In both HIV-infected individuals and healthy controls, CD8+ T-cells from the gastrointestinal tract express low levels of perforin as compared to their counterparts in blood [11
]. Nevertheless, HIV-specific CD8+ T-cells are abundant in rectal mucosa of chronically infected individuals [12
]. Following in vitro
these cells express a broad range of cytokines/chemokines (IFNγ, IL-2, MIP1-β, and TNFα) and the degranulation marker CD107 [14
]. A study of rectal HIV Gag-specific CD8+ T-cell responses in 15 HIV-positive individuals not on highly-active antiretroviral therapy (HAART), with a broad range of viral loads and CD4+ T-cell counts, revealed a positive correlation between total response magnitude (i.e., percent Gag-responsive CD8+ T-cells), polyfunctionality (i.e., production of 3 or more effector molecules, also referred to as response “quality”) and CD4+ T-cell count, as well as an inverse correlation between response magnitude and plasma viral load [15
]. Thus, in this study, individuals with the highest blood CD4+ T-cell counts and lowest plasma viral loads had the strongest, most polyfunctional rectal CD8+ T-cell responses.
In a subsequent study, CD8+ T-cell responses from paired blood and rectal biopsy samples were obtained from 17 elite controllers (viral load [VL] <75 copies/mL), 11 viremic controllers (VL 75–2,000 copies/mL), 14 non-controllers (VL >10,000 copies/mL), and 10 HAART-treated subjects (VL <75 copies/mL) and assessed for their ability to degranulate and/or secrete multiple cytokines in response to HIV Gag stimulation [16
]. There was considerable heterogeneity in all groups; however, mucosal CD8+ T-cell responses in controllers were significantly more robust and polyfunctional than in either non-controllers or HAART-suppressed individuals. Importantly, in this study there were no differences in the magnitude or quality of peripheral blood CD8+ T-cell responses between controllers and non-controllers. Additionally, controllers with “protective” class I HLA alleles (HLA-B13, B27, B57, B58, and B81) had significantly more polyfunctional mucosal Gag-specific CD8+ T-cells than controllers lacking these alleles, and showed a trend towards higher response magnitudes [16
]. HIV controllers also had significant preservation of rectal CD4+ T-cells as compared to non-controllers. However, all HIV-positive groups had significantly lower rectal CD4+ T-cell percentages than seronegatives [16
In a companion study, Ferre and colleagues evaluated Gag-specific CD4+ T-cell responses in rectal mucosa from the same patients [*17
]. Controllers had significantly higher magnitude rectal CD4+ T-cell responses than patients on HAART, and the frequency of polyfunctional mucosal CD4+ T-cells was significantly greater in controllers than in either non-controllers or patients on HAART. Intriguingly, controllers with the strongest and most polyfunctional rectal CD4+ T-cell responses in this study possessed the HLA class II alleles HLA-DRB1*13 and/or HLA-DQB1*06 in addition to protective MHC class I alleles [*17
]. Although this study was not statistically powered to distinguish the protective effects of MHC class I versus MHC class II alleles, an earlier report found an association between the HLA-DRB1*13/HLA-DQB1*06 haplotype, long-term nonprogression and strong p24-specific lymphoproliferative responses in the absence of any protective MHC class I alleles [18
Taken together, these findings reveal that many HIV controllers, particularly those with “protective” HLA alleles, have strong, polyfunctional mucosal CD4+ and CD8+ T-cell responses that are not necessarily mirrored in blood. Additionally, both the magnitude and “quality” of mucosal CD4+ T-cell responses positively correlated with the strength of mucosal CD8+ T-cell responses. This suggests that mucosal CD4+ T-cell “help” supports the development and maintenance of robust CD8+ T-cell responses. Mucosal CD8+ T-cells, in turn, eradicate infected cells, thereby limiting de novo infection of CD4+ T-cells; accordingly, these two cell types likely act synergistically to limit virus production and preserve relatively high CD4+ T-cell frequencies in mucosal tissues of HIV controllers.