Innate-like T cells in the immunopathogenesis of HIV-1 infection

Abstract

The immunodynamics of HIV infection have been studied for over three decades in the hopes of determining underlying mechanisms that contribute to the sustained immune dysfunction observed even in individuals on therapy. Conventional and adaptive T cells are both the target of the virus and considered the main players in controlling viral burden. However, there are unconventional T cells with innate-like, rapid effector functions that are also altered in HIV infection. Among these are iNKT cells and MAIT cells, which both decline in frequency, are dysfunctional, and have an altered phenotype in the blood in chronic HIV infection. The dynamics of their loss, phenotype, and dysfunction are a major focus of this thesis. In order to study MAIT and iNKT cell dynamics in acute HIV-1 infection, the unique acute HIV infection cohort, RV217, was used with donor matched pre- and post-HIV infection blood samples in the acute infection stage. An additional study where ART is initiated in the acute infection stage, RV254, which collected both blood and rectosigmoid biopsy samples, was also used. This cohort allowed for both the study colonic MAIT and iNKT cell dynamics in acute HIV infection, as well as the impact of early ART initiation on blood and colonic iNKT cells.

In Paper I, an optimized multiparameter immunofluorescence panel (OMIP) was generated to measure the frequency and phenotype of iNKT and MAIT cells in individuals from RV217. In Paper II, detailed studies of the RV217 cohort revealed that MAIT cells express markers of activation and exhaustion, and briefly expand alongside an elevated functional capacity in the acute infection stage. However, by 3 months post-infection the MAIT cell response to E. coli stimulation in vitro declined. Total transcriptome analysis showed that MAIT cells upregulate an innate-like transcriptional signature. This finding, coupled with the expansion of a subset of MAIT cells that express the NK-cell receptor CD56 and produce more of the antiviral cytokine, IFNγ, in response to innate cytokine stimulation IL-12 and IL-18 in vitro, suggests that MAIT cells become progressively more innate-like during the course of acute HIV infection. The OMIP was also used to study iNKT cells in acute HIV-1 infection in Paper III. The RV217 cohort showed that iNKT cells are preferentially depleted in the blood in acute HIV infection, particularly CD4+ iNKT cells. Remaining iNKT cells express markers of activation and become dysfunctional during acute infection. Colonic samples revealed that CD4+ iNKT cells are depleted more substantially than in the blood in the acute infection stage. The early ART treatment cohort, RV254, demonstrated that early ART initiation is able to prevent iNKT cell activation and depletion in the blood, but unable to stop their depletion in the colon during acute HIV infection. The work in Paper IV, shows that conventional adaptive CD8 T cells can develop an innate-like functionality mediated by the FcγRIIIA (CD16) during chronic stages of HIV infection. Expression of CD16 occurs in late-stage differentiated CD8 T cells, is associated with expression of the IKZF2 transcription factor (Helios) and an NKp80+IL-7Rα-surface phenotype. Interestingly, this CD8 T cell subset mediates antibody-dependent cellular cytotoxicity (ADCC) against HIV protein coated target cells at a level on par with NK cells on a per cell basis.

In summary, the work in this thesis sheds new light on the behavior and responses of unconventional T cell subsets during acute HIV infection. Furthermore, the work defines a novel function of conventional adaptive CD8 T cells in chronic HIV infection. Altogether, this thesis provides new insights on the role of innate-like functions in the human T cell compartment in the immunopathogenesis of HIV-1 infection.