Investigation of multiple concurrent Human papillomavirus infections, oncogenicity, and STI co-infection as risk factors for Human immunodeficiency virus infection.
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Background: Human papillomavirus (HPV) is one of the most common sexually transmitted infections (STIs) globally and a necessary factor for cervical cancer development. While HPV infection has been associated with increased Human immunodeficiency virus (HIV) risk, the underlying mechanisms remain unclear. Since STIs upregulate cytokine production and immune cell recruitment, and reduce epithelial barrier integrity, this study investigated whether the immune responses associated with HPV infection contribute to a genital immune environment conducive to an increased risk of HIV infection. Methods: This study included a baseline assessment of 167 HIV negative women participating in the CAPRISA 008 trial. The Roche Linear Array was used to detect the presence of 37 HPV genotypes in cervicovaginal lavage (CVL) pellets. The concentrations of 48 cytokines and 9 matrix metalloproteinases (MMPs) were assessed in matching CVL supernatants by multiplex ELISA. The frequencies of activated or proliferating T cells, NK cells, and of HIV target cells were assessed on cervical cytobrush-derived specimens by flow cytometry. Multiplex PCR was conducted to determine infection with common discharge-associated STIs. Results: The study demonstrated a 50.8% HPV prevalence. HPV infection was associated with younger age, older male partners, not living with a regular partner, and higher parity. HPV infection was also associated with greater levels of IL-5, IL-6 and G-CSF, an association otherwise masked by the inflammatory nature of other STI. Concomitant HPV/STI infection resulted in reduced concentrations of IL-6 and IL-1RA relative to HPV-STI+ women. In multivariate analyses controlling for other STI and nugent score, HPV-infected women had increased concentrations of SDF-1α (β = 0.148 pg/ml). Women with HR-HPV had higher concentrations of MCP-1 (β = 0.127 pg/ml) and IL-13 (β = 0.117 pg/ml), and greater frequencies of lymphocytes (β = 1.987 pg/ml) relative to those infected with LR-HPV. Having multiple HPV infections was associated with reduced concentrations of IL-5 (β = -0.170 pg/ml). Conclusion: While discharge-related STIs are inflammatory, a more subtle immune profile was associated with HPV infection that did not overtly relate to an increased potential for HIV risk. However, this study demonstrated an association between HR-HPV and biomarkers of inflammation, suggesting the need for longitudinal investigation to confirm a biological mechanism for the relationship between persistent HR-HPV infection and HIV acquisition.