Higher Frequency of NK and CD4+ T-Cells in Mucosa and Potent Cytotoxic Response in HIV Controllers

Abstract

HIV infection induces immune alterations, mainly in gut mucosa, where the main target cells reside. However, the evolution of the infection is variable among infected individuals, as evidenced by HIV controllers who exhibit low or undetectable viral load in the absence of treatment. The aim of this study was to evaluate the frequency, phenotype and activity of T and NK cells in peripheral blood and gut mucosa in a cohort of Colombian HIV controllers. Blood and gut biopsies were included. The frequency and the activation status of T and NK cells were performed by flow cytometry. In addition, Gag-stimulated CD8+ T-cells and cytokine-stimulated NK cells were tested for cytotoxic activity. Finally, microbial translocation was measured by plasma lipopolysaccharide quantification. Compared with HIV-progressors, HIV controllers exhibited higher frequency of CD4+ T and NK cells, and lower expression of activation molecules in blood and mucosal immune cells, as well as lower microbial translocation. An increased production of molecules associated with cytotoxic activity of CD8+ T-cells in blood and mucosa and a higher percentage of polyfunctional CD8+ T cells in blood were also observed in HIV controllers. In addition, an increased activity of NK cells was observed in blood. These findings suggest that HIV controllers have a potent immune response, mainly mediated by cytotoxic cells that control HIV replication, which contribute to reducing alterations at the gut mucosa.

Role of Different Subpopulations of CD8+ T Cells during HIV Exposure and Infection

“…In addition to the effector and memory phenotypes, some subpopulations of CD8 + T cells, defined according to the expression of activation markers, seem to play a role in the viral control exhibited by HIV-controllers. In these individuals, a low frequency of CD8 + T cells co-expressing HLA-DR and CD38, a subpopulation related to a less efficient control of infection, have been described compared to HIV-progressors by other researchers and by us ( 57 , 83 ). In addition, controllers exhibited a higher frequency of CD8 + T cells expressing the activation marker HLA-DR but not CD38, mainly in HIV-specific cells; this activation phenotype was associated with better survival capacity, higher frequency of polyfunctional cells, and greater proliferative and cytotoxic capacity that results in higher ability to suppress the virus ( 56 , 57 ).…”

“…As just described, the response of CD8 + T cells has been reported to be one of the main mechanisms involved in controlling viral replication during HIV infection. In fact, a better response of these cells is frequently related to the HIV controller phenotype, since these individuals exhibit immunodominant HIV-specific CD8 + T cell responses in both periphery and GALT tissue, and a higher proliferative and cytotoxic capacity ( 56 , 83 , 84 ). In fact, HIV-controllers exhibit a higher functional response of specific CD8 + T cells, detecting cells reaching up to five simultaneous functions, including CD107a, IFN-γ, MIP-1β, IL-2, and TNF-α in response to Gag peptides; as expected, the higher frequency of these polyfunctional cells is inversely correlated with the viral load ( 85 ).…”

Increased Natural Killer Cell Activation in HIV-Infected Immunologic Non-Responders Correlates with CD4+ T Cell Recovery after Antiretroviral Therapy and Viral Suppression

“…Cytotoxic or activated NK cells have been found to accumulate in lymph nodes after HIV/SIV infection [56, 57]. To determine whether NK cells from HIV+ immune non-responders were activated to gain the function of cytotoxicity against CD4+ T cells, we have isolated NK cells ex vivo and co-cultured with CD4+ T cells from the same healthy control donor.…”

Follicular CD8+ T Cells: Origin, Function and Importance during HIV Infection

“…CD8 + T cells are critical for the control of HIV infection. This has been demonstrated by the decrease of viral load with the appearance of virus-specific CD8 + T cells ( 96 , 97 ), its increase after their depletion ( 98 ) and the higher frequency and functionality of CD8 + T cells in HIV-infected non-progressors individuals ( 99 , 100 ). CD8 + T cells are largely confined to secondary lymphoid organs during natural HIV infection and migrate to these locations after autologous adoptive transfer ( 101 – 103 ).…”