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Cervicovaginal Inflammation Facilitates Acquisition of Less Infectious HIV Variants.

ABSTRACT: We evaluated whether genital inflammation affects the selection of the transmitted virus. Among South African women, we found that preinfection genital inflammation facilitates transmission of less infectious human immunodeficiency virus, but highly infectious viruses are able to establish infection regardless of inflammation status. This suggests that viral phenotype can influence transmission risk.

SUBMITTER: Selhorst P

PROVIDER: S-EPMC5159604 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Cervicovaginal Inflammation Facilitates Acquisition of Less Infectious HIV Variants.

Selhorst Philippe P Masson Lindi L Ismail Sherazaan D SD Samsunder Natasha N Garrett Nigel N Mansoor Leila E LE Abdool Karim Quarraisha Q Abdool Karim Salim S SS Passmore Jo-Ann S JS Williamson Carolyn C

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20160929 1

We evaluated whether genital inflammation affects the selection of the transmitted virus. Among South African women, we found that preinfection genital inflammation facilitates transmission of less infectious human immunodeficiency virus, but highly infectious viruses are able to establish infection regardless of inflammation status. This suggests that viral phenotype can influence transmission risk. ...[more]

PMID: 27694480

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Cervicovaginal bacteria impact HIV acquisition in young African women

Project description:Cervicovaginal bacteria impact HIV acquisition in young African women

| PRJEB14858 | ENA

Lactobacillus-Deficient Cervicovaginal Bacterial Communities Are Associated with Increased HIV Acquisition in Young South African Women.

Project description:Elevated inflammation in the female genital tract is associated with increased HIV risk. Cervicovaginal bacteria modulate genital inflammation; however, their role in HIV susceptibility has not been elucidated. In a prospective cohort of young, healthy South African women, we found that individuals with diverse genital bacterial communities dominated by anaerobes other than Gardnerella were at over 4-fold higher risk of acquiring HIV and had increased numbers of activated mucosal CD4+ T cells compared to those with Lactobacillus crispatus-dominant communities. We identified specific bacterial taxa linked with reduced (L. crispatus) or elevated (Prevotella, Sneathia, and other anaerobes) inflammation and HIV infection and found that high-risk bacteria increased numbers of activated genital CD4+ T cells in a murine model. Our results suggest that highly prevalent genital bacteria increase HIV risk by inducing mucosal HIV target cells. These findings might be leveraged to reduce HIV acquisition in women living in sub-Saharan Africa.

| S-EPMC5270628 | biostudies-literature

Genital inflammation and the risk of HIV acquisition in women.

Project description:BackgroundWomen in Africa, especially young women, have very high human immunodeficiency virus (HIV) incidence rates that cannot be fully explained by behavioral risks. We investigated whether genital inflammation influenced HIV acquisition in this group.MethodsTwelve selected cytokines, including 9 inflammatory cytokines and chemokines (interleukin [IL]-1α, IL-1β, IL-6, tumor necrosis factor-α, IL-8, interferon-γ inducible protein-10 [IP-10], monocyte chemoattractant protein-1, macrophage inflammatory protein [MIP]-1α, MIP-1β), hematopoietic IL-7, and granulocyte macrophage colony-stimulating factor, and regulatory IL-10 were measured prior to HIV infection in cervicovaginal lavages from 58 HIV seroconverters and 58 matched uninfected controls and in plasma from a subset of 107 of these women from the Centre for the AIDS Programme of Research in South Africa 004 tenofovir gel trial.ResultsHIV seroconversion was associated with raised genital inflammatory cytokines (including chemokines MIP-1α, MIP-1β, and IP-10). The risk of HIV acquisition was significantly higher in women with evidence of genital inflammation, defined by at least 5 of 9 inflammatory cytokines being raised (odds ratio, 3.2; 95% confidence interval, 1.3-7.9; P = .014). Genital cytokine concentrations were persistently raised (for about 1 year before infection), with no readily identifiable cause despite extensive investigation of several potential factors, including sexually transmitted infections and systemic cytokines.ConclusionsElevated genital concentrations of HIV target cell-recruiting chemokines and a genital inflammatory profile contributes to the high risk of HIV acquisition in these African women.

| S-EPMC4565995 | biostudies-literature

Role of cervicovaginal microbiota in genital inflammation

Project description:We performed gene expression analysis using the SCRB-Seq method from cervical and peripheral blood antigen presenting cells that were collected from women with different cervicovaginal bacterial community types.

2015-05-19 | GSE68452 | GEO

Prothymosin α variants isolated from CD8+ T cells and cervicovaginal fluid suppress HIV-1 replication through type I interferon induction.

Project description:Soluble factors from CD8(+) T cells and cervicovaginal mucosa of women are recognized as important in controlling human immunodeficiency virus type 1 (HIV-1) infection and transmission. Previously, we have shown the strong anti-HIV-1 activity of prothymosin α (ProTα) derived from CD8(+) T cells. ProTα is a small acidic protein with wide cell distribution, to which several functions have been ascribed, depending on its intracellular or extracellular localization. To date, activities of ProTα have been attributed to a single protein known as isoform 2. Here we report the isolation and identification of 2 new ProTα variants from CD8(+) T cells and cervicovaginal lavage with potent anti-HIV-1 activity. The first is a splice variant of the ProTα gene, known as isoform CRA_b, and the second is the product of a ProTα gene, thus far classified as a pseudogene 7. Native or recombinant ProTα variants potently restrict HIV-1 replication in macrophages through the induction of type I interferon. The baseline expression of interferon-responsive genes in primary human cervical tissues positively correlate with high levels of intracellular ProTα, and the knockdown of ProTα variants by small interfering RNA leads to downregulation of interferon target genes. Overall, these findings suggest that ProTα variants are innate immune mediators involved in immune surveillance.

| S-EPMC4425839 | biostudies-literature

Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women.

Project description: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 >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.

| S-EPMC5893390 | biostudies-literature

Toll-like receptor variants are associated with infant HIV-1 acquisition and peak plasma HIV-1 RNA level.

Project description:ObjectiveWe evaluated the association of single nucleotide polymorphisms (SNPs) in TLRs with infant HIV-1 acquisition and viral control.DesignInfant HIV-1 outcomes were assessed in a Kenyan perinatal HIV-1 cohort.MethodsInfants were genotyped for six candidate and 118 haplotype-tagging polymorphisms in TLRs 2, 3, 4, 7, 8, and 9, MYD88 and TIRAP. Cox proportional hazards and linear regression were performed to assess associations with time to HIV-1 acquisition, time to infant mortality, and peak viral load.ResultsAmong 368 infants, 56 (15%) acquired HIV-1 by month 1 and 17 (4.6%) between 1 and 12 months. Infants with the TLR9 1635A (rs352140) variant were more likely to acquire HIV-1 by 1 month [hazard ratio = 1.81, 95% confidence interval (CI) = 1.05-3.14, P = 0.033] and by 12 months (hazard ratio = 1.62, CI = 1.01-2.60, P = 0.044) in dominant models adjusted for maternal plasma HIV-1 RNA level and genetic ancestry. Among 56 infants infected at 1 month of age or less, at least one copy of the TLR9 1635A allele was associated with a 0.58 log₁₀ copies/ml lower peak viral load (P = 0.002). Female infants with at least one copy of the TLR8 1G (rs3764880) variant had a 0.78 log₁₀ copies/ml higher peak viral load (P = 0.0009) and having at least one copy of the C allele for a haplotype tagging TLR7 variant (rs1634319) was associated with a 0.80 log₁₀ copies/ml higher peak viral load in female infants (P = 0.0003).ConclusionIn this African perinatal cohort, we found several TLR polymorphisms associated with HIV-1 acquisition and progression. Defining mechanisms for these TLR associations may inform HIV-1 prevention strategies that leverage innate responses.

| S-EPMC4124859 | biostudies-literature

L-selectin and P-selectin are novel biomarkers of cervicovaginal inflammation for preclinical mucosal safety assessment of anti-HIV-1 microbicide.

Project description:A major obstacle thwarting preclinical development of microbicides is the lack of a validated biomarker of cervicovaginal inflammation. Therefore, the present study aims to identify novel noninvasive soluble markers in a murine model for assessment of microbicide mucosal safety. By performing cytokine antibody array analysis, we identified two adhesion molecules, L-selectin and P-selectin, which significantly increased when mucosal inflammation was triggered by nonoxynol-9 (N9), an anti-HIV-1 microbicide candidate that failed clinical trials, in a refined murine model of agent-induced cervicovaginal inflammation. We found that patterns of detection of L-selectin and P-selectin were obviously different from those of the two previously defined biomarkers of cervicovaginal inflammation, monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6). The levels of these two soluble selectins correlated better than those of MCP-1 and IL-6 with the duration and severity of mucosal inflammation triggered by N9 and two approved proinflammatory compounds, benzalkonium chloride (BZK) and sodium dodecyl sulfate (SDS), but not by two nonproinflammatory compounds, carboxymethyl celluose (CMC; microbicide excipients) and tenofovir (TFV; microbicide candidate). These data indicated that L-selectin and P-selectin can serve as additional novel cervicovaginal inflammation biomarkers for preclinical mucosal safety evaluation of candidate microbicides for the prevention of infection with HIV and other sexually transmitted pathogens.

| S-EPMC3370781 | biostudies-literature

HIV binding, penetration, and primary infection in human cervicovaginal tissue.

Project description:We have developed human cervicovaginal organ culture systems to examine the initiating events in HIV transmission after exposure to various sources of HIV infectivity, including semen. Newly infected cells were detected in the cervical submucosa 3-4 days after exposure to a primary HIV isolate. At earlier times, extensive and stable binding occurred when cervical surfaces were exposed to virions or seminal cells. Cervical mucus provided some protection for the endocervical surface, by physically trapping virions and seminal cells. Confocal microscopy combined with 3D surface reconstruction revealed that virions could both bind to the external surface of the cervical epithelium and actually penetrate beneath the epithelial surface. In quantitative assays, pretreatment with a blocking antibody directed against beta1 integrin reduced HIV virion binding. Collectively, these results highlight a continuum of complex interactions that occurs when natural sources of HIV infectivity are deposited onto mucosal surfaces in the female reproductive tract.

| S-EPMC1183539 | biostudies-literature

The Potential Role of FREM1 and Its Isoform TILRR in HIV-1 Acquisition through Mediating Inflammation.

Project description:FREM1 (Fras-related extracellular matrix 1) and its splice variant TILRR (Toll-like interleukin-1 receptor regulator) have been identified as integral components of innate immune systems. The potential involvement of FREM1 in HIV-1 (human immunodeficiency virus 1) acquisition was suggested by a genome-wide SNP (single nucleotide polymorphism) analysis of HIV-1 resistant and susceptible sex workers enrolled in the Pumwani sex worker cohort (PSWC) in Nairobi, Kenya. The studies showed that the minor allele of a FREM1 SNP rs1552896 is highly enriched in the HIV-1 resistant female sex workers. Subsequent studies showed that FREM1 mRNA is highly expressed in tissues relevant to mucosal HIV-1 infection, including cervical epithelial tissues, and TILRR is a major modulator of many genes in the NF-κB signal transduction pathway. In this article, we review the role of FREM1 and TILRR in modulating inflammatory responses and inflammation, and how their influence on inflammatory responses of cervicovaginal tissue could enhance the risk of vaginal HIV-1 acquisition.

| S-EPMC8346017 | biostudies-literature

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