HIV-1 DNA and Immune Activation Levels Differ for Long-Lived T-Cells in Lymph Nodes, Compared with Peripheral Blood, during Antiretroviral Therapy

Elucidating the mechanisms underlying the persistence and location of the HIV reservoir is critical for developing cure interventions. While it has been shown that levels of T-cell activation and the size of the HIV reservoir are greater in rectal tissue and lymph nodes (LN) than in blood, the relative contributions of T-cell subsets to this anatomic difference are unknown. We measured and compared HIV-1 DNA content, expression of the T-cell activation markers CD38 and HLA-DR, and expression of the exhaustion markers programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) in naive, central memory (CM), transitional memory (TM), and effector memory (EM) CD4(+) and CD8(+) T-cells in paired blood and LN samples among 14 people with HIV who were receiving antiretroviral therapy. HIV-1 DNA levels, T-cell immune activation, and TIGIT expression were higher in LN than in blood, especially in CM and TM CD4(+) T-cell subsets. Immune activation was significantly higher in all CD8(+) T-cell subsets, and memory CD8(+) T-cell subsets from LN had higher levels of PD-1 expression, compared with blood, while TIGIT expression levels were significantly lower in TM CD8(+) T-cells. The differences seen in CM and TM CD4(+) T-cell subsets were more pronounced among participants with CD4(+) T-cell counts of <500 cells/mu L within 2 years after antiretroviral therapy initiation, thus highlighting increased residual dysregulation in LN as a distinguishing feature of and a potential mechanism for individuals with suboptimal CD4(+) T-cell recovery during antiretroviral therapy.IMPORTANCE This study provides new insights into the contributions of different CD4(+) and CD8(+) T-cell subsets to the anatomic differences between LN and blood in individuals with HIV who have optimal versus suboptimal CD4(+) T-cell recovery. To our knowledge, this is the first study comparing paired LN and blood CD4(+) and CD8(+) T-cell differentiation subsets, as well as those subsets in immunological responders versus immunological suboptimal responders. This study provides new insights into the contributions of different CD4(+) and CD8(+) T-cell subsets to the anatomic differences between LN and blood in individuals with HIV who have optimal versus suboptimal CD4(+) T-cell recovery. To our knowledge, this is the first study comparing paired LN and blood CD4(+) and CD8(+) T-cell differentiation subsets, as well as those subsets in immunological responders versus immunological suboptimal responders.