CD8+ T cells are strongly linked to viral control mechanisms in HIV elite controllers. Substantial evidence has suggested that cytolytic activity and other effector functions are the mechanism by which these cells control HIV, at least in blood. However, the vast majority of HIV replication in elite controllers likely occurs in lymphoid tissue, where CD8+ T cell immune surveillance mechanisms are undefined. Here we directly assessed the functional and phenotypic properties of tissue-based HIV-specific CD8+ T cells in the lymphoid tissues controllers.
We obtained human peripheral blood mononuclear cells (PBMC) and lymph node mononuclear cells (LNMC) from HIV-infected controllers, non-controllers and ART-treated individuals. We performed multi-parametric flow cytometry to define the phenotypic and functional profile of HIV-specific CD8+ T cells as identified by MHC-class I tetramers or responsiveness to peptide stimulation. The results were analyzed using FlowJo, GraphPad Prism, and SPICE.
We here demonstrate that cytolytic memory CD8+ T cells, as defined by the expression of perforin and granzyme B, are almost absent in lymph nodes (LN) of elite controllers. While high frequencies of HIV-specific CD8+ T cells could readily be detected in LN by MHC-class I tetramers, these cells very rarely express perforin and granzyme B. Instead, HIV-specific CD8+ T cells from LN of controllers possess high levels of non-cytolytic polyfunctional responses directed against HIV peptides. Such responses were low or absent in non-controllers or those on ART. HLA-B27/57+ elite controllers demonstrate a selective and high frequencies of CD8+ T cells targeting immunodominant Gag epitopes. Finally, HIV-specific LN CD8+ T cells from EC do not display enhanced ability to enter B cell follicles as defined by the expression of the chemokine receptor CXCR5, nor are those CXCR5+ cells more cytolytic compared to non-controllers and those on ART.
Together these findings redefine previous concepts of CD8+ T cell mediated control of HIV disease progression. During established infection, HIV replication appears to be controlled in lymphoid tissues by non-cytolytic rather than cytolytic mechanisms. Knowledge regarding how HIV is controlled in this setting should be used to inform the identification and development of potentially curative interventions.