Women who have genital inflammation are at increased risk of sexual HIV infection. The purpose of this review is to evaluate the mechanisms for this relationship, causes of genital inflammation, and ...strategies to manage this condition.
We have recently shown in a cohort of South African women that HIV seroconversion was associated with persistently raised genital inflammatory cytokines (including MIP-1α, MIP-1β, and IP-10). Elevated inflammatory cytokine concentrations may facilitate HIV infection by recruiting and activating HIV target cells and disrupting the mucosal epithelial barrier. Bacterial vaginosis and sexually transmitted infections (STIs), which are predominantly asymptomatic in women, cause lower genital tract inflammation and increased HIV acquisition risk. In Africa, where syndromic management of STIs and bacterial vaginosis is standard-of-care, the substantial burden of asymptomatic infections has likely contributed to high-HIV incidence rates.
A genital inflammatory profile contributes to the high risk of HIV acquisition in African women. STIs and bacterial vaginosis are poorly managed in Africa and other developing nations and as such remain major drivers of persistent genital inflammation and HIV acquisition among these women.
Introduction
Young women in sub‐Saharan Africa are disproportionately affected by HIV, accounting for 25% of all new infections in 2017. Several behavioural and biological factors are known to impact ...a young woman's vulnerability for acquiring HIV. One key, but lesser understood, biological factor impacting vulnerability is the vaginal microbiome. This review describes the vaginal microbiome and examines its alterations, its influence on HIV acquisition as well as the efficacy of HIV prevention technologies, the role of the rectal microbiome in HIV acquisition, advances in technologies to study the microbiome and some future research directions.
Discussion
Although the composition of each woman's vaginal microbiome is unique, a microbiome dominated by Lactobacillus species is generally associated with a “healthy” vagina. Disturbances in the vaginal microbiota, characterized by a shift from a low‐diversity, Lactobacillus‐dominant state to a high‐diversity non‐Lactobacillus‐dominant state, have been shown to be associated with a range of adverse reproductive health outcomes, including increasing the risk of genital inflammation and HIV acquisition. Gardnerella vaginalis and Prevotella bivia have been shown to contribute to both HIV risk and genital inflammation. In addition to impacting HIV risk, the composition of the vaginal microbiome affects the vaginal concentrations of some antiretroviral drugs, particularly those administered intravaginally, and thereby their efficacy as pre‐exposure prophylaxis (PrEP) for HIV prevention. Although the role of rectal microbiota in HIV acquisition in women is less well understood, the composition of this compartment's microbiome, particularly the presence of species of bacteria from the Prevotellaceae family likely contribute to HIV acquisition. Advances in technologies have facilitated the study of the genital microbiome's structure and function. While next‐generation sequencing advanced knowledge of the diversity and complexity of the vaginal microbiome, the emerging field of metaproteomics, which provides important information on vaginal bacterial community structure, diversity and function, is further shedding light on functionality of the vaginal microbiome and its relationship with bacterial vaginosis (BV), as well as antiretroviral PrEP efficacy.
Conclusions
A better understanding of the composition, structure and function of the microbiome is needed to identify opportunities to alter the vaginal microbiome and prevent BV and reduce the risk of HIV acquisition.
Antibiotics continue to be the standard-of-care for bacterial vaginosis (BV), although recurrence rates are high. Vaginal probiotics may improve durability of BV treatment, although few probiotics ...for vaginal health contain Lactobacillus spp. that commonly colonize the lower female genital tract. Characteristics of vaginal Lactobacillus strains from South African women were evaluated for their probiotic potential in vitro compared to strains from commercial vaginal products, including growth at varying pHs, ability to lower pH, produce D-/L-lactate and H2O2, influence growth of BV-associated Gardnerella vaginalis and Prevotella bivia, adherence to cervical cells and susceptibility to antibiotics. Fifty-seven Lactobacillus strains were purified from cervico-vaginal fluid, including L. crispatus, L. jensenii, L. gasseri, L. mucosae, and L. vaginalis. L crispatus strains grew better at pHs below 4.5 and lowered pH more effectively than other strains. Production of D-/L-lactate and H2O2 varied between Lactobacillus species and strains. Lactobacillus strains generally inhibited P. bivia more uniformly than G. vaginalis isolates. All vaginal Lactobacillus isolates were resistant to metronidazole while susceptibility to clindamycin varied. Furthermore, vaginal Lactobacillus strains tended to be broadly susceptible to penicillin, amoxicillin, rifampicin and rifabutin. Whole-genome-sequencing of five of the best-performing vaginal Lactobacillus strains confirmed their likely safety, due to antimicrobial resistance elements being largely absent, while putative intact prophages were present in the genomes of two of the five strains. Overall, vaginal Lactobacillus strains largely performed better in these in vitro assays than probiotic strains currently used in probiotics for vaginal health. Including the best-performing vaginal Lactobacillus isolates in a region-specific probiotic for vaginal health may result in improved BV treatment options.
Abstract
There has been an emphasis on schools to promote healthy lifestyles and many intervention programmes have attempted this. Most programmes are evaluated at the time and/or shortly afterwards. ...This is a review of the impact and sustainability of the Health for Life programme 2–5 years after the initial phase. It captures the experiences of the senior school staff who delivered the programme through semi-structured interviews. Senior teachers recognized the importance of promoting healthy lifestyles in primary schools. They reported positively on aspects of the programme, in particular its flexibility and how it enabled schools to develop a new relationship with parents and how schools have sustained the initial programme. They discussed the main barriers to intervention and how they could be mitigated. Delivering a sustainable healthy lifestyle primary schools programme which has an impact is feasible but challenging for school staff. To maximize the likelihood of delivery, interventions must be championed by a member of the Senior Leadership Team, embedded in the curriculum, hands-on, easy to manage, and flexible to the needs of individual schools but requires support (financial, training and advisory). With these conditions the sustainability and impact of the programme was significant.
Human papillomavirus (HPV) infection correlates with higher rates of HIV acquisition, but the underlying biological mechanisms are unclear. Here we study associations between HPV and HIV acquisition ...and relate these to vaginal cytokine profiles in an observational cohort of women at high risk of HIV infection (CAPRISA 004, n = 779) and with 74% HPV prevalence. We report here that HPV infection associates with a 2.5-fold increase in HIV acquisition risk in this population (95% CI: 1.2-5.3). Among 48 vaginal cytokines profiled, cytokines associated with HPV infection overlap substantially with cytokines associated with HIV risk, but are distinct from those observed in HPV negative women. Although our data do not establish a causative link between HPV status and the risk of HIV, we suggest that increasing HPV vaccination coverage may carry an additional benefit of reducing the risk of contracting HIV infection, particularly in regions with high HPV prevalence.
The objectives of the study were to investigate prevalence of cervical human papillomavirus (HPV) genotypes to inform HPV vaccination strategy in South Africa and to study factors associated with HPV ...prevalence. Sexually active, HIV-negative women, aged 16-22 years recruited from Soweto (n = 143) and Cape Town (n = 148) were tested for cervical HPV and other genital infections. Overall HPV prevalence was 66.7% (194/291) in young women. Cape Town women were more likely to have multiple HPV infections than the Soweto women (48.0%, 71/148 versus 35.0%, 50/143 respectively, p = 0.033) and probable HR-HPV types (34.5%, 51/148 versus 21.7%, 31/143 respectively, p = 0.022). The most frequently detected HPV types were HPV-16 (11.7%), HPV-58 (10.3%), HPV-51 (8.9%), HPV-66 (8.6%), HPV-18 and HPV-81 (7.6% each). HPV types targeted by the bivalent HPV vaccine (HPV-16/18) were detected in 18.6% (54/291) of women, while those in the quadrivalent vaccine (HPV-6/11/16/18) were detected in 24.7% (72/291) of women; and those in the nonavalent vaccine (HPV-6/11/16/18/31/33/45/52/58) were detected in 38.5% (112/291) of women. In a multivariable analysis, bacterial vaginosis remained significantly associated with HPV infection (OR: 4.0, 95% CI: 1.4-12.6). Women were more likely to be HPV positive if they had received treatment for STI during the past 6-months (OR: 3.4, 95% CI: 1.1-12.4) or if they had ever been pregnant (OR: 2.3, 95% CI: 1.1-5.5). Compared to women who reported only one sexual partner, those with increased number of lifetime sex partners were more likely to have HPV (4-10 partners: OR: 2.9, 95% CI: 1.1-8.0). The high prevalence of HPV types targeted by the nonavalent HPV vaccine encourages the introduction of this vaccine and catch-up HPV vaccination campaigns in South Africa. The high burden of BV and concurrent STIs also highlights the need to improve the prevention and appropriate management of sexually-acquired and other genital tract infections in South African youth.
Young women in sub-Saharan Africa are disproportionally affected by HIV infection and unintended pregnancies. However, hormonal contraceptive (HC) use may influence HIV risk through changes in ...genital tract microbiota and inflammatory cytokines. To investigate this, 130 HIV negative adolescent females aged 15-19 years were enrolled into a substudy of UChoose, an open-label randomized crossover study (NCT02404038), comparing acceptability and contraceptive product preference as a proxy for HIV prevention delivery methods. Participants were randomized to injectable norethisterone enanthate (Net-En), combined oral contraceptives (COC) or etonorgesterol/ethinyl estradiol combined contraceptive vaginal ring (CCVR) for 16 weeks, then crossed over to another HC for 16 weeks. Cervicovaginal samples were collected at baseline, crossover and exit for characterization of the microbiota and measurement of cytokine levels; primary endpoints were cervical T cell activation, vaginal microbial diversity and cytokine concentrations. Adolescents randomized to COCs had lower vaginal microbial diversity and relative abundance of HIV risk-associated taxa compared to Net-En or CCVR. Cervicovaginal inflammatory cytokine concentrations were significantly higher in adolescents randomized to CCVR compared to COC and Net-En. This suggests that COC use may induce an optimal vaginal ecosystem by decreasing bacterial diversity and inflammatory taxa, while CCVR use is associated with genital inflammation.
Effective contraceptives are a global health imperative for reproductive-aged women. However, there remains a lack of rigorous data regarding the effects of contraceptive options on vaginal bacteria ...and inflammation. Among 218 women enrolled into a substudy of the ECHO Trial (NCT02550067), we evaluate the effect of injectable intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel implant (LNG), and a copper intrauterine device (Cu-IUD) on the vaginal environment after one and six consecutive months of use, using 16S rRNA gene sequencing and multiplex cytokine assays. Primary endpoints include incident BV occurrence, bacterial diversity, and bacterial and cytokine concentrations. Secondary endpoints are bacterial and cytokine concentrations associated with later HIV seroconversion. Participants randomized to Cu-IUD exhibit elevated bacterial diversity, increased cytokine concentrations, and decreased relative abundance of lactobacilli after one and six months of use, relative to enrollment and other contraceptive options. Total bacterial loads of women using Cu-IUD increase 5.5 fold after six months, predominantly driven by increases in the concentrations of several inflammatory anaerobes. Furthermore, growth of L. crispatus (MV-1A-US) is inhibited by Cu
ions below biologically relevant concentrations, in vitro. Our work illustrates deleterious effects on the vaginal environment induced by Cu-IUD initiation, which may adversely impact sexual and reproductive health.
The genital tract of African women has been shown to differ from what is currently accepted as 'normal', defined by a pH≤4.5 and lactobacilli-dominated microbiota. Adolescent girls and young women ...(AGYW) from sub-Saharan Africa are at high risk for HIV, and we hypothesized that specific biological factors are likely to be influential. This study aimed to compare characteristics of vaginal health in HIV-negative AGYW (16-22-years-old), from two South African communities, to international norms. We measured plasma hormones, vaginal pH, presence of BV (Nugent scoring), sexually transmitted infections (multiplex PCR for Chlamydia trachomatis, Neisseria gonorrhoea, Trichomonas vaginalis, Mycoplasma genitalium) and candidiasis (Gram stain) in AGYW (n = 298) from Cape Town and Soweto. Cervicovaginal microbiota was determined by 16S pyrosequencing; 44 genital cytokines were measured by Luminex; and cervical T-cell activation/proliferation (CCR5, HLA-DR, CD38, Ki67) was measured by multiparametric flow cytometry. 90/298 (30.2%) AGYW were negative for BV, candidiasis and bacterial STIs. L. crispatus and L. iners were the dominant bacteria in cervicovaginal swabs, and the median vaginal pH was 4.7. AGYW with L. crispatus-dominant microbiota (42.4%) generally had the lowest cytokine concentrations compared to women with more diverse microbiota (34/44 significantly upregulated cytokines). Frequencies of CCR5+CD4+ T-cells co-expressing CD38 and HLA-DR correlated positively with interleukin (IL)-6, TNF-α, GRO-α, macrophage inflammatory protein (MIP)-1α, and IL-9. While endogenous oestrogen had an immune-dampening effect on IL-6, TNF-related apoptosis-inducing ligand (TRAIL) and IL-16, injectable hormone contraceptives (DMPA and Net-EN) were associated with significantly lower endogenous hormone concentrations (p<0.0001 for oestrogen and progesterone) and upregulation of 34/44 cytokines. Since genital inflammation and the presence of activated CD4+ T cells in the genital tract have been implicated in increased HIV risk in South African women, the observed high levels of genital cellular activation and cytokines from AGYW may point towards biological factors increasing HIV risk in this region.
Bacterial vaginosis (BV) causes genital inflammation and increased HIV acquisition risk. The standard-of-care for BV, antibiotic therapy, is associated with high recurrence rates. Probiotics may ...improve treatment outcomes, although substantial heterogeneity in efficacy has been observed during clinical trials. To evaluate the potential to improve existing probiotics, we compared the inflammatory and antimicrobial (adhesion, H
O
, D-lactate and L-lactate production) characteristics of 23 vaginal Lactobacillus isolates from South African women, commercial vaginal probiotics (L. casei rhamnosus, L. acidophilus) and 4 reference strains. All lactobacilli induced inflammatory cytokine production by genital epithelial cells and produced D-lactate. Of six isolates assessed, five suppressed inflammatory responses to Gardnerella vaginalis. Although the L. acidophilus probiotic was the most adherent, many clinical isolates produced greater amounts of H
O
, D-lactate and L-lactate than the probiotics. The most L-lactate and H
O
were produced by L. jensenii (adjusted p = 0.0091) and L. mucosae (adjusted p = 0.0308) species, respectively. According to the characteristics evaluated, the top 10 isolates included 4 L. jensenii, 2 L. crispatus, 1 L. mucosae, 1 L. vaginalis and the L. acidophilus probiotic. There is potential to develop an improved vaginal probiotic using clinical Lactobacillus isolates. Inflammatory profiles are critical to evaluate as some isolates induced substantial cytokine production.
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