HLA class I-restricted T-cell responses may contribute to the control of human immunodeficiency virus infection, but such responses are not always necessary for long-term virus control

Abstract

A rare subset of human immunodeficiency virus (HIV)-infected individuals maintains undetectable HIV RNA levels without therapy ("elite controllers"). To clarify the role of T-cell responses in mediating virus control, we compared HLA class I polymorphisms and HIV-specific T-cell responses among a large cohort of elite controllers (HIV-RNA < 75 copies/ml), "viremic" controllers (low-level viremia without therapy), "noncontrollers" (high-level viremia), and "antiretroviral therapy suppressed" individuals (undetectable HIV-RNA levels on antiretroviral therapy). The proportion of CD4(+) and CD8(+) T cells that produce gamma interferon (IFN-gamma) and interleukin-2 (IL-2) in response to Gag and Pol peptides was highest in the elite and viremic controllers (P < 0.0001). Forty percent of the elite controllers were HLA-B*57 compared to twenty-three percent of viremic controllers and nine percent of noncontrollers (P < 0.001). Other HLA class I alleles more common in elite controllers included HLA-B*13, HLA-B*58, and HLA-B*81 (P < 0.05 for each). Within elite and viremic controller groups, those with protective class I alleles had higher frequencies of Gag-specific CD8(+) T cells than those without these alleles (P = 0.01). Noncontrollers, with or without protective alleles, had low-level CD8(+) responses. Thus, certain HLA class I alleles are enriched in HIV controllers and are associated with strong Gag-specific CD8(+)IFN-gamma(+)IL-2(+) T cells. However, the absence of evidence of T cell-mediated control in many controllers suggests the presence of alternative mechanisms for viral control in these individuals. Defining mechanisms for virus control in "non-T-cell controllers" might lead to insights into preventing HIV transmission or preventing virus replication.

FIG. 1.

Lymphocyte gating is performed by using forward and side scatter parameters. CD3⁺ CD4⁺ and CD3⁺ CD4⁻ populations are identified to characterize CD4⁺ and CD8⁺ T-cell populations. On the right, representative flow plots of cytokine secretion for unstimulated negative control, Staphylococcal enterotoxin B-stimulated positive control and Gag peptide pools are shown.

FIG. 2.

Gag-specific T-cell responses among HIV-infected and uninfected individuals. Four-color flow cytometry using fresh blood stimulated for 6 h in the presence of brefeldin A was performed. All results are corrected for background. (A) Frequencies of CD3⁺ CD4⁺ lymphocytes (CD4⁺ T cells) that produce IFN-γ and IL-2 in response to a Gag peptide pool are shown for different groups. (B and C) The frequencies of CD3⁺ CD4⁻ (CD8⁺ T cells) that produce IFN-γ/IL-2 or IFN-γ are depicted in panel B and C, respectively.

FIG. 3.

Pol- and Env-specific T-cell responses among HIV-infected and uninfected individuals. Four-color flow cytometry using fresh blood stimulated for 6 h in the presence of brefeldin A was performed. All results are corrected for background. The top three panels represent Pol-specific responses, where the frequencies CD4⁺ T cells that produce IFN-γ and IL-2, CD8⁺ T cells that produce IFN-γ and IL-2, and CD8⁺ T cells that produce IFN-γ alone are shown for different individual subject groups. Note that the scale in this figure is different from that of Fig. 2.

FIG. 4.

Distribution of individual responses to Gag-peptide pools. Frequency of Gag-specific CD4⁺IFN-γ⁺IL-2⁺ and CD8⁺ IFN-γ⁺ IL-2⁺ T cells among different clinical subject groups (A and B, respectively). Many controllers lack evidence of strong Gag-specific CD4⁺ or CD8⁺ T-cell responses.

FIG. 5.

Distribution of HLA class I alleles. The proportion of individuals among elite controllers (n = 30), viremic controllers (n = 31), and noncontrollers (n = 293) who have the corresponding allele is shown. Only the HLA class I alleles significantly enriched among elite and viremic controllers are shown.

FIG. 6.

HLA type and Gag-specific T-cell responses. The frequency of Gag-specific CD8⁺ and CD4⁺ IFN-γ⁺ IL-2⁺ T-cell responses among controllers and noncontrollers with protective and without protective HLA alleles is shown. Protective alleles are defined as HLA-B*13, HLA-B*27, HLA-B*57, HLA-B*58, and HLA-B*81.