HIV-1 Elite Controllers Are Characterized by Elevated Levels of CD69-Expressing Natural Killer Cells.

Background: HIV type 1 ((human immunodeficiency virus) HIV-1) elite controllers (ECs) are a rare subset of people living with HIV-1 (PLWH) who control viral replication in the absence of antiretroviral treatment (ART) and may provide a model for a functional cure. We investigated the role of natural killer (NK) cells in HIV-1 ECs from South Africa.

Methods: Phenotypic (CD69, CD38, CD57, PD-1), functional (CD107a, IFN-γ (inferferon gamma)), and nutrient transporter profiles (glucose transporter 1, CD98) of NK cells from ECs (n = 20), viremic progressors (VPs; n = 19), PLWH on ART (n = 20), and people without HIV-1 (PWOH; n = 21) were analyzed using flow cytometry.

Higher CCR5 density on CD4 + T-cells in mothers and infants is associated with increased risk of in-utero HIV-1 transmission.

Objective: CCR5-tropic viruses are preferentially transmitted during perinatal HIV-1 infection. CCR5 density on CD4 + T-cells likely impacts susceptibility to HIV-1 infection.

Design: Fifty-two mother-infant dyads were enrolled.

Reduced CCR5 Expression and Immune Quiescence in Black South African HIV-1 Controllers.

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).

Systemic DPP4/CD26 is associated with natural HIV-1 control: Implications for COVID-19 susceptibility.

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.

Normalization of B Cell Subsets but Not T Follicular Helper Phenotypes in Infants With Very Early Antiretroviral Treatment.

Infant HIV-1-infection is associated with high morbidity and mortality if antiretroviral treatment (ART) is not initiated promptly. We characterized development of circulating T follicular helper cells (cTfh) and their relationship to naïve/memory B cell subsets in a cohort of neonates initiating ART within the first week of life. Infants were diagnosed within 48 hours of birth and started ART as soon as possible.

Lack of association of KIR2DL1-R and KIR2DL1-C with HIV-1 control in black South Africans with HLA-C2.

Activating/inhibitory Killer-cell Immunoglobulin-like Receptors (KIRs) partly regulate Natural Killer (NK) cells. KIR2DL1 allotypes with cysteine at position-245 (KIR2DL1-C) express at lower levels and demonstrate weaker inhibitory signaling compared to allotypes with arginine at position-245 (KIR2DL1-R). The functional consequence of either allotype in infectious diseases is unknown.

Low Pretreatment Viral Loads in Infants With HIV in an Era of High-maternal Antiretroviral Therapy Coverage.

Background: With expansion of antiretroviral therapy (ART) programs, transmission rates are low but new infant infections still occur. We investigated predictors of pre-ART viral load (VL) and CD4+ T-cell counts and percentages in infants diagnosed with HIV at birth in a setting with high coverage of maternal ART and infant prophylaxis.

Methods: As part of an early treatment study, 97 infants with confirmed HIV-infection were identified at a hospital in Johannesburg, South Africa.

A child with perinatal HIV infection and long-term sustained virological control following antiretroviral treatment cessation.

Understanding HIV remission in rare individuals who initiated antiretroviral therapy (ART) soon after infection and then discontinued, may inform HIV cure interventions. Here we describe features of virus and host of a perinatally HIV-1 infected child with long-term sustained virological control. The child received early limited ART in the Children with HIV Early antiRetroviral therapy (CHER) trial.

Serum levels of inflammatory cytokines in Rift Valley fever patients are indicative of severe disease.

Background: Rift Valley fever (RVF) is a mosquito-borne viral zoonosis affecting domestic and wild ruminants, camels and humans. Outbreaks of RVF are characterized by a sudden onset of abortions and high mortality amongst domestic ruminants. Humans develop disease ranging from a mild flu-like illness to more severe complications including hemorrhagic syndrome, ocular and neurological lesions and death.

Differences are evident within the CXCR4-CXCL12 axis between ethnically divergent South African populations.

The G-protein-coupled receptor, CXCR4, is highly expressed on a number of cell types, and together with its ligand, CXCL12, plays an important role in immune development and trafficking of cells. CXCR4 promotes tumor growth, angiogenesis and metastasis, and is a prognostic marker in a number of different types of tumors. Additionally, CXCR4 is utilized, together with CD4, for entry of T-tropic HIV viruses.

A novel FCGR3A intragenic haplotype is associated with increased FcγRIIIa/CD16a cell surface density and population differences.

FcγRIIIa (CD16a) cell surface density affects immune complex binding and initiation of effector mechanisms. Investigations into the clinical relevance of variable FcγRIIIa surface density require baseline data from healthy individuals. In this study, proportions of FcγRIIIa-positive leukocyte subsets and corresponding FcγRIIIa cell surface densities were determined in whole blood from 53 healthy individuals (22 Black individuals, 31 Caucasians).

Marked differences in CCR5 expression and activation levels in two South African populations.

The chemokine receptor CCR5 is pivotal in determining an individual's susceptibility to HIV-1 infection and rate of disease progression. To establish whether population-based differences exist in cell surface expression of CCR5 we evaluated the extent of CCR5 expression across all peripheral blood cell types in individuals from two populations, South African Africans (SAA) and South African Caucasians (SAC). Significant differences in CCR5 expression, both in number of CCR5 molecules per cell (density) and the percentage of CCR5-expressing cells, were observed between the two study groups, within all cell subsets.

Natural killer cell responses to HIV-1 peptides are associated with more activating KIR genes and HLA-C genes of the C1 allotype.

Background: What characterizes individuals whose natural killer (NK) cells are able to respond to HIV-1 peptides is not known.

Methods: The association between NK cell responses and KIR gene profiles and HLA-B and HLA-C alleles was investigated among 76 HIV-1-infected women in South Africa previously categorized as responders (n = 39) or nonresponders (n = 37) to HIV-1 peptide pools in a whole blood intracellular cytokine assay. Viral load was significantly lower and CD4 T-cell counts higher among responders compared with nonresponders (P = 0.

Natural killer cells that respond to human immunodeficiency virus type 1 (HIV‐1) peptides are associated with control of HIV‐1 infection.

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 = .

FOXP3 expression is upregulated in CD4T cells in progressive HIV-1 infection and is a marker of disease severity.

Background: Understanding the role of different classes of T cells during HIV infection is critical to determining which responses correlate with protective immunity. To date, it is unclear whether alterations in regulatory T cell (Treg) function are contributory to progression of HIV infection.

Methodology: FOXP3 expression was measured by both qRT-PCR and by flow cytometry in HIV-infected individuals and uninfected controls together with expression of CD25, GITR and CTLA-4.

Cutting Edge: Unusual NK cell responses to HIV-1 peptides are associated with protection against maternal-infant transmission of HIV-1.

Most infants exposed to HIV-1 in utero and at delivery do not acquire infection. We show that mothers and infants who have CD3-negative cells that respond to HIV-1 peptides are substantially less likely to transmit and acquire infection, respectively. The CD3-negative cells, shown to be NK cells, respond with remarkable specificity and high magnitude to HIV-1 peptides from Env (envelope) and Reg (regulatory) protein regions, as measured by a whole blood intracellular cytokine assay only in the context of HIV-1 infection or exposure.

Identification of human immunodeficiency virus-1 specific CD8+ and CD4+ T cell responses in perinatally-infected infants and their mothers.

Background: There are few data describing the specificity, breadth and magnitude of T cell responses to HIV-1 in infancy.

Methods: HIV-specific CD8+ and CD4+ T cell responses to peptide pools representing Gag, Env, Pol, Nef and the regulatory regions (Reg) were simultaneously measured in 18 perinatally-infected infants and 14 of their chronically-infected mothers, using a whole blood interleukin-2 and interferon-gamma flow cytometric intracellular cytokine staining assay.

Results: HIV-specific CD8+ T cell responses were detected in all the infants aged 6 weeks and older (range 0.

Host CCL3L1 gene copy number in relation to HIV-1-specific CD4+ and CD8+ T-cell responses and viral load in South African women.

HIV-specific T-cell responses play an important role in control of infection. Because CCL3 has immune modulatory and antiviral activities, we hypothesized that host CCL3 genotype (CCL3L1 gene duplications) would influence the development of effective HIV-specific immune responses. Copy numbers of CCL3L1 were determined for 71 HIV-infected women, and HIV-specific CD4 and CD8 T-cell responses to overlapping peptide pools spanning the HIV-1 subtype C genome were simultaneously measured by an interferon-gamma and interleukin-2 whole-blood flow cytometric assay.

Development of a whole blood intracellular cytokine staining assay for mapping CD4(+) and CD8(+) T-cell responses across the HIV-1 genome.

A whole blood peptide mapping intracellular cytokine staining (ICS) assay was developed that allows the direct comparison, at the individual peptide level, of CD4(+) and CD8(+) T-cell responses that span every encoded protein, in patients infected with HIV-1. Whole blood samples from HIV-1 infected patients were stimulated with overlapping synthetic peptides spanning nine subtype C HIV-1 gene regions (Gag, Pol, Nef, Env, Tat, Rev, Vif, Vpu, Vpr). Following stimulation and permeabilization, cells were stained with fluorochrome labelled antibodies to CD3, CD8 (CD4(+) cells were defined as CD8 negative cells), and IL-2 and IFN-gamma.

Age-related changes in expression of CXCR4 and CCR5 on peripheral blood leukocytes from uninfected infants born to human immunodeficiency virus type 1-infected mothers.

Cross-sectional analysis of human immunodeficiency virus-exposed, uninfected infants revealed high proportions of CXCR4-expressing cells in their cord blood, which declined at 4.5 months and increased between 9 and 15 months to levels approaching those of uninfected adults. Proportions of CCR5-expressing cells, however, were very low in cord blood and subsequently increased with age.

Circulating levels of stromal cell-derived factor 1alpha and interleukin 7 in HIV type 1 infection and pulmonary tuberculosis are reciprocally related to CXCR4 expression on peripheral blood leukocytes.

In sub-Saharan Africa the coincidence of HIV-1 and Mycobacterium tuberculosis coinfection is ever-increasing, this being associated with increased progression to disease and reduced patient survival. Raised plasma levels of stromal cell-derived factor (SDF)-1alpha and interleukin (IL)-7, cytokines important in T cell development, and in the modulation of surface CXCR4 expression, have been reported to be associated with HIV-1 disease progression. We have previously shown specific disease group-related down modulation in vivo of the SDF-1 ligand, CXCR4, in HIV-1-seropositive patients, patients with pulmonary tuberculosis, and patients coinfected with M.