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Unique Individuals who exhibit either suppressive HIV-1 control, or the ability to maintain low viral load set-points and preserve their CD4+ T cell counts for extended time periods in the absence of antiretroviral therapy, are broadly termed HIV-1 controllers. We assessed the extent to which black South African controllers (n=9), differ from uninfected healthy controls (HCs, n=22) in terms of lymphocyte and monocyte CCR5 expression (density and frequency of CCR5-expressing cells), immune activation as well as peripheral blood mononuclear cell (PBMC) mitogen-induced chemokine/cytokine production. In addition, relative CD4+ T cell CCR5 mRNA expression was assessed in a larger group of controllers (n=20) compared to HCs (n=10) and HIV-1 progressors (n=12). Despite controllers having significantly higher frequencies of activated CD4+ and CD8+ T cells (HLA-DR+) compared to HCs, CCR5 density was significantly lower in these T cell populations (P =0.039 and P =0.064, respectively). This lower CCR5 density was largely attributable to controllers with higher VLs (>400 RNA copies/ml). Significantly lower CD4+ T cell CCR5 density in controllers was maintained (P =0.036) when HCs (n=12) and controllers (n=9) were matched for age. CD4+ T cell CCR5 mRNA expression was significantly less in controllers compared to HCs (P =0.007) and progressors (P =0.002), whereas HCs and progressors were similar (P =0.223). The levels of soluble CD14 in plasma did not differ between controllers and HCs, suggesting no demonstrable monocyte activation. While controllers had lower monocyte CCR5 density compared to the HCs (P =0.02), significance was lost when groups were age-matched (P =0.804). However, when groups were matched for both CCR5 promoter haplotype and age (n=6 for both) reduced CCR5 density on monocytes in controllers relative to HCs was highly significant (P =0.009). Phytohemagglutinin-stimulated PBMCs from the controllers produced significantly less CCL3 (P =0.029), CCL4 (P =0.008) and IL-10 (P=0.028) compared to the HCs, which was largely attributable to the controllers with lower VLs (<400 RNA copies/ml). Our findings support a hypothesis of an inherent (genetic) predisposition to lower CCR5 expression in individuals who naturally control HIV-1, as has been suggested for Caucasian controllers, and thus, likely involves a mechanism shared between ethnically divergent population groups. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV)-specific natural killer (CD3- cells), CD4, and CD8 T cellular responses were determined in 79 HIV-1-infected women in response to HIV-1 peptide pools (Gag, Pol, Nef, Reg, and Env) with use of a whole-blood intracellular cytokine staining assay that measures interferon-γ and/or interleukin-2. HIV-specific CD3- cell responses to any region (Env and Reg predominantly targeted) were associated with lower viral load (P=.031) and higher CD4 T cell count (P=.015). Env-specific CD3- cell responses were stronger in women who had both Gag CD4 and CD8 T cell responses and, in turn, was associated with lower viral load (P=.005). CD3- cell responders had significantly higher representation of CD4 T cell responses to Env and Reg (P=.012 and P=.015, respectively) and higher magnitudes of CD4 T cell responses (P=.017 and P=.037, respectively) than did nonresponders. Peptide-specific natural killer cells are associated with markers of less severe disease progression among HIV-1-infected women (lower viral load and higher CD4 T cell count) and with stronger HIV-specific T cell responses. [ABSTRACT FROM AUTHOR]

The current intersection of the COVID-19 and HIV-1 pandemics, has raised concerns about the risk for poor COVID-19 outcomes particularly in regions like sub-Saharan Africa, disproportionally affected by HIV. DPP4/CD26 has been suggested to be a potential therapeutic target and a biomarker for risk in COVID-19 patients with high risk co-morbidities. We therefore evaluated soluble DPP4 (sDPP4) levels and activity in plasma of 131 HIV-infected and 20 HIV-uninfected South African individuals. Flow cytometry was performed to compare cell surface expression of DPP4/CD26 and activation markers on peripheral blood mononuclear cells of extreme clinical phenotypes. Progressors had lower specific DPP4 activity and lower frequency of CD3+ T-cells expressing CD26 than HIV-1 controllers, but more activated CD3+CD26+ T-cells. The frequency of CD26-expressing T-cells negatively correlated with HLA-DR+ and CD38+ T-cells. Divergent DPP4/CD26 expression between HIV-1 controllers and progressors may have implications for risk and treatment of COVID-19 in people living with HIV. [Display omitted] • Elevated DPP4/CD26 is known to associate with COVID-19 high risk comorbidities. • Progressors have lower DPP4 activity than HIV-1 controllers. • Progressors have substantially lower frequencies but more activated CD26+ T-cells. • DPP4/CD26 associates with differential HIV-1 control. • Targeting DPP4/CD26 in HIV-1 and COVID-19 may be dependent on HIV-1 progression. [ABSTRACT FROM AUTHOR]

Activating/inhibitory Killer-cell Immunoglobulin-like Receptors (KIRs) partly regulate Natural Killer (NK) cells. KIR2DL1 allotypes with cysteine at position-245 (KIR2DL1-C245) express at lower levels and demonstrate weaker inhibitory signaling compared to allotypes with arginine at position-245 (KIR2DL1-R245). The functional consequence of either allotype in infectious diseases is unknown. Since NK cells mediate antiviral immunity, we investigated KIR2DL1-R245 and KIR2DL1-C245 in association with HIV-1 virological control in untreated immunocompetent black South Africans. Allotype carriage, determined by KIR2DL1 sequencing, was similar between uninfected South Africans (n = 104) and other black African populations, but differed significantly from Europeans, while no significant differences were noted between uninfected and HIV-1-infected individuals (n = 52). KIR2DL1 expression, measured by flow cytometry, in uninfected individuals showed higher KIR2DL1-R245 expression compared to KIR2DL1-C245 in white donors (n = 27), while black donors (n = 21) generally expressed lower levels of both allotypes. KIR2DL1 expression was reduced in HLA-C2 carriers, most evident in black HLA-C2/C2 donors. KIR2DL1-R245 and KIR2DL1-C245 did not associate with viral load when HLA-C2 ligands were present, however in HLA-C1 homozygotes, individuals with only KIR2DL1-R245, showed lower viral loads compared to carriers of both allotypes. The lack of association of KIR2DL1-R245 or KIR2DL1-C245 with HIV-1 control in HLA-C2 carriers may relate to lower KIR2DL1 expression levels in a population with high HLA-C2 prevalence. [ABSTRACT FROM AUTHOR]