Bacterial Vaginosis, Not HIV, Is Primarily Responsible for Increased Vaginal Concentrations of Proinflammatory Cytokines

Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington 98195, USA.
AIDS research and human retroviruses (Impact Factor: 2.33). 06/2008; 24(5):667-71. DOI: 10.1089/aid.2007.0268
Source: PubMed


The relative effect of HIV-1 infection compared with vaginal infections on vaginal cytokine concentrations is not well characterized. We compared vaginal fluid samples from HIV-1-infected women with those from HIV-negative women, to assess the effect of HIV-1 infection on concentrations of vaginal proinflammatory cytokines and the mucosal defense molecule secretory leukocyte protease inhibitor (SLPI). Twenty-seven HIV-1-infected women and 54 HIV-negative controls, matched for bacterial vaginosis (BV) status, had proinflammatory cytokine [interleukin (IL)-1beta, IL-6, IL-8] and SLPI concentrations measured from archived cervicovaginal lavage and vaginal swab samples using an enzyme-linked immunosorbent assay (ELISA). Log-transformed concentrations were compared by BV and HIV status in univariate analysis using Student's t-test, and in multivariate analysis using a linear regression model. In univariate analysis there were no significant differences in cytokine concentrations among HIV-1-infected and HIV-negative women. In a multivariable linear regression model, BV was significantly associated with an increase in IL-1 beta (p = 0.003). HIV infection was associated with an increased concentration of SLPI (p = 0.008), while BV status was significantly associated with a decrease in SLPI concentrations (p = 0.005). Neither HIV nor BV was associated with changes in IL-6 or IL-8. HIV does not have a major impact on vaginal concentrations of proinflammatory cytokines when controlling for the presence of bacterial vaginosis.

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    • "Additionally, bacteria can inactivate TLRs through induction of immunosuppressive anti-inflammatory cytokines such as IL-10 and through direct inhibition of pathogen associated molecular pattern (PAMP)-TLR interaction (St John et al., 2007; Witkin et al., 2007b). In studies involving relatively healthy HIV-1 infected women, vaginal pro-inflammatory cytokine concentrations were similar to those in uninfected women, suggesting that BV, not HIV-1 infections may be the predominant factor influencing vaginal pro-inflammatory cytokine concentrations (Mitchell et al., 2008). Understanding how differences in TLR polymorphisms can translate to reproductive tract immune response is critical for understanding the differential effect in the occurrence and persistence of BV and other microbiota. "
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    ABSTRACT: Bacterial vaginosis (BV) is a common vaginal disorder in women of reproductive age, especially among women with HIV-1 infection. Several bacterial products including lipopolysaccharides (LPS), lipoteichoic acids (LTA), and peptidoglycans (PGN) are stimulatory ligands for Toll-like receptors (TLRs), and recent evidence indicates the important role of variation in TLR genes for permitting overgrowth of gram negative and BV-type flora. We assessed whether genetic polymorphisms in five TLR genes (TLR1, TLR2, TLR4, TLR6, and TLR9) could be determinants of differential host immune responses to BV in 159 HIV-1-positive African American adolescents enrolled in the Reaching for Excellence in Adolescent Care and Health (REACH) study. BV was assessed biannually and diagnosed either by a Nugent score of at least 7 of 10, or using the Amsel criteria. Cox-proportional hazards regression models, adjusted for concurrent Chlamydia and Gonorrhea infections, douching, and absolute CD4 cell count, were used to identify host genetic factors associated with BV. Two SNPs were associated with BV as diagnosed by the Nugent score and the combined criteria: a minor allele G of rs4986790 (frequency=0.07), which encodes a His to Tyr substitution in TLR4 (HR=1.47, 95% CI 1.15-1.87) and rs187084 (frequency=0.24) on TLR9. The minor allele of rs1898830 (frequency=0.13) was associated with an increased hazard of BV defined by the Amsel criteria (HR=1.86, 95% CI 1.17-2.95). Further studies are warranted to confirm the associations of TLR gene variants and also to understand the underlying pathways and immunogenetic correlates in the context of HIV-1 infection.
    Full-text · Article · Sep 2012 · Journal of Reproductive Immunology
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    • "Simultaneous isolation of Mycoplasma, Gardnerella, and anaerobes, described as a " pathologic core, " combined with failure to isolate Lactobacillus in a vaginal sample, has been found to be strongly associated with BV [48]. Despite a general lack of external signs of inflammation in BV (as indicated by the -osis suffix signifying overgrowth, rather than the -itis suffix signifying inflammation) [49], many studies associate BV with increased proinflammatory signalling via TLR stimulation [50] [51] [52]. BV is characterized by an increase in the overall bacterial load in the vagina, with possible implications for TLR stimulation and immune activation. "
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    ABSTRACT: Immune activation is increasingly recognized as a critical element of HIV infection and pathogenesis, causing expansion of virus founder populations at the mucosal port of entry and eventual exhaustion of cellular immune effectors. HIV susceptibility is well known to be influenced by concurrent sexually transmitted infections; however, the role of commensal vaginal microbiota is poorly characterized. Bacterial vaginosis (BV) is a risk factor for HIV acquisition in studies worldwide; however, the etiology of BV remains enigmatic, and the mechanisms by which BV increases HIV susceptibility are not fully defined. A model of how vaginal microbiota influences HIV transmission is considered in the context of a well-established cohort of HIV-exposed seronegative (HESN) commercial sex workers (CSW) in Nairobi, Kenya, many of whom have increased levels of anti-inflammatory factors in vaginal secretions and reduced peripheral immune activation (immune quiescence). Elucidation of the relationship between complex microbial communities and inflammatory mucosal responses underlying HIV infection should be a priority for future prevention-focussed research.
    Full-text · Article · Mar 2012
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    ABSTRACT: Cervical cytobrush sampling is a relatively non-invasive method for obtaining mucosal cells from the female genital tract. To define mucosal immune cells sampled by cervical cytobrushing and to validate this approach for local immunity studies, we investigated the impact of human immunodeficiency virus (HIV) status and inflammation on the yield and composition of cervical cytobrush specimens. Cervical cytobrush samples were obtained from 89 chronically HIV-infected and 46 HIV-negative women. The HIV-infected women had significantly higher yields of CD3(+), CD45(+), CD19(+), CD14(+), Langerin(+) and CD24(+) cells than the uninfected women. While cytobrush-derived T cells from uninfected women were predominantly CD4(+) (4.2 CD4 : 1 CD8), CD8(+) T cells were predominant in HIV-infected women (0.6 CD4 : 1 CD8). The majority of CD4(+) and CD8(+) T cells from HIV-infected and uninfected women were of the effector memory (CD45RA(-) CCR7(-) CD27(-)) phenotype. HIV-infected women had significantly elevated levels of interleukin (IL)-1beta, IL-6 and IL-8 in cervical supernatants compared with uninfected women. We observed a significant positive correlation between T-cell counts and IL-1beta, tumour necrosis factor (TNF)-alpha and IL-12 concentrations. Neutrophil counts correlated significantly with cervical concentrations of IL-1beta, TNF-alpha, IL-8, IL-6 and IL-10. Antigen-presenting cell numbers correlated significantly with TNF-alpha and IL-12 concentrations. HIV-infected women on antiretroviral therapy had similar levels of cervical lymphocyte infiltration and inflammation to women naïve to therapy. In conclusion, we suggest that inflammation at the cervix and HIV infection are likely to be key determinants in the absolute number of mucosal immune cells recovered by cervical cytobrushing.
    Full-text · Article · Sep 2009 · Immunology
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