Impact of chronic sexual abuse and depression on inflammation and wound healing in the female reproductive tract of HIV-uninfected and HIV-infected women.

Sexual violence is associated with increased risk of HIV acquisition/transmission in women. Forced sex can result in physical trauma to the reproductive tract as well as severe psychological distress. However, immuno-biological mechanisms linking sexual violence and HIV susceptibility are incompletely understood. Using the Women\u27s Interagency HIV Study repository, a total of 77 women were selected to form 4 groups, stratified by HIV serostatus, in the following categories: 1) no sexual abuse history and low depressive symptom score (below clinically significant cut-off, score

Impact of Chronic Sexual Abuse and HIV on Genital Tract Biomarker Expression in Women

Background: Sexual violence is associated with increased risk for HIV acquisition/transmission in women. Chronic exposure to sexual violence can result in genital tract trauma and psychosocial stress subsequently affecting immune functions. We hypothesized that women with chronic sexual abuse and depression would have dysregulated genital tract immune mediators that can affect HIV risk. Methods: Using the Women\u27s Interagency HIV Study (WIHS) repository, we identified 4 groups of HIV+ and HIV- women (8-10/group) representing chronic sexual abuse exposure and depression (CES-D score \u3e 16): 1) no history of sexual abuse at baseline or depression (Control); 2) no history of sexual abuse at baseline but current depression (Depression); 3) chronic sexual abuse but no depression (Abuse); 4) chronic sexual abuse with current depression (Abuse+Depression). Cytokines (IL-6, IL-8, IL-1α, IL-1β, TNF-α, TGF-β), chemokines (MIP-3α, IP-10, MCP-1) and antimicrobials (Secretory leukocyte protease inhibitor (SLPI), Elafin, and Human beta defensin 2 (HBD-2)) were analyzed in cervical vaginal lavage (CVL) samples using ELISA. Linear regression was used to model levels of biomarkers with both depression and abuse as predictors. Models were run separately for HIV+ and HIV- women, with CD4 counts and viral load as covariates for HIV+ group. Results: In HIV- women reporting Abuse+Depression we found significantly higher levels of IP-10 compared to Control and Depression groups. Abuse+Depression group also had significantly higher levels of IL-1α but significantly lower levels of TGF-β, compared to Depression group. In HIV+ women, significantly lower levels of MIP-3α were found in the Abuse+Depression group compared to Controls whereas MCP-1 levels were highest in the Abuse group. When comparing by HIV status, HIV+ women reporting depression had significantly higher levels of IP-10 compared to HIV- women reporting depression. MCP-1 levels were significantly higher in HIV+ Abuse group compared to HIV- Abuse group. However, for MIP-3α, levels were significantly lower in HIV+ Abuse+Depression compared to HIV- Abuse+Depression. In HIV- women, there was evidence of an interaction between abuse and depression for IL-1a and IP-10. Conclusions: Our data suggests genital immune biomarkers are affected by chronic sexual abuse and HIV status. Further studies are needed to understand biological mechanisms of HIV acquisition/transmission in these women

Impact of chronic sexual abuse and depression on inflammation and wound healing in the female reproductive tract of HIV-uninfected and HIV-infected women.

Sexual violence is associated with increased risk of HIV acquisition/transmission in women. Forced sex can result in physical trauma to the reproductive tract as well as severe psychological distress. However, immuno-biological mechanisms linking sexual violence and HIV susceptibility are incompletely understood. Using the Women's Interagency HIV Study repository, a total of 77 women were selected to form 4 groups, stratified by HIV serostatus, in the following categories: 1) no sexual abuse history and low depressive symptom score (below clinically significant cut-off, scores <16) (Control); 2) no sexual abuse history but high depressive symptom score, ≥16 (Depression); 3) chronic sexual abuse exposure and low depressive symptom score (Abuse); 4) chronic sexual abuse exposure and high depressive symptom score (Abuse+Depression). Inflammation-associated cytokines/chemokines/proteases (TNF-α, IL-6, IL-1α, IL-1β, TGF-β MIP-3α, IP-10, MCP-1, Cathepsin B), anti-inflammatory/anti-HIV mediators (Secretory leukocyte protease inhibitor (SLPI), Elafin, beta defensin 2 (HBD2), alpha defensins (HNP 1-3), Thrombospondin (TSP-1), Serpin A1, A5, Cystatin A, B), and wound-healing mediators (Gro-α, VEGF, PDGF, EGF, FGF, IGF), were measured in cervical-vaginal lavage (CVL) using ELISA. Linear regression was used to model association of biomarkers with depression and abuse as predictor variables; the interaction between depression and abuse was also tested. Anti-HIV activity in CVL was tested using TZM-bl indicator cell line. In HIV-uninfected women, median levels of IL-6 (p = 0.04), IL-1α (p<0.01), TGF-β (p = 0.01), IP-10 (p = <0.01), PDGF (p<0.01) and FGF (p<0.01), differed significantly between groups. Specifically, an association was found between chronic sexual abuse and increased IL-1α (p<0.01), MIP-3α (p = 0.04), IP-10 (p<0.01), Serpin B1 (p = 0.01), FGF (p = 0.04) and decreased TGF-β (p<0.01), MCP-1 (p = 0.02), PDGF (p<0.01). Further, there was evidence of significant interactions between chronic sexual abuse and current depression for IL-1α, IP-10, Serpin A1, Cystatin B, and FGF. In HIV-infected women, median levels of TNF-α (p<0.01), IL-6 (p = 0.05), MIP-3α (p<0.01), and MCP-1 (p = 0.01), differed significantly between groups. Specifically, an association was found between chronic sexual abuse and increased MCP-1 (p = 0.03), Gro-α (p = 0.01) and decreased TNF-α (p<0.01), IL-1α (p = 0.02), MIP-3α (p<0.01) and Cathepsin B (p = 0.03). Current depressive symptoms were associated with significantly decreased MIP-3α (p<0.01). There was evidence of significant interactions between chronic sexual abuse and current depression for MCP-1 and FGF. No significant differences were observed in anti-HIV activity among all eight groups. Heat-map analyses revealed distinct immune network patterns, particularly in the Abuse groups for both HIV-infected and uninfected women. Our data indicates a complex relationship between chronic sexual abuse exposure, depressive symptoms, and FRT immune mediators that are also affected by HIV status. Association of chronic sexual abuse with increase in inflammation-associated cytokine/chemokine expression, along with impaired wound-healing associated growth-factors can create a microenvironment that can facilitate HIV infection. Evaluation of longitudinal changes in exposures and biomarkers are needed to untangle the immuno-biological mechanisms that may put women who endure life-long sexual abuse at increased risk for HIV

Impact of chronic sexual abuse and depression on inflammation and wound healing in the female reproductive tract of HIV-uninfected and HIV-infected women - Fig 3

<p><b>Heat map of Spearman’s coefficients for HIV-uninfected (A) and HIV-infected (B) samples stratified by abuse and depression status.</b> Distinct associative patterns were observed among (A i-iv) HIV negative Control, Depression, Abuse, Abuse+Depression as well as (B i-iv) HIV-infected Controls, Depression, Abuse and Abuse+Depression. Each cell of the heat map denotes the Spearman correlation coefficients. Cells highlighted in shades of RED indicates a positive association with darker shades representing stronger associations. Similarly, cells highlighted in shades of BLUE indicates a negative association with darker shades representing stronger associations. Statistically significant (p<0.05) associations are denoted in BOLD. Missing numbers (white) indicate there was no variation within that subgroup usually due to undetectable values, therefore the correlation coefficient could not be calculated. Boxed-in sections highlight clustering patterns.</p

Participant characteristics among (A) HIV-uninfected and (B) HIV-infected women.

<p>Any Abuse history includes emotional, physical, sexual abuse. SLV: Since last visit, in the past 6 months. Some categories have missing values and therefore, might not add up to the sample size for that group.</p

Differences in cervico-vaginal immune mediators by abuse status in HIV-uninfected women.

<p>CVL from Control women with no history of sexual abuse and depression (n = 10), women with current depression (n = 11), women with history of chronic sexual abuse (n = 10), and women with history of chronic sexual abuse and current depression (n = 8), were tested for levels of (A) IP-10, (B) IL-1α, (C) IL-6 and (D) PDGF by standard ELISA assays. Data is presented as log pg/mL of protein. Bars depict median. P value is indicated as follows: ***, p<0.0001; **, P<0.001; *,. P<0.05.</p

Hypothetical model of interaction between exposure to chronic sexual abuse, depression, immune dysregulation and HIV susceptibility.

<p>Our model hypothesizes that exposure to sexual abuse can directly result in immune dysregulation leading to increased HIV susceptibility. Depression resulting from exposure to sexual abuse can also lead to immune dysregulation and increased HIV susceptibility. Our major findings are also summarized schematically. Immune mediators are shown as gradients with the wider end of the arrows denoting groups where the concentrations were higher.</p

Main effects and Interaction models for the effects of depression and abuse on FRT biomarkers in HIV-uninfected (A) and HIV-infected (B) women.

<p>Linear regression models were used. Abuse defined as childhood sexual abuse and adult sexual abuse reported at baseline.</p