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Several clinical trials have demonstrated that antiretroviral (ARV) drugs taken as pre-exposure prophylaxis (PrEP) can prevent HIV infection, with the magnitude of protection ranging from -49 to 86% (refs. ). Although these divergent outcomes are thought to be due primarily to differences in product adherence, biological factors likely contribute. Despite selective recruitment of higher-risk participants for prevention trials, HIV risk is heterogeneous even within higher-risk groups. To determine whether this heterogeneity could influence patient outcomes following PrEP, we undertook a post hoc prospective analysis of results from the CAPRISA 004 trial for 1% tenofovir gel (n = 774 patients), one of the first trials to demonstrate protection against HIV infection. Concentrations of nine proinflammatory cytokines were measured in cervicovaginal lavages at [greater than] 2,000 visits, and a graduated cytokine score was used to define genital inflammation. In women without genital inflammation, tenofovir was 57% protective against HIV (95% confidence interval (CI): 7-80%) but was 3% protective (95% CI: -104-54%) if genital inflammation was present. Among women who highly adhered to the gel, tenofovir protection was 75% (95% CI: 25-92%) in women without inflammation compared to -10% (95% CI: -184-57%) in women with inflammation. Immunological predictors of HIV risk may modify the effectiveness of tools for HIV prevention; reducing genital inflammation in women may augment HIV prevention efforts., Author(s): Lyle R McKinnon (corresponding author) [1, 2, 3]; Lenine J Liebenberg [1, 3]; Nonhlanhla Yende-Zuma [1]; Derseree Archary [1, 3]; Sinaye Ngcapu [1, 3]; Aida Sivro [1, 2, 3]; [...]

: Introduction: Semen induces mucosal changes in the female reproductive tract to improve pregnancy outcomes. Since semen‐induced alterations are likely short‐lived and genital inflammation is linked to HIV acquisition in women, we investigated the contribution of recent semen exposure on biomarkers of genital inflammation in women at high HIV risk and the persistence of these associations. Methods: We assessed stored genital specimens from 152 HIV‐negative KwaZulu‐Natal women who participated in the CAPRISA 008 trial between November 2012 and October 2014. During the two‐year study period, 651 vaginal specimens were collected biannually (mean five samples per woman). Cervicovaginal lavage (CVL) was screened for prostate‐specific antigen (PSA) by ELISA, whereas Y‐chromosome DNA (YcDNA) detection and quantification were conducted by RT‐PCR, representing semen exposure within 48 hours (PSA+YcDNA+) and semen exposure within three to fifteen days (PSA−YcDNA+). Soluble protein concentrations were measured in CVLs by multiplexed ELISA. T‐cell frequencies were assessed in cytobrushes by flow‐cytometry, and vulvovaginal swabs were used to detect common vaginal microbes by PCR. Linear mixed models adjusting for factors associated with genital inflammation and HIV risk were used to assess the impact of semen exposure on biomarkers of inflammation over multiple visits. Results: Here, 19% (125/651) of CVLs were PSA+YcDNA+, 14% (93/651) were PSA−YcDNA+ and 67% (433/651) were PSA−YcDNA−. Semen exposure was associated with how often women saw their partners, the frequency of vaginal sex in the past month, HSV‐2 antibody detection, current gonorrhoea infection and Nugent Score. Both PSA detection (PSA+YcDNA+) and higher cervicovaginal YcDNA concentrations predicted increases in several cytokines, barrier‐related proteins (MMP‐2, TIMP‐1 and TIMP‐4) and activated CD4+CCR5+HLA‐DR+ T cells (β = 0.050; CI 0.001 to 0.098; p = 0.046) and CD4+HLA‐DR+ T cells (β = 0.177; CI 0.016 to 0.339; p = 0.032) respectively. PSA detection was specifically associated with raised pro‐inflammatory cytokines (including IL‐6, TNF‐α, IP‐10 and RANTES), and with the detection of BVAB2 (OR = 1.755; CI 1.116 to 2.760; p = 0.015), P. bivia (OR = 1.886; CI 1.102 to 3.228; p = 0.021) and Gardnerella vaginalis (OR = 1.815; CI 1.093 to 3.015; p = 0.021). Conclusions: More recent semen exposure was associated with raised levels of inflammatory biomarkers and the detection of BV‐associated microbes, which declined by three to fifteen days of post‐exposure. Although transient, semen‐induced alterations may have implications for HIV susceptibility in women., Introduction Semen induces mucosal alterations at the female reproductive tract to improve pregnancy outcomes [1‐3]. However, the contribution of semen‐associated changes to human immunodeficiency virus (HIV) risk in women remains [...]

Cervical cancer disproportionately affects women of reproductive age, with 80% of cases occurring in low- and middle-income countries. Persistent infection with high-risk human papillomavirus (HPV) genotypes has been described as the most common non-systemic biological risk factor for the development of cervical cancer. The mucosal immune system plays a significant role in controlling HPV infection by acting as the first line of host defense at the mucosal surface. However, the virus can evade host immunity using various mechanisms, including inhibition of the antiviral immune response necessary for HPV clearance. Pro-inflammatory cytokines and the vaginal microbiome coordinate cellmediated immune responses and play a pivotal role in modulating immunity. Recently, diverse vaginal microbiome (associated with bacterial vaginosis) and genital inflammation have emerged as potential drivers of high-risk HPV positivity and disease severity in women. The potential role of these risk factors on HPV recurrence and persistence remains unclear. This article reviews the role of cellular or cytokine response and vaginal microbiome dysbiosis in the clearance, persistence, and recurrence of HPV infection. [ABSTRACT FROM AUTHOR]

Objectives: Genital herpes simplex virus (HSV) infections are common in South Africa and worldwide. While HSV-2 is known to cause genital lesions, HSV-1 is better known to cause oral infections. Due to the global rise in genital HSV-1 infections, we aimed to compare the genital cytokine environment associated with HSV-1 and HSV-2 infections and their relation to the proinflammatory genital immune environment associated with HIV risk in African women.Methods: HSV-1 and HSV-2 DNA were detected by quantitative real-time PCR in menstrual cup specimens collected from 251 HIV-negative women participating in the CAPRISA 083 study in Durban, South Africa. HSV shedding was defined as detection at >150 copies/mL. Forty-eight cytokines were measured in genital fluid by multiplexed ELISA, and multivariable regression models determined associations between genital cytokines and HSV DNA detection.Results: HSV-1 DNA detection (24/251 (9.6%)) and shedding (13/24 (54.2%)) was more common than HSV-2 (detection in 14/251 (5.6%), shedding in 0/14). None of the women with detectable HSV had evidence of genital lesions. HSV-2 DNA detection was associated with increased interleukin (IL)-18 and decreased cutaneous T-cell attracting chemokine concentrations, but only in univariable analysis. By contrast, in both univariable and multivariable analyses, the detection of HSV-1 DNA was associated with reduced concentrations of granulocyte-colony stimulating factor, IL-7, IL-4, platelet-derived growth factor-ββ and five proinflammatory cytokines associated with HIV risk: IL-6, IL-1β, macrophage inflammatory protein (MIP)-1α, MIP-1β and tumour necrosis factor-α.Conclusions: That HSV-1 DNA was more commonly detected and shed than HSV-2 emphasises the need for clinical screening of both viruses, not just HSV-2 in young women. Efforts to reduce genital inflammation may need to consider implementing additional strategies to mitigate a rise in HSV replication. [ABSTRACT FROM AUTHOR]

CD4+ T cells expressing α4β7 play an important role in HIV pathogenesis. Indicative integrins in HIV: The gut is thought to be a major viral reservoir in HIV infection, and studies in nonhuman primates suggest that targeting the α4β7 integrin on T cells may be a viable therapy. Sivro et al. now extend these findings to humans by examining HIV acquisition in multiple African cohorts. Higher frequencies of α4β7+ circulating CD4+ T cells before infection were associated with increased HIV acquisition, viral load at set point, and more rapid CD4+ T cell decline. These exciting data confirm that integrin targeting could help reduce the spread of HIV. The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin α4β7 promotes the homing of immune cells to this site, including those that serve as viral targets. Data from simian immunodeficiency virus (SIV) animal models suggest that α4β7 blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of α4β7+ peripheral blood CD4+ T cells, independent of other T cell phenotypes and genital inflammation, were associated with increased rates of HIV acquisition in South African women. A similar acquisition effect was observed in a Kenyan cohort and in nonhuman primates (NHPs) after intravaginal SIV challenge. This association was stronger when infection was caused by HIV strains containing V2 envelope motifs with a preference for α4β7 binding. In addition, pre-HIV α4β7+ CD4+ T cells predicted a higher set-point viral load and a greater than twofold increased rate of CD4+ T cell decline. These results were confirmed in SIV-infected NHPs. Increased frequencies of pre-HIV α4β7+ CD4+ T cells were also associated with higher postinfection expression of lipopolysaccharide binding protein, a microbial translocation marker, suggestive of more extensive gut damage. CD4+ T cells expressing α4β7 were rapidly depleted very early in HIV infection, particularly from the GI mucosa, and were not restored by early antiretroviral therapy. This study provides a link between α4β7 expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-α4β7 monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting α4β7 integrin as a clinical intervention during HIV infection. [ABSTRACT FROM AUTHOR]

Editorial summary Advances in molecular tools to characterize the microbiome have led to the discovery of unique roles for microbes in human disease. Findings that the female genital microbiome can influence HIV acquisition and prevention emphasize the importance of microbiome analysis in clinical trials that assess the efficacy of HIV prevention interventions.

Objectives: In sub-Saharan Africa, approximately 86% of HIV infections in adolescents aged 15-19 years occur among girls. Their heightened susceptibility is likely influenced by converging sociobehavioural and biological factors, although the relative contributions remain unclear. To address this, we compared known and hypothesised risk factors for HIV between cisgender adolescent girls and adult women in South Africa and evaluated the relationships between these factors and sexually transmitted infection (STI) status., Methods: This cross-sectional observational study included adolescent (n=305; 14-19 years) and adult females (n=114; 25-35 years) in two South African provinces (Western Cape (WC), KwaZulu-Natal (KZN)). Demographic and sociobehavioural data were collected by questionnaire. Colposcopy was conducted to identify cervicovaginal abnormalities, and tests for bacterial vaginosis (BV), Chlamydia trachomatis , Neisseria gonorrhoeae and Trichomonas vaginalis were performed., Results: Adults reported higher risk sexual behaviour than adolescents across multiple variables, although adolescents were more likely to have STIs than adults (62.8% vs 34.0%, respectively, p=0.0010 for WC; 42.5% vs 16.4%, respectively, p=0.0002 for KZN). Adolescents did, however, report earlier sexual debut (16 years old vs 17 years old, p<0.0001 for both sites) and KZN adolescents were more likely to use intravaginal sexual enhancers than adults (34.6% vs 20.6%, respectively, p=0.0417). Numbers of sexual partners (β-coefficient: 0.34, SE: 0.12, p=0.0054) and sex acts within the previous 3 months (β-coefficient: 0.25, SE: 0.09, p=0.0062) were associated with STIs in adolescents and trended to significance for adults. Intravaginal sexual enhancer use (KZN only; β-coefficient: 0.95, SE: 0.38, p=0.0118) and biological risk factors, including BV Nugent score (β-coefficient: 0.09, SE: 0.04, p=0.0257) and signs of cervicovaginal injury/inflammation (β-coefficient: 1.07, SE: 0.45, p=0.0171), were associated with STIs in adolescents but not adults., Conclusions: Risk factors for STIs including HIV may differ between age groups of girls and women, and mitigation interventions may need to be tailored accordingly., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Studies of seronegative individuals in HIV discordant relationships provide important insights into the effects of HIV exposure on the seronegative partner, but few have examined the impact of partner serostatus on disease progression in seropositive individuals. We investigated the impact of HIV serostatus on clinical and biological factors influencing HIV disease progression in 337 HIV-infected heterosexual individuals in stable long-term HIV-seroconcordant or HIV-serodiscordant relationships. Seroconcordant individuals had significantly higher plasma viral loads (pVLs) than HIV-infected partners in serodiscordant partnerships [4.4 log10 copies RNA/mL (interquartile range 3.7-5.0) versus 3.9 (3.3-4.5), P < 0.0001], irrespective of gender. pVLs correlated inversely with CD4 T-cell counts, although CD4 counts did not differ significantly between seroconcordant and serodiscordant individuals. HIV+ seroconcordant individuals had higher frequencies of CCR5 CD4 and CD8 T cells (P = 0.03 and P = 0.02, respectively) than HIV+ individuals in serodiscordant relationships and higher concentrations of plasma IL-1β (P = 0.04), TNF-α (P = 0.02), and IL-10 (P = 0.02). Activated CD4 T-cell frequencies and TNF-α were the most influential in determining variation in pVLs, independently of CD4 counts. In addition, HIV+ seroconcordant women had significantly higher genital VLs (gVLs) than HIV+ women in serodiscordant relationships (P < 0.001), with pVLs correlating significantly with gVLs (Rho = 0.65, P < 0.0001). Cervical and blood T-cell activation tended to correlate positively, although partner seroconcordance did not influence genital T-cell activation. We conclude that HIV+ seroconcordant individuals have higher frequencies of activated, CCR5-expressing T cells in blood and higher pVLs and gVLs than their HIV+ counterparts in discordant relationships, which could translate to faster disease progression or larger viral reservoir.

The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin α 4 β 7 promotes the homing of immune cells to this site, including those that serve as viral targets. Data from simian immunodeficiency virus (SIV) animal models suggest that α 4 β 7 blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of α 4 β 7 + peripheral blood CD4 + T cells, independent of other T cell phenotypes and genital inflammation, were associated with increased rates of HIV acquisition in South African women. A similar acquisition effect was observed in a Kenyan cohort and in nonhuman primates (NHPs) after intravaginal SIV challenge. This association was stronger when infection was caused by HIV strains containing V2 envelope motifs with a preference for α 4 β 7 binding. In addition, pre-HIV α 4 β 7 + CD4 + T cells predicted a higher set-point viral load and a greater than twofold increased rate of CD4 + T cell decline. These results were confirmed in SIV-infected NHPs. Increased frequencies of pre-HIV α 4 β 7 + CD4 + T cells were also associated with higher postinfection expression of lipopolysaccharide binding protein, a microbial translocation marker, suggestive of more extensive gut damage. CD4 + T cells expressing α 4 β 7 were rapidly depleted very early in HIV infection, particularly from the GI mucosa, and were not restored by early antiretroviral therapy. This study provides a link between α 4 β 7 expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-α 4 β 7 monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting α 4 β 7 integrin as a clinical intervention during HIV infection., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Mucosal and systemic immune mediators have been independently associated with HIV acquisition risk, but the relationship between compartments remains unclear., Methods: To address this, the concentrations of 12 cytokines were compared in matched plasma and cervicovaginal lavages (CVLs) from 57 HIV-positive women before their acquisition of HIV (cases) and 50 women who remained uninfected (controls) during the CAPRISA 004 trial., Results: Although genital IP-10 concentrations were significantly higher in cases, plasma IP-10 concentrations were inversely associated with HIV risk. Comparing differences in mucosal and systemic cytokine concentrations between cases and controls, mucosa-biased gradients indicating higher cervicovaginal lavage relative to plasma concentrations were observed for all 5 chemokines in the panel. Four were significantly associated with HIV acquisition, including IP-10 (odds ratio [OR] 1.73, 95% confidence interval [CI]: 1.27 to 2.36), macrophage inflammatory protein-1β (OR 1.72, 95% CI: 1.23 to 2.40), interleukin (IL)-8 (OR 1.50, 95% CI: 1.09 to 2.05), and monocyte chemotactic protein-1 (OR 1.36, 95% CI: 1.01 to 1.83). None of the other 7 cytokines tested predicted HIV risk. Decision tree analyses confirmed this association, with gradients of IP-10, IL-8, and granulocyte-macrophage colony-stimulating factor concentrations correctly classifying 77% of HIV outcomes., Conclusions: Our findings suggest that mucosa-biased gradients of IP-10, macrophage inflammatory protein-1β, IL-8, and monocyte chemotactic protein-1 are associated with an increased risk of HIV infection., Competing Interests: The authors have no conflicts of interest to disclose.