpublished data).

Figure 5. Correlation between the Contribution of Individual HLA Class I Alleles to the Total HIV-1-Specific CD8⁺ T Cell Response during Primary Infection and the HR for HIV-1 Infection Outcome

The percent contribution of individual HLA class I alleles to the total HIV-1-specific CD8⁺ T cell response during primary infection was correlated to the HR for four different HIV-1 infection outcomes (time to CD4 <200, time to AIDS 1987, time to AIDS 1993, and time to death) for the respective HLA alleles.