Janine Jewanraj1,2, Sinaye Ngcapu1,2, Farzana Osman1, Veron Ramsuran1,2,3, Maryam Fish3, Andile Mtshali1,2, Ravesh Singh2,4, Leila E Mansoor1,5, Salim S Abdool Karim1,6, Quarraisha Abdool Karim1,6, Jo-Ann S Passmore1,7,8, Lenine J P Liebenberg1,2. 1. Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa. 2. Department of Medical Microbiology, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa. 3. KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), Durban, South Africa. 4. Department of Microbiology, National Health Laboratory Services, KwaZulu-Natal Academic Complex, Inkosi Albert Luthuli Central Hospital, Durban, South Africa. 5. School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa. 6. Department of Epidemiology, Columbia University, New York, NY, USA. 7. Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa. 8. National Health Laboratory Services, Johannesburg, South Africa.
Abstract
INTRODUCTION: Semen induces mucosal changes in the female reproductive tract to improve pregnancy outcomes. Since semen-induced alterations are likely short-lived and genital inflammation is linked to HIV acquisition in women, we investigated the contribution of recent semen exposure on biomarkers of genital inflammation in women at high HIV risk and the persistence of these associations. METHODS: We assessed stored genital specimens from 152 HIV-negative KwaZulu-Natal women who participated in the CAPRISA 008 trial between November 2012 and October 2014. During the two-year study period, 651 vaginal specimens were collected biannually (mean five samples per woman). Cervicovaginal lavage (CVL) was screened for prostate-specific antigen (PSA) by ELISA, whereas Y-chromosome DNA (YcDNA) detection and quantification were conducted by RT-PCR, representing semen exposure within 48 hours (PSA+YcDNA+) and semen exposure within three to fifteen days (PSA-YcDNA+). Soluble protein concentrations were measured in CVLs by multiplexed ELISA. T-cell frequencies were assessed in cytobrushes by flow-cytometry, and vulvovaginal swabs were used to detect common vaginal microbes by PCR. Linear mixed models adjusting for factors associated with genital inflammation and HIV risk were used to assess the impact of semen exposure on biomarkers of inflammation over multiple visits. RESULTS: Here, 19% (125/651) of CVLs were PSA+YcDNA+, 14% (93/651) were PSA-YcDNA+ and 67% (433/651) were PSA-YcDNA-. Semen exposure was associated with how often women saw their partners, the frequency of vaginal sex in the past month, HSV-2 antibody detection, current gonorrhoea infection and Nugent Score. Both PSA detection (PSA+YcDNA+) and higher cervicovaginal YcDNA concentrations predicted increases in several cytokines, barrier-related proteins (MMP-2, TIMP-1 and TIMP-4) and activated CD4+CCR5+HLA-DR+ T cells (β = 0.050; CI 0.001 to 0.098; p = 0.046) and CD4+HLA-DR+ T cells (β = 0.177; CI 0.016 to 0.339; p = 0.032) respectively. PSA detection was specifically associated with raised pro-inflammatory cytokines (including IL-6, TNF-α, IP-10 and RANTES), and with the detection of BVAB2 (OR = 1.755; CI 1.116 to 2.760; p = 0.015), P. bivia (OR = 1.886; CI 1.102 to 3.228; p = 0.021) and Gardnerella vaginalis (OR = 1.815; CI 1.093 to 3.015; p = 0.021). CONCLUSIONS: More recent semen exposure was associated with raised levels of inflammatory biomarkers and the detection of BV-associated microbes, which declined by three to fifteen days of post-exposure. Although transient, semen-induced alterations may have implications for HIV susceptibility in women.
INTRODUCTION: Semen induces mucosal changes in the female reproductive tract to improve pregnancy outcomes. Since semen-induced alterations are likely short-lived and genital inflammation is linked to HIV acquisition in women, we investigated the contribution of recent semen exposure on biomarkers of genital inflammation in women at high HIV risk and the persistence of these associations. METHODS: We assessed stored genital specimens from 152 HIV-negative KwaZulu-Natal women who participated in the CAPRISA 008 trial between November 2012 and October 2014. During the two-year study period, 651 vaginal specimens were collected biannually (mean five samples per woman). Cervicovaginal lavage (CVL) was screened for prostate-specific antigen (PSA) by ELISA, whereas Y-chromosome DNA (YcDNA) detection and quantification were conducted by RT-PCR, representing semen exposure within 48 hours (PSA+YcDNA+) and semen exposure within three to fifteen days (PSA-YcDNA+). Soluble protein concentrations were measured in CVLs by multiplexed ELISA. T-cell frequencies were assessed in cytobrushes by flow-cytometry, and vulvovaginal swabs were used to detect common vaginal microbes by PCR. Linear mixed models adjusting for factors associated with genital inflammation and HIV risk were used to assess the impact of semen exposure on biomarkers of inflammation over multiple visits. RESULTS: Here, 19% (125/651) of CVLs were PSA+YcDNA+, 14% (93/651) were PSA-YcDNA+ and 67% (433/651) were PSA-YcDNA-. Semen exposure was associated with how often women saw their partners, the frequency of vaginal sex in the past month, HSV-2 antibody detection, current gonorrhoea infection and Nugent Score. Both PSA detection (PSA+YcDNA+) and higher cervicovaginal YcDNA concentrations predicted increases in several cytokines, barrier-related proteins (MMP-2, TIMP-1 and TIMP-4) and activated CD4+CCR5+HLA-DR+ T cells (β = 0.050; CI 0.001 to 0.098; p = 0.046) and CD4+HLA-DR+ T cells (β = 0.177; CI 0.016 to 0.339; p = 0.032) respectively. PSA detection was specifically associated with raised pro-inflammatory cytokines (including IL-6, TNF-α, IP-10 and RANTES), and with the detection of BVAB2 (OR = 1.755; CI 1.116 to 2.760; p = 0.015), P. bivia (OR = 1.886; CI 1.102 to 3.228; p = 0.021) and Gardnerella vaginalis (OR = 1.815; CI 1.093 to 3.015; p = 0.021). CONCLUSIONS: More recent semen exposure was associated with raised levels of inflammatory biomarkers and the detection of BV-associated microbes, which declined by three to fifteen days of post-exposure. Although transient, semen-induced alterations may have implications for HIV susceptibility in women.
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