CROI 2016 Abstract eBook
283 Low ART Adherence Is AssociatedWith Higher Inflammation Despite HIV Suppression Jose R. Castillo-Mancilla 1 ;ToddT. Brown 2 ; Kristine M. Erlandson 1 ; Frank J. Palella 3 ; Edward M. Gardner 4 ; Bernard J. Macatangay 5 ; Elizabeth Breen 6 ; Lisa Jacobson 2 ; Peter L. Anderson 1 ; Nikolas I.Wada 2 1 Univ of Colorado, Denver, CO, USA; 2 Johns Hopkins Univ, Baltimore, MD, USA; 3 Northwestern Univ, Chicago, IL, USA; 4 Denver Hlth Med Cntr, Denver, CO, USA; 5 Univ of Pittsburgh Sch of Med, Pittsburgh, PA, USA; 6 Univ of California Los Angeles, Los Angeles, CA, USA Background: A significant proportion of virologically-suppressed HIV-infected individuals on antiretroviral therapy (ART) exhibit residual inflammation. It is unclear whether variable ART adherence, which could result in intermittent viral replication, partially explains this phenomenon. We aimed to determine if suboptimal ART adherence is associated with increased inflammation despite HIV suppression. Methods: Longitudinal adherence data (4-day self-report) and serum concentrations of 24 biomarkers of inflammation and immune activation were measured at the same study visit in virologically-suppressed (<50 copies/ml) HIV-infected men in the Multicenter AIDS Cohort Study (MACS) from 1998 to 2009. We used generalized gamma regression to estimate the effect of <100% ART adherence on the concentrations of these biomarkers. We also categorized adherence using the clinically meaningful cutoffs of <85%, 85-99%, and 100%. Data are presented as percentage differences in biomarker concentrations across groups; we adjusted for multiple testing by controlling the false discovery rate at 5% using the Benjamini-Hochberg procedure. Results: We studied 927 men (225 African American; 143 Hispanic) for a total of 2901 person-visits at which HIV viral suppression was documented. Median (range) age was 48 (21-81) years. ART included PI-based (50%), NNRTI-based (46%) and NRTI-only (3%) regimens. Models were adjusted for covariates associated with both adherence and biomarker concentrations in univariate analyses: age, race, HCV co-infection, and depression. Individuals reporting <100% adherence had higher concentrations of pro-inflammatory cytokines and C-reactive protein compared to men reporting 100% adherence (Table, shaded column). Differences were significant at p <0.05 for six biomarkers, but only for TNF-α and IFN-γ after adjusting for multiple tests. Further evaluation of adherence sub-categories showed that, after controlling for multiple testing, significantly higher concentrations of four biomarkers were identified in individuals reporting <85% adherence (Table). Conclusions: Suboptimal self-reported adherence was associated with higher concentrations of inflammatory biomarkers in virally-suppressed HIV-infected men. This suggests that adherence variations could have significant biological consequences beyond plasma HIV RNA suppression, possibly due to residual viral replication (i.e., below the limit of detection). Maximizing ART adherence could improve chronic inflammation and its deleterious long-term consequences.
284 Progesterone (P4) Indirectly Increases Susceptibility to HIVWithin Genital Mucosa Jason Neidleman 1 ; Joseph Chen 2 ; Nargis Kohgadai 2 ; Janis A. Müller 3 ; JeremyW. Martin 1 ; Jan Münch 3 ; Ruth M. Greenblatt 2 ; Linda Giudice 2 ;Warner C. Greene 1 ; Nadia R. Roan 2 1 Gladstone Insts, San Francisco, CA, USA; 2 Univ of California San Francisco, San Francisco, CA, USA; 3 Univ of Ulm, Ulm, Germany Background: HIV risk is linked to use of P4-based hormonal contraceptives. However, the molecular basis of how P4 increases susceptibility to HIV transmission in women is not well understood. Because the endometrium is a P4-responsive tissue in the female reproductive tract (FRT) and serves as a potential portal of entry for HIV, we hypothesized that P4 may increase vulnerability to HIV infection in the endometrium. Here, we assessed how P4 impacts the dominant cell types of this tissue, the endometrial epithelial cells (eEC) and underlying stromal fibroblasts (eSF), in the context of how they affect HIV infection of permissive cells. Methods: Primary eSF and eEC were co-cultured in a transwell system, and the effects of estradiol (E2) alone or in the presence of P4 (E2P4) on permeability of eEC monolayers was assessed. Infection of eSF, eEC, and patient-matched PBMCs with HIV, with each type of cell on its own or upon co-culture, were conducted.
Results: Compared to E2, E2P4 increased permeability of eEC, suggesting that luminal contents have increased access to underlying eSF during the secretory phase when P4 levels are high. HIV did not infect eEC or eSF. However, eEC and eSF both markedly affected infection of co-cultured CD4+ T cells. Whereas eEC decreased HIV infection of CD4+ T cells by 80% (compared to CD4+ T cells alone), eSF increased infection rates up to 81-fold. Comparison of eEC and eSF by microarray revealed anti-HIV factors SLPI and b-defensin as the top differentially expressed genes, and SLPI production by eEC and not eSF was confirmed at the protein level. Mechanistic analysis of how eSF promote HIV infection of CD4+ T cells revealed two mechanisms: trans-infection of CD4+ T cells, and increasing permissivity of the co-cultured cells. Of significance for prevention strategies, eSF-mediated enhancement of HIV infection increases the IC50 of tenofovir. Conclusions: These data lead to a model whereby in comparison to the lower FRT, which is subject to increased HIV susceptibility induced by sexual intercourse or ulcerative STDs, the upper FRT is prone to natural “cyclical susceptibility” via E2P4-induced permeability. Under conditions where P4 is high, the eEC layer is more permeable and HIV gains access to eSF, which promotes HIV infection of resident mucosal CD4+ T cells. This model may help explain why P4-based contraceptives are associated with higher HIV transmission risk in women, and suggest targeting the ability of eSF to enhance HIV infection as a new prevention approach.
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