Elevated Cervical White Blood Cell Infiltrate Is Associated with Genital HIV Detection in a Longitudinal Cohort of Antiretroviral Therapy-Adherent Women

Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 10/2010; 202(10):1543-52. DOI: 10.1086/656720
Source: PubMed


Identification of factors associated with the presence of human immunodeficiency virus (HIV) in female genital secretions is critical for intervention strategies targeting transmission and eliminating replication of genital virus. We sought to monitor the prevalence of genital HIV shedding in antiretroviral therapy-adherent women over time and to assess changes in the genital microenvironment.
Levels of cell-free HIV (HIV RNA) and HIV-infected cells (HIV DNA) were monitored in peripheral blood samples and cervical and vaginal fluid samples at monthly intervals in 11 women for 1 year. Genital tract infections and fluctuations in cervical and vaginal white blood cell counts were also evaluated at each study visit.
Plasma HIV was undetectable at the majority of study visits; when detected, it was only at low levels. Throughout the study, genital HIV RNA and DNA were detected in each person. Combined genital HIV (RNA and DNA) was detected at 49.2% of study visits and was associated with an elevated concentration of cervical white blood cell infiltrate (odds ratio, 2.52 [95% confidence interval, 1.01-6.22]; P = .04). Infiltrate was not associated with a clinical disorder or patient-reported symptoms.
Despite antiretroviral therapy adherence and clinically suppressed plasma viremia, HIV was intermittently detected in genital secretions and was associated with subclinical inflammation and cells trafficking to the cervical mucosa.

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    • "The presence of HIV tat and gp120 in the mucosal environment of HIV-infected individuals is critical for the disruption of epithelial junctions and the exposure of nectin-1. The presence of HIV virions and HIV gene products in oral and genital epithelium is well described [15], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], especially in circulating HIV-infected immune cells [117], [118], [119]. Secretion of HIV tat and gp120 into blood has been shown [54], [55], [56], [57], [120], [121], [122]. "
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    ABSTRACT: Herpes simplex virus (HSV) types 1 and 2 are the most common opportunistic infections in HIV/AIDS. In these immunocompromised individuals, HSV-1 reactivates and replicates in oral epithelium, leading to oral disorders such as ulcers, gingivitis, and necrotic lesions. Although the increased risk of HSV infection may be mediated in part by HIV-induced immune dysfunction, direct or indirect interactions of HIV and HSV at the molecular level may also play a role. In this report we show that prolonged interaction of the HIV proteins tat and gp120 and cell-free HIV virions with polarized oral epithelial cells leads to disruption of tight and adherens junctions of epithelial cells through the mitogen-activated protein kinase signaling pathway. HIV-induced disruption of oral epithelial junctions facilitates HSV-1 paracellular spread between the epithelial cells. Furthermore, HIV-associated disruption of adherens junctions exposes sequestered nectin-1, an adhesion protein and critical receptor for HSV envelope glycoprotein D (gD). Exposure of nectin-1 facilitates binding of HSV-1 gD, which substantially increases HSV-1 infection of epithelial cells with disrupted junctions over that of cells with intact junctions. Exposed nectin-1 from disrupted adherens junctions also increases the cell-to-cell spread of HSV-1 from infected to uninfected oral epithelial cells. Antibodies to nectin-1 and HSV-1 gD substantially reduce HSV-1 infection and cell-to-cell spread, indicating that HIV-promoted HSV infection and spread are mediated by the interaction of HSV gD with HIV-exposed nectin-1. Our data suggest that HIV-associated disruption of oral epithelial junctions may potentiate HSV-1 infection and its paracellular and cell-to-cell spread within the oral mucosal epithelium. This could be one of the possible mechanisms of rapid development of HSV-associated oral lesions in HIV-infected individuals.
    PLoS ONE 02/2014; 9(2):e88803. DOI:10.1371/journal.pone.0088803 · 3.23 Impact Factor
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    • "(C) Polarized oriented buccal explants were treated with GFP-labeled recombinant tat at 30 ng/explant for 1 and 3 h and sectioned and examined for tat penetration by confocal microscopy. GR, granulosum; SP, spinosum; BL, basal; LP, lamina propria. of replicating HIV and viral p24 were detected in peripheral blood mononuclear cells of ART-treated patients (Crowe and Sonza, 2000; Hatano et al., 2010; Henning et al., 2010; Schupbach et al., 2005; Zhang and Crumpacker, 2001), which may migrate into mucosal epithelium leading to spread of HIV (Crowe and Sonza, 2000; Henning et al., 2010; Sonza et al., 2001). HIV tat-and/or gp120-mediated TJ disruption was detected only after prolonged incubation of cells (4–5 days) and this effect was not observed during shorter incubation periods (1–3 days). "
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    ABSTRACT: The incidence of human papillomavirus (HPV)-associated epithelial lesions is substantially higher in human immunodeficiency virus (HIV)-infected individuals than in HIV-uninfected individuals. The molecular mechanisms underlying the increased risk of HPV infection in HIV-infected individuals are poorly understood. We found that HIV proteins tat and gp120 were expressed within the oral and anal mucosal epithelial microenvironment of HIV-infected individuals. Expression of HIV proteins in the mucosal epithelium was correlated with the disruption of epithelial tight junctions (TJ). Treatment of polarized oral, cervical and anal epithelial cells, and oral tissue explants with tat and gp120 led to disruption of epithelial TJ and increased HPV pseudovirion (PsV) paracellular penetration in to the epithelium. PsV entry was observed in the basal/parabasal cells, the cells in which the HPV life cycle is initiated. Our data suggest that HIV-associated TJ disruption of mucosal epithelia may potentiate HPV infection and subsequent development of HPV-associated neoplasia.
    Virology 11/2013; 446(1-2):378-88. DOI:10.1016/j.virol.2013.08.018 · 3.32 Impact Factor
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    • "We found that 39.5% of women with undetectable PVL had detectable HIV-DNA in the genital tract, a rate very similar to those previously reported (median 34%, IQR = 30–40) [8]–[10], [15]–[17]. Overall, there was a positive correlation between HIV-DNA shedding in the genital tract and the level of HIV-DNA in PBMCs, although this correlation was less pronounced than the one we previously found between gut-associated lymphoïd tissue and blood [18]. "
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    ABSTRACT: To assess the impact of long-term combined antiretroviral therapy (cART) on HIV-RNA and HIV-DNA levels in cervicovaginal secretions of HIV-1-infected women with sustained undetectable plasma RNA viral load (PVL); to explore factors predictive of residual viral shedding; and to evaluate the risk of heterosexual transmission. Women with undetectable PVL (<50 copies/mL) for >6 months were included in this cross-sectional study. HIV-RNA and HIV-DNA were measured in blood and cervicovaginal lavage fluid (CVL). Women were systematically tested for genital infections. The risk of transmission to male partners during unprotected intercourse was estimated. Eighty-one women composed the study population: all had HIV-RNA <40 copies/mL in CVL. HIV-DNA was detectable in CVL of 29/78 patients (37%). There was a weak positive correlation between HIV-DNA levels in PBMCs and CVL (r = 0.20; p = 0.08). In multivariate analysis, two factors were associated with HIV-DNA detection in CVL: previous AIDS-defining illnesses (OR = 11; 95%CI = 2-61) and current residual viremia (20<PVL<50 cp/mL) (OR = 3.4; 95%CI = 1.1-10.9). Neither the classes of cART regimen nor the presence of genital bacterial or fungal colonization were associated with HIV-DNA detection in CVL. Twenty-eight percent of the women had unprotected intercourse with their regular HIV-seronegative male partner, for between 8 and 158 months. None of their male partners became infected, after a total of 14 000 exposures. In our experience, HIV-RNA was undetectable in the genital tract of women with sustained control of PVL on cART. HIV-DNA shedding persisted in about one third of cases, with no substantial evidence of residual infectiousness.
    PLoS ONE 08/2013; 8(8):e69686. DOI:10.1371/journal.pone.0069686 · 3.23 Impact Factor
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