Reduction in terminally differentiated T cells in virologically controlled HIV-infected aging patients on long-term antiretroviral therapy

Abstract

Several studies have shown an increased accumulation of terminally differentiated T cells during HIV infection, suggestive of exhaustion/senescence, causing dysregulation of T cell homeostasis and function and rapid HIV disease progression. We have investigated whether long-term antiretroviral therapy (ART), which controls viremia and restores CD4 T cell counts, is correlated with reduction in terminally differentiated T cells, improved ratios of naïve to memory and function of T cells in 100 virologically controlled HIV-infected patients. We show that while the median frequencies of terminally differentiated CD4+ and CD8+ T cells (CD28-, CD27-, CD57+ and CD28-CD57+), were higher in the virologically controlled HIV-infected patients’ cohort compared with uninfected individuals’ cohort, the frequencies of these cells significantly decreased with increasing CD4 T cell counts in HIV-infected patients. Although, the naïve CD4+ and CD8+ T cells were lower in HIV patients’ cohort than uninfected cohort, there was a significant increase in both naïve CD4+ and CD8+ T cells with increasing CD4 T cell counts in HIV-infected patients. The underlying mechanism behind this increased naïve CD4+ and CD8+ T cells in HIV-infected patients was due to an increase in recent thymic emigrants, CD4+CD31+, as compared to CD4+CD31-. The CD4+ T cells of HIV-infected patients produced cytokines, including IL-2, IL-10 and IFN-γ comparable to uninfected individuals. In conclusion, virologically controlled HIV-infected patients on long-term ART show a significant reduction in terminally differentiated T cells, suggestive of decreased exhaustion/senescence, and improvement in the ratios of naïve to memory and function of T cells.

Evaluation of HIV-specific T-cell responses in HIV-infected older patients with controlled viremia on long-term antiretroviral therapy

“…Additionally, it has been reported that HIV-specific CD4 T-cell responses (IFN-γ, IL-2, TNF-α) during early infection or untreated infection may predict disease progression and effective viral control [ 31 , 32 , 37 , 38 ]. Conversely, our study found a significant increase in HIV-specific IFN-γ production in virologically controlled HIV + on long-term ART with improved CD4 T-cell counts, supporting that these HIV + patients had immune recovery of CD4 + T-cells and function [ 25 ]. Our data also showed a significant increase overall in HIV-specific CD8 + IFN-γ T-cells in HIV + , however, this response decreased with increasing CD4 T-cell counts.…”

“…The cryopreserved PBMC (1-3x10 6 /well) were stained with LIVE/DEAD Fixable Dead cell Stain- AQUA (Invitrogen), T-cell markers and cytokines markers in various combinations as described in our previous study [ 25 ]. Briefly for this study we used: CD3 + –BV570 (BioLegend), CD4 + –APC (eBioscience), CD8β + –ECD (Beckman Coulter), CD107a– PE-Cy7 (BioLegend), IFN-γ–APCe780 (eBioscience), Granzyme-B–A700 (BD Pharmogen), TNF-α–PE (eBioscience).…”

“…All wells were incubated for 2 hours with a combination of 1X Monensin Solution (2μM/ml) and 1X Brefeldin A Solution (3.0μg/ml) (eBioscience). The antibody staining protocol is described in our previous study [ 25 ]. Samples were analysis on the BD LSR II instrument, using DiVa acquisition (BDIS, Mountain View, CA).…”

HIV Infection-Associated Frailty: The Solution for Now Is Antiretroviral Drugs: A Perspective

“…We found that the longer patients took ART, the better the immune function of host cells, not only their CD4 count numbers but the entire immune repertoire of those responding to ART. 4 In a sense the patients were “getting younger,” the markers we studied showed remarkable improvement approaching values of those of uninfected controls (specifically, there was a reduction in terminally differentiated markers and significant improvement in cytokine secretion in the presence of HIV-specific peptides).…”

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

“…Moreover, some evidence supports the theory that HIV-1 can establish latent infection in actively replicating CD4 + T cells, suggesting that HIV-1 infection of both resting and activated primary CD4 + T cells could result in latency (Chavez et al, 2015). The T TD , corresponding to aged T-cell populations that reflect HIV-1 disease progression (Cao et al, 2009) and in which integrated HIV-1 DNA is also detected, are a very small reservoir with a reduced frequency in HIV-1 individuals under suppressive ART and improved CD4 + T cell counts (Chomont et al, 2009;Behrens et al, 2018). Finally, T SCM are permissive to HIV-1 infection and contribute to its persistence by their capacity of self-renewal and prolonged survival rate.…”