HIV Controllers with HLA-DRB1*13 and HLA-DQB1*06 Alleles Have Strong, Polyfunctional Mucosal CD4⁺T-Cell Responses

Abstract

A small percentage of human immunodeficiency virus (HIV)-infected individuals, termed elite controllers, are able to spontaneously control HIV replication in blood. As the gastrointestinal mucosa is an important site of HIV transmission and replication as well as CD4؉ T-cell depletion, it is important to understand the nature of the immune responses occurring in this compartment. Although the role of the HIV-specific CD8؉ T-cell responses in mucosal tissues has been described, few studies have investigated the role of mucosal HIV-specific CD4 ؉ T cells. In this study, we assessed HIV-specific CD4 ؉ T-cell responses in the rectal mucosa of 28 "controllers" (viral load [VL] of <2,000 copies/ml), 14 "noncontrollers" (VL of >10,000 copies/ml), and 10 individuals on highly active antiretroviral therapy (HAART) (VL of <75 copies/ml). Controllers had highermagnitude Gag-specific mucosal CD4؉ T-cell responses than individuals on HAART (P < 0. 05), as measured by their ability to produce gamma interferon (IFN-␥), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-␣), and macrophage inflammatory protein 1␤ (MIP-1␤). The frequency of polyfunctional mucosal CD4 ؉ T cells was also higher in controllers than in noncontrollers or individuals on HAART (P < 0.05). Controllers with the strongest HIV-specific CD4؉ T-cell responses possessed class II HLA alleles, HLA-DRB1*13 and/or HLA-DQB1*06, previously associated with a nonprogression phenotype. Strikingly, individuals with both HLA-DRB1*13 and HLA-DQB1*06 had highly polyfunctional mucosal CD4 ؉ T cells compared to individuals with HLA-DQB1*06 alone or other class II alleles. The frequency of polyfunctional CD4 ؉ T cells in rectal mucosa positively correlated with the magnitude of the mucosal CD8 ؉ T-cell response (Spearman's r ‫؍‬ 0.43, P ‫؍‬ 0.005), suggesting that increased CD4 ؉ T-cell "help" may be important in maintaining strong CD8 ؉ T-cell responses in the gut of HIV controllers.

Hierarchy of CD4 T Cell Epitopes of the ANRS Lipo5 Synthetic Vaccine Relies on the Frequencies of Pre-Existing Peptide-Specific T Cells in Healthy Donors

“…In elite controllers, both CD4 and CD8 T lymphocytes react very efficiently with HIV Ags and exhibit a polyfunctional profile (9)(10)(11)(12)(13). Association of resistance to HIV infection with HLA class I (11,14,15) and class II (13,16,17) molecules also confirms the key role of the cellular response in immunity to HIV. Accordingly, HLA class I and class II alleles associated with slower HIV-1 progression contribute to a strong HIV-1-specific CD8 and CD4 T cell response, respectively (13,14,18).…”

“…Association of resistance to HIV infection with HLA class I (11,14,15) and class II (13,16,17) molecules also confirms the key role of the cellular response in immunity to HIV. Accordingly, HLA class I and class II alleles associated with slower HIV-1 progression contribute to a strong HIV-1-specific CD8 and CD4 T cell response, respectively (13,14,18). The protective effect of HLA-B57 and HLA-B27 is mainly supported by a reduced number of epitopes, but these epitopes generate a response of large amplitude that dominates the HIVspecific CTL response (14,18).…”

“…Other vaccines do not induce appropriate cellular responses specific for HIV (5), although a large body of evidence suggests that HIV-specific cellular responses contribute to control HIV viremia (6)(7)(8). In elite controllers, both CD4 and CD8 T lymphocytes react very efficiently with HIV Ags and exhibit a polyfunctional profile (9)(10)(11)(12)(13). Association of resistance to HIV infection with HLA class I (11,14,15) and class II (13,16,17) molecules also confirms the key role of the cellular response in immunity to HIV.…”

Short Communication: HIV+ Viremic Slow Progressors Maintain Low Regulatory T Cell Numbers in Rectal Mucosa but Exhibit High T Cell Activation

“…Rectal biopsies were obtained by flexible sigmoidoscopy 26 and mucosal leukocytes isolated using collagenase and mechanical disruption. 25 PBMCs and rectal cells were stained with anti-CD3 (clone UCHT1; BD Pharmingen), anti-CD4 (SFCI12T4D11, Beckman Coulter, Brea, CA, or L200, BD Pharmingen), anti-CD8 (SK1 or 3B5, Invitrogen), anti-CD25 (M-A251, BD Pharmingen), anti-CD127 (hIL-7R-M21, BD Pharmingen), anti-CD38 (HIT2, BD Pharmingen), antiprogrammed-death-receptor 1 (PD-1) (eBioJ105, eBioscience), and Live/Dead Fixable Aqua dead cell stain (Invitrogen, Carlsbad, CA), followed by intracellular staining with anti-FOXP3 (PCH101, eBioscience) using the FOXP3 Staining Buffer Set (eBioscience, San Diego, CA).…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…HIV-specific CD4þ T cells from HICs also exhibit high avidity for immunodominant Gag peptides, which may allow them to react to low levels of antigens [151]. The class II HLA alleles HLA-DRB1*13 and HLA-DQB1*06 have been associated with strong HIV-specific CD4þ T cell responses in HICs [152].…”