Defining the Nature of CD8+ T Cell Responses in Lymphoid Tissues of HIV-1 Elite Controllers: An Implication for HIV Cure
Acquired Immunodeficiency Syndrome (AIDS) is an immunodeficiency caused by infection with Human Immunodeficiency Virus (HIV). Since its first documentation in 1981, the AIDS pandemic has claimed the lives of 32 million people worldwide. The introduction of antiretroviral therapy drugs (ART) and combined therapy in 1995 has transformed HIV infections from a “death-sentence” into a manageable and often non-fatal chronic condition. Still, no cure is available. While without ART most HIV-infected individuals (>99%) progress to AIDS, a subset of infected individuals (<1%), known as elite controllers (ECs), can spontaneously control viremia and maintain undetectable plasma viral load for many years. Effector functions of CD8+ T cells have been strongly correlated with the EC status. However, while this correlation has been established primarily in blood, HIV mainly replicates in lymphoid tissues (LTs) such as lymph nodes (LNs) and gut-associated lymphoid tissue (GALT), where CD8+ T cell-mediated immune responses are not well defined. Therefore, this study aims to investigate CD8+ T cell responses in LTs, specifically LNs, of HIV-infected individuals and to define mechanisms of viral control in LNs of ECs. In order to achieve this goal, we obtained LNs and blood samples from HIV- donors, ECs, ART-treated individuals (ARTs), and viremic individuals who are not on ART, hereafter termed chronic progressors (CPs). Using an integrative single-cell approach, we identified that most HIV-specific CD8+ T cells in LNs of HIV-infected individuals, especially in ECs, were tissue-resident memory T cells (TRM). While CD8+ T cells in LNs of ECs could potently suppress viral replication, they surprisingly did not display strong cytolytic activities. Instead, these cells were more poised for trafficking into B cell follicles (BCFs), downregulated expression of inhibitory receptors, and concurrently produced multiple cytokines upon stimulation with HIV antigens, which could be functionally linked to efficient protein translation capacity. Together, these results suggest that CD8+ T cells in LTs controls HIV replication through non-cytolytic mechanisms, instead of cytotoxic mechanisms like CD8+ T cells in blood. In conclusion, this dissertation highlights the tissue compartmentalization of CD8+ T cells’ effector functions in anti-HIV immunity. Furthermore, the induction of TRM and CD8+ T cell-mediated non-cytolytic mechanisms should be pursued as therapeutic strategies aiming to establish a durable control of HIV.
Immunology|Cellular biology|Pharmaceutical sciences
Nguyen, Son Ngoc, "Defining the Nature of CD8+ T Cell Responses in Lymphoid Tissues of HIV-1 Elite Controllers: An Implication for HIV Cure" (2020). Dissertations available from ProQuest. AAI28000360.