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HIV-Exposed Seronegative Sex Workers Express Low T-Cell Activation and an Intact Ectocervical Tissue Microenvironment.

ABSTRACT: Immunological correlates of natural resistance to HIV have been identified in HIV-exposed seronegative (HESN) individuals and include a low-inflammatory genital mucosal status. The cervicovaginal epithelium has not been studied for such correlates despite constituting an important barrier against sexual HIV transmission. To fill this gap in knowledge, we collected samples of blood, cervical mononuclear cells, cervicovaginal lavage, and ectocervical tissue from Kenyan HESN sex workers (n = 29) and controls (n = 33). The samples were analyzed by flow cytometry, protein profiling, 16S rRNA gene sequencing, in situ image analysis, and tissue-based RNA sequencing. A significantly higher relative proportion of regulatory T cells in blood (B7⁺CD25^hiFoxP3⁺CD127^loCD4⁺ and B7⁺Helios⁺FoxP3⁺CD4⁺), and a significantly lower proportion of activated cervical T cells (CCR5⁺CD69⁺CD4⁺ and CCR5⁺CD69⁺CD8⁺), were found in the HESN group compared with the controls. In contrast, there were no statistically significant differences between the study groups in cervicovaginal protein and microbiome compositions, ectocervical epithelial thickness, E-cadherin expression, HIV receptor expression, and tissue RNA transcriptional profiles. The identification of an intact ectocervical microenvironment in HESN individuals add new data to current knowledge about natural resistance to sexual transmission of HIV.

SUBMITTER: Rohl M

PROVIDER: S-EPMC7998094 | biostudies-literature |

REPOSITORIES: biostudies-literature

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HIV-exposed seronegative sex workers express high levels of regulatory T cells, low levels of T cell activation and an intact ectocervical tissue microenvironment

Project description:Immunological correlates of natural resistance to HIV have been identified in HIV-exposed seronegative (HESN) individuals. The cervicovaginal epithelium has not been studied for such correlates despite constituting an important barrier against sexual HIV transmission. To fill this gap in knowledge, we collected samples of blood and genital mucosa from Kenyan HESN sex workers (n=29) and controls (n=33). The samples were analyzed by several methods including tissue-based RNA sequencing. A significantly higher relative proportion of regulatory T cells and lower proportion of activated cervical T cells were found in the HESN group compared with the controls. However, they had comparable tissue RNA transcriptional profiles. In conclusion, the identification of an increased proportion of regulatory T cells in blood, a lower proportion of activated cervical T cells, and an intact ectocervical microenvironment in HESN individuals add new data to current knowledge about natural resistance to sexual transmission of HIV.

2021-04-20 | GSE165132 | GEO

HIV-exposed seronegative sex workers express high levels of regulatory T cells, low levels of T cell activation and an intact ectocervical tissue microenvironment

Project description:HIV-exposed seronegative sex workers express high levels of regulatory T cells, low levels of T cell activation and an intact ectocervical tissue microenvironment

| PRJNA693314 | ENA

Monocyte Gene and Molecular Expression Profiles Suggest Distinct Effector and Regulatory Functions in Beninese HIV Highly Exposed Seronegative Female Commercial Sex Workers.

Project description:We have previously reported that the female genital tract (FGT) of Beninese HIV highly-exposed seronegative (HESN) commercial sex workers (CSWs), presented elevated frequencies of a myeloid HLA-DR+CD14+CD11c+ population presenting "tolerogenic" monocyte derived dendritic cells (MoDC) features. In order to assess whether a differential profile of monocytes may be involved in the generation of these genital MoDCs, we have herein characterized the blood monocyte compartment of Beninese HESNs (HIV-uninfected ≥ 10 years CSWs) and relevant controls (HIV-uninfected 2.5-5 years CSWs herein termed "early HESNs"), HIV-infected CSWs, and low-risk HIV-uninfected women from the general population. Transcriptomic analyses by RNA-Seq of total sorted blood monocytes demonstrate that in comparison to the control groups, HESNs present increased expression levels of FCGR2C, FCAR, ITGAX, ITGAM, CR2, CD68, and CD163 genes, associated with effector functions. Moreover, we found increased expression levels of genes associated with protection/control against SHIV/HIV such as CCL3, CCL4, CCL5, BHLHE40, and TNFSF13, as well as with immune regulation such as IL-10, Ahr, CD83, and the orphan nuclear receptor (NR)4A1, NR4A2, and NR4A3. Through multicolor flow cytometry analyses, we noticed that the frequencies of intermediate and non-classical monocyte populations tended to be elevated in the blood of HESNs, and exhibited increased expression levels of effector CD16, CD11c, CD11b, as well as regulatory HLA-G, IL-10, and IFN-α markers when compared to HIV-uninfected women and/or HIV-infected CSWs. This profile is compatible with that previously reported in the FGT of HESNs, and likely confers an enormous advantage in their resistance to HIV infection.

| S-EPMC8878004 | biostudies-literature

Highly-Exposed HIV-1 seronegative Female Commercial Sex Workers sustain in their genital mucosa increased frequencies of tolerogenic myeloid and regulatory T-cells.

Project description:We and others have shown that HIV-1 highly-exposed seronegative (HESN) female commercial sex workers (CSWs) maintain low genital inflammatory conditions to prevent HIV infection. HIV-1 interacts with toll-like receptors (TLR)-7/8 to induce interferon (IFN)-α, an important antiviral and immunomodulatory cytokine, which act together with interleukin (IL)-10, human leukocyte antigen (HLA)-G and immunoglobulin-like transcript (ILT)-4 to initiate a "tolerogenic/regulatory" anti-inflammatory loop. In view of further unravelling elements associated with natural immunity to HIV-1, we have characterised TLR-7, IFN-α, IL-10, HLA-G and ILT-4 expression profiles in the genital tract of female CSWs and HIV-1-uninfected non-CSWs from Benin. Endocervical myeloid HLA-DR+ cells from HESN CSWs expressed higher levels of IFN-α, TLR-7, IL-10 and HLA-G than those from both HIV-1-infected CSWs and HIV-1-uninfected non-CSWs. Further characterization of the endocervical myeloid HLA-DR+ cells in HESN CSWs revealed a population of "tolerogenic" CD103+ CD14+ CD11c+ myeloid cells expressing high levels of IFN-α and IL-10. Concomitantly, HESN CSWs had higher frequencies of endocervical regulatory CD4+ T-cells when compared to those from the two other groups of women. These novel findings provide strong evidence to support the implication of tolerogenic myeloid cells expressing high levels of antiviral molecules in shaping the genital mucosal immune response to prevent HIV infection.

| S-EPMC5338327 | biostudies-literature

Heterogeneity of HIV-1 Replication in Ectocervical and Vaginal Tissue Ex Vivo.

Project description:In clinical trials evaluating HIV-1 prevention products, ex vivo exposure of mucosal tissue to HIV-1 is performed to inform drug levels needed to suppress viral infection. Understanding assay and participant variables that influence HIV-1 replication will help with assay implementation. Demographic and behavioral data were obtained from 61 healthy women aged 21-45. Paired cervical tissue (CT) and vaginal tissue (VT) biopsies were collected and treated with HIV-1BaL or HIV-1JR-CSF, washed, and cultured. On days 3, 7, and/or 11, culture supernatant was collected, and viral replication was monitored by p24 ELISA. Tissue was extracted at study end, and HIV-1 relative RNA copies were determined by polymerase chain reaction. Cumulative p24 and RNA were log-transformed and analyzed using a linear mixed model, t-test, and an intraclass correlation coefficient (ICC). HIV replication was similar between CT and VT for each virus, but HIV-1BaL had 1.5 log10 and 0.9 log10 higher levels of p24 than HIV-1JR-CSF in CT and VT, respectively (p < .001), which correlated with HIV-1 relative RNA copies. Cumulative p24 and RNA copies in both tissues demonstrated low intraperson correlation for both viruses (ICC ≤0.513 HIV-1BaL; ICC ≤0.419 HIV-1JR-CSF). Enrollment into previous clinical studies in which genital biopsies were collected modestly decreased the HIV-1BaL cumulative p24 for CT, but not for VT. To improve the ex vivo challenge assay, viruses should be evaluated for replication in mucosal tissue before study implementation, baseline mucosal tissue is not needed if a placebo/no treatment group is included within the clinical trial, and previous biopsy sites should be avoided.

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Epigenetic control of IRF1 responses in HIV-exposed seronegative versus HIV-susceptible individuals.

Project description:Not all individuals exposed to HIV become infected. Understanding why these HIV-exposed seronegative individuals remain uninfected will help inform the development of preventative measures against HIV infection. Interferon regulatory factor-1 (IRF1) plays a critical role both in host antiviral immunity and in HIV-1 replication. This study examined IRF1 expression regulation in the ex vivo peripheral blood mononuclear cells of HIV-exposed seronegative commercial sex workers who can be epidemiologically defined as relatively resistant to HIV infection (HIV-R), versus HIV-uninfected, susceptible controls (HIV-S). Whereas HIV-susceptible individuals demonstrated a biphasic, prolonged increase in IRF1 expression after interferon-? stimulation, HIV-R individuals demonstrated a robust, but transient response. We also found that the IRF1 promoter in HIV-R was primed by increased basal histone deacetylase-2 binding, independently of transcription regulators, STAT1 and nuclear factor-?B/p65, implicating an epigenetic silencing mechanism. Interestingly, the transitory IRF1 response in HIV-R was sufficient in comparable regulation of interleukin-12 and interleukin-4 expression compared with the HIV-susceptible controls. This is the first study characterizing IRF1 responsiveness in individuals who demonstrate altered susceptibility to HIV infection. These data suggest that transitory IRF1 responsiveness in HIV-R may be one of the key contributors to the altered susceptibility to HIV infection during the early stages of primary HIV infection.

| S-EPMC3062355 | biostudies-literature

Natural killer cell phenotype is altered in HIV-exposed seronegative women.

Project description:Highly exposed seronegative (HESN) individuals present a unique setting to study mechanisms of protection against HIV acquisition. As natural killer (NK) cell activation and function have been implicated as a correlate of protection in HESN individuals, we sought to better understand the features of NK cells that may confer protection. We used mass cytometry to phenotypically profile NK cells from a cohort of Beninese sex workers and healthy controls. We found that NK cells from HESN women had increased expression of NKG2A, NKp30 and LILRB1, as well as the Fc receptor CD16, and decreased expression of DNAM-1, CD94, Siglec-7, and NKp44. Using functional assessments of NK cells from healthy donors against autologous HIV-infected CD4+ T cells, we observed that NKp30+ and Siglec-7+ cells had improved functional activity. Further, we found that NK cells from HESN women trended towards increased antibody-dependent cellular cytotoxicity (ADCC) activity; this activity correlated with increased CD16 expression. Overall, we identify features of NK cells in HESN women that may contribute to protection from HIV infection. Follow up studies with larger cohorts are warranted to confirm these findings.

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Project description:HIV-1-specific T lymphocyte responses in individuals exposed to HIV-1 but who remain persistently seronegative (HESNs) have been reported in some but not all previous studies. This study was designed to resolve unequivocally the question of whether HESNs make HIV-1-specific T cell responses. We performed a blind investigation to measure HIV-1-specific T cell responses in both HIV-1-serodiscordant couples and HIV-1-unexposed seronegative controls (HUSNs). We found low-frequency HIV-1-specific T cells in both HESNs and HUSNs but show that the response rates were higher over time in the former (P = 0.01). Furthermore, the magnitudes of the HIV-1-specific T cell responses were significantly higher among responding HESNs than among HUSNs over time (P = 0.002). In both groups, responses were mediated by CD4 T cells. The responses were mapped to single peptides, which often corresponded to epitopes restricted by multiple HLA-DR types that have previously been detected in HIV-1-infected patients. HIV-1-specific T cell responses in HUSNs and some HESNs likely represent cross-reactivity to self or foreign non-HIV-1 antigens. The significantly greater T cell responses in HESNs, including in two who were homozygous for CCR5?32, demonstrates that HIV-1-specific T cell responses can be induced or augmented by exposure to HIV-1 without infection.

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| S-EPMC3785803 | biostudies-literature

Regulatory T cell (T reg) function in HIV exposed seronegative (ESN) individuals

Project description:T reg frequency, activation and function was studied in ESN individuals. Between the subjects with a HIV-specific T cell response, we identified two groups, one, where the T regs were able to suppress T cell proliferation and one where they lacked this capability. Sorted T regs from this two groups were analysed for their expression pattern.

2012-07-19 | GSE38778 | GEO

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