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Supplemental Digital Content is Available in the Text. 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. The Kruskal–Wallis test and followed by the Mann–Whitney U test were used to determine differences among the study groups. The Spearman rank correlation coefficient was used to determine significant associations. Results: Compared with the other study groups, the percentage of CD69-expressing NK cells was higher in ECs, whereas the percentage of CD38-expressing NK cells was higher in VPs. Percentages of CD69+CD38− NK cells were elevated in ECs compared with VPs (P = 0.003), but were not different to PLWH on ART and PWOH. Differentiation, exhaustion, and metabolic profiles were not different in ECs compared with PLWH on ART and PWOH; however, NK cell function was lower than in PWOH. Conclusions: These findings demonstrate that NK cells from ECs have an activated, mature profile with low levels of immune exhaustion and a reduced metabolic phenotype suggesting functional competence. This insight could inform the development of novel immunotherapeutic strategies for treating HIV-1. [ABSTRACT FROM AUTHOR]

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]

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. During the RVF outbreak in South Africa in 2010/11, a total of 278 human cases were laboratory confirmed, including 25 deaths. The role of the host inflammatory response to RVF pathogenesis is not completely understood. Methods: Virus load in serum from human fatal and non-fatal cases was determined by standard tissue culture infective dose 50 (TCID50) titration on Vero cells. Patient serum concentration of chemokines and cytokines involved in inflammatory responses (IL-8, RANTES, CXCL9, MCP-1, IP-10, IL-1β, IL-6, IL-10, TNF and IL-12p70) was determined using cytometric bead assays and flow cytometry. Results: Fatal cases had a 1-log10 higher TCID50/ml serum concentration of RVF virus (RVFV) than survivors (p < 0.05). There were no significant sequence differences between isolates recovered from fatal and non-fatal cases. Chemokines and pro- and anti-inflammatory cytokines were detected at significantly increased (IL-8, CXCL9, MCP-1, IP-10, IL-10) or decreased (RANTES) levels when comparing fatal cases to infected survivors and uninfected controls, or when comparing combined infected patients to uninfected controls. Conclusions: The results suggest that regulation of the host inflammatory responses plays an important role in the outcome of RVFV infection in humans. Dysregulation of the inflammatory response contributes to a fatal outcome. The cytokines and chemokines identified in this study that correlate with fatal outcomes warrant further investigation as markers for disease severity. [ABSTRACT FROM AUTHOR]

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. Cultured peripheral blood mononuclear cells were stimulated with anti-CD3 and cell proliferation was assessed by CFSE dilution. Principal Findings: HIV infected individuals had significantly higher frequencies of CD4+FOXP3+ T cells (median of 8.11%; range 1.33%-26.27%) than healthy controls (median 3.72%; range 1.3-7.5%; P = 0.002), despite having lower absolute counts of CD4+FOXP3+ T cells. There was a significant positive correlation between the frequency of CD4+FOXP3+ T cells and viral load (rho = 0.593 P = 0.003) and a significant negative correlation with CD4 count (rho =20.423 P = 0.044). 48% of our patients had CD4 counts below 200 cells/ml and these patients showed a marked elevation of FOXP3 percentage (median 10% range 4.07%-26.27%). Assessing the mechanism of increased FOXP3 frequency, we found that the high FOXP3 levels noted in HIV infected individuals dropped rapidly in unstimulated culture conditions but could be restimulated by T cell receptor stimulation. This suggests that the high FOXP3 expression in HIV infected patients is likely due to FOXP3 upregulation by individual CD4+ T cells following antigenic or other stimulation. Conclusions/Significance: FOXP3 expression in the CD4+ T cell population is a marker of severity of HIV infection and a potential prognostic marker of disease progression. [ABSTRACT FROM AUTHOR]

The article studies CC chemokines in the context of their ability to influence or instruct adaptive anti-HIV T-cell immune responses in HIV-1-infected individuals. It attempts to determine whether gene duplications of CCL3L1, selected as a measure of host CCL3 chemokine production capacity, influenced the integrity of HIV-1-specific CD4 and CD8 T-cell responses and viral load in HIV-1-infected women.

An abstract of the article "Unusual natural killer cell responses to HIV-1 peptides are associated with protection against maternal-infant transmission of HIV-1," by Caroline Tiemessen and colleagues, is presented.

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. All mothers were living with HIV-1, 27 of the infants acquired HIV-1 in utero and 25 infants remained uninfected., Methods: CCR5 density, together with frequencies of CD4 + and CD8 + T-cells expressing immune activation (CCR5, ICOS and HLA-DR) and immune checkpoint (TIGIT and PD-1) markers, were measured in whole blood from the dyads close to delivery., Results: Compared with mothers who did not transmit, mothers who transmitted HIV-1 had less exposure to ART during pregnancy ( P = 0.015) and higher plasma viral load close to delivery ( P = 0.0005). These mothers, additionally, had higher CCR5 density on CD4 + and CD8 + T-cells and higher frequencies of CCR5, ICOS and TIGIT-expressing CD8 + T-cells. Similarly, compared with infants without HIV-1, infants with HIV-1 had higher CCR5 density on CD4 + and CD8 + T-cells and higher frequencies of CCR5, TIGIT, and PD-1-expressing CD4 + and CD8 + T-cells as well as higher frequencies of HLA-DR-expressing CD8 + T-cells. CCR5 density on maternal CD4 + T-cells remained significantly associated with transmission after adjusting for maternal viral load and CD4 + T cell counts. Mother-infant dyads with shared high CCR5 density phenotypes had the highest risk of transmission/acquisition of infection compared with dyads with shared low-CCR5 density phenotypes., Conclusion: This study provides strong evidence of a protective role for a combined mother-infant low CD4 + T-cell CCR5 density phenotype in in-utero transmission/acquisition of HIV-1., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: 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. Methods: Infants were diagnosed within 48 hours of birth and started ART as soon as possible. The frequency and phenotype of cTfh and B cells were analyzed at enrollment (birth -19 days) and at 4, 12, and 72 weeks of age in blood of 27 HIV-1-intrauterine-infected and 25 HIV-1 exposed uninfected (HEU) infants as part of a study in Johannesburg, South Africa. cTfh cells were divided into Tfh1, Tfh2, and Tfh17 subsets. B cell phenotypes were defined as naïve, resting memory, activated memory and tissue-like memory cells. Results: HIV-1-infected infants had higher frequencies of cTfh cells than HEU infants up to 12 weeks of age and these cTfh cells were polarized toward the Tfh1 subset. Higher frequencies of Tfh1 and lower frequencies of Tfh2 and Tfh17 correlated with lower CD4+ T cell percentages. Lower frequencies of resting memory, with corresponding higher frequencies of activated memory B cells, were observed with HIV-1 infection. Importantly, dysregulations in B cell, but not cTfh cell, subsets were normalized by 72 weeks. Conclusion: Very early ART initiation in HIV-1-infected infants normalizes B cell subsets but does not fully normalize perturbations in cTfh cell subsets which remain Tfh1 polarized at 72 weeks. It remains to be determined if very early ART improves vaccine antibody responses despite the cTfh and B cell perturbations observed over the time course of this study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shalekoff, Loubser, Dias, Strehlau, Shiau, Wang, He, Abrams, Kuhn and Tiemessen.)

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. These findings identify an important new measure of protective immunity to HIV-1 that highlights the importance of innate immunity in preventing the establishment of HIV-1 infection.

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.

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. tuberculosis and HIV-1. In this study, both SDF-1alpha and IL-7 plasma levels were significantly elevated from normal in similar disease groups (p < 0.001). Both SDF-1alpha and IL-7 plasma levels correlated negatively with the percentage of all subsets of leukocytes expressing CXCR4, across the study groups regardless of the presence or absence of disease. This suggests that CXCR4 receptors are likely modulated in similar ways by increased levels of these cytokines, even though the underlying mechanism of their increased production is likely to be different. In addition, plasma levels of SDF-1alpha correlated negatively with percentage of CD4(+) T cells, and both SDF-1alpha and IL-7 levels correlated positively with plasma HIV-1 viral load. Collectively, these results confirm a role for SDF-1alpha and IL-7 in HIV-1 disease progression, and suggest that these cytokines play a role in the modulation of CXCR4.