Permissive and Protective Factors Associated With Presence, Level, and Longitudinal Pattern of Cervicovaginal HIV Shedding

Abstract

Background Cervicovaginal HIV level (CV-VL) influences HIV transmission. Plasma viral load (PVL) correlates with CV-VL but discordance is frequent. We evaluated how PVL, behavioral, immunologic and local factors/conditions individually and collectively correlate with CV-VL. Methods CV-VL was measured in cervicovaginal lavage fluid (CVL) over 976 person-visits for 481 HIV-infected women in a longitudinal cohort study. We correlated identified factors with CV-VL at individual person-visits and detectable/undetectable PVL strata by univariate and multivariate linear regression, and with shedding pattern (never, intermittent, persistent ≥3 shedding-visits) in 136 women with ≥3 visits by ordinal logistic regression. Results 450/959 (46.9%) of person-visits with available PVL were discordant. 435/959 (45.3%) had detectable PVL with undetectable CV-VL and 15/959 (1.6%) undetectable PVL with detectable CV-VL. Lower CV-VL correlated with HAART usage (P=0.01). Higher CV-VL correlated with higher PVL (P<0.001), inflammation-associated cellular changes (P=0.03), cervical ectopy (P=0.009), exudate (P=0.005), and trichomoniasis (P=0.03). In multivariate analysis of the PVL-detectable stratum, increased CV-VL correlated with the same factors and friability (P=0.05), while with undetectable PVL, decreased CV-VL correlated with HAART use (P=0.04). In longitudinal analysis, never (40.4%) and intermittent (44.9%) shedding were most frequent. Higher-frequency shedders were more likely to have higher initial PVL (OR=2.47/log10 increase), HSV-2 seropositivity (OR=3.21) and alcohol use (OR=2.20). Conclusions While PVL correlates strongly with CV-VL, discordance is frequent. When PVL is detectable, cervicovaginal inflammatory conditions correlate with increased shedding. However, genital shedding is sporadic and not reliably predicted by associated factors. HAART, by reducing PVL, is the most reliable means of reducing cervicovaginal shedding.

HIV-1 Shedding From the Female Genital Tract is Associated With Increased Th1 Cytokines/Chemokines That Maintain Tissue Homeostasis and Proportions of CD8+FOXP3+ T Cells

“…Specifically, we observed significant increases in chemokines that promote recruitment of Th 1 and FOXP3+ T cells to tissue sites (IL-7, fractalkine), 19,20 and cytokines that maintain memory T cells (IL-7) and Th 1 /inflammation (IL-12p70). Importantly, the mucosal microenvironment associated with active HIV-1 shedding in this cohort is consistent with local viral replication 1,2,5,21 in the genital tract or associated lymph nodes rather than the passive transfer of virus from plasma to genital tissues. 22 The decreased number of FOXP3+ and T-bet+ T cells in the cervix during genital shedding may be due to increased cell death associated with viral replication, 23 changes in T cell phenotype due to down-regulation of FOXP3+ associated with increases in IL-7, 24,25 or may reflect trafficking of these cells to local lymph nodes where HIV-1 is thought to primarily replicate.…”

“…Genital HIV-1 shedding was defined as HIV-1 RNA detected at >30 copies/mL. Subjects were categorized as described 5 into non-shedders (HIV-1 never detected in CVL), intermittent shedders (at least 1 visit with and without shedding) or as persistent shedders (HIV-1 detected in CVL at all visits) based on shedding data from all visits in the parent study (median 6 visits, interquartile range (IQR): 5-10 visits). In the current study a smaller number of visits were assayed for each outcome due to limited sample availability (Supplemental Figure 1).…”

Accurate measurement of female genital tract fluid dilution in cervicovaginal lavage samples

“…Proteomic studies also have been conducted using CVL samples [11]. Molecular methods have been used to measure the abundance of viral pathogens in CVL samples, including: human papillomavirus (HPV) [12, 13], hepatitis C virus (HCV) [14], herpes simplex virus type 2 (HSV-2) [15-18], human immunodeficiency virus type 1 (HIV-1) [7, 15, 19], and cytomegalovirus (CMV) [20]. CVL samples from women volunteers have been analyzed to determine whether topical zinc deficiency is a risk factor in recurrent vulvovaginal candidiasis [21] and if dissolved nitric oxide gas is associated with bacterial vaginosis (BV) [22].…”

Secreted Mucosal Antimicrobials in the Female Reproductive Tract that are Important to Consider forHIVPrevention

“…In HIVpositive women, the presence of STI and local inflammation or immune activation has been positively associated with increased viral shedding in the genital tract. [119][120][121][122][123][124] Whereas inflammatory mediators can facilitate HIV replication, antimicrobials, SLPI, and elafin have potent anti-inflammatory functions that are potentially protective.…”