Cervicovaginal Shedding of HIV Type 1 Is Related to Genital Tract Inflammation Independent of Changes in Vaginal Microbiota

Abstract

We examined the relationship of proinflammatory vaginal cytokines and secretory leukocyte protease inhibitor (SLPI) with genital HIV-1 shedding after controlling for genital coinfections. Fifty-seven HIV-1-infected women in Seattle, WA (n = 38) and Rochester, NY (n = 19) were followed every 3-4 months for a total of 391 visits. At each visit, plasma and cervicovaginal lavage (CVL) were tested for HIV-1 RNA using qPCR. Vaginal samples were tested for bacterial vaginosis, yeast, hydrogen peroxide-producing Lactobacillus colonization, Trichomonas vaginalis, Neisseria gonorrhea, Chlamydia trachomatis, CMV, and HSV shedding. CVL interleukins (IL)-1β, IL-6, IL-8, and SLPI were measured using ELISA. Linear regression with generalized estimating equations examined effects of cytokine concentrations on CVL HIV-1 RNA, adjusted for plasma HIV RNA, and measured coinfections. CVL IL-1β and IL-8 were significantly associated with CVL HIV-1 RNA. This persisted after adjusting for plasma HIV-1 RNA. Higher levels of IL-1β were associated with higher concentrations of HIV-1 RNA in CVL (β = 0.25, 95% CI 0.09, 0.42), as were higher levels of IL-8 (β = 0.34, 95% CI 0.17, 0.50). Adjusting for the presence of the coinfections described, this relationship was attenuated for IL-1β (β = 0.16; 95% CI -0.01, 0.33) but still significant for IL-8 (β = 0.29; 95% CI 0.13, 0.45). The proinflammatory cytokines IL-1β and IL-8 are associated with higher cervicovaginal HIV-1 RNA concentrations, even after controlling for plasma viral load and vaginal microbial cofactors. This association suggests that there may be additional, noninfectious causes of inflammation that increase cervicovaginal HIV-1 shedding.

Stable CD4 Expression and Local Immune Activation in the Ectocervical Mucosa of HIV-Infected Women

“…Furthermore, local immune activation in the ectocervix of the HIV + women was shown by upregulated cellular markers and cytokine expression. Many studies have described CD4 cell subpopulations and inflammatory markers in cervical mononuclear cell preparations and in cervi- covaginal secretions of HIV + women (12,21,(31)(32)(33). However, this is, to our knowledge, the first report of expression in situ of these immune markers in genital tissues of HIV + women.…”

“…18). Increased levels of genital tract proinflammatory cytokines can promote viral replication in the mucosa and thereby recruit immune target cells leading to increased HIV shedding (19)(20)(21). When an HIV-infected sexual partner is involved, HIV particles in the seminal fluid and the fluid itself may also cause genital epithelial damage and further inflammation (22,23).…”

Persistent Mycoplasma genitalium Infection of Human Endocervical Epithelial Cells Elicits Chronic Inflammatory Cytokine Secretion

“…Although epithelial toxicity appears to be minimal, in fact the profile of cytokine secretion by persistently infected endocervical epithelial cells included several key proinflammatory mediators for localized inflammation that are consistently increased in both acute (26) and, as we show here, persistent infection. IL-8 is a potent chemotactic molecule for neutrophils and has been positively associated with HIV shedding in cervicovaginal lavages (28). Therefore, persistent M. genitalium infection could have significant consequences for HIV shedding and/or acquisition of primary virus infection at the cervical mucosa.…”

Sexually transmitted coinfections. HIV coinfections

“…Tünetmentes, N. gonorrhoeae-fertőzött nők esetében nagyobb a HIVtranszmisszió rizikója, tünetes infekció esetén a vírus ürí-tése a genitális váladékokból fokozott, és a go-kezelés hatására csökken, férfi aknál és nőknél is [29,30,31]. A fokozott vírusürítés a HIV-átvitel kockázatát 6-7-szeresére növeli.…”