CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

TUESDAY, FEBRUARY 24, 2015 Session P-C2 Poster Session

Poster Hall

2:30 pm– 4:00 pm The Mucosa in HIV/SIV Pathogenesis 267 Impact of Mucosal Immunity and HIV Persistence on CD4/CD8 Ratio After ART Initiation Sergio Serrano-Villar 1 ;Talía Sainz 2 ;TaeWook-Chun 3 ; Netanya S. Utay 5 ; Zhong-Min Ma 4 ; Basile Siewe 6 ; Steven Deeks 7 ; Richard Pollard 4 ; Christopher Miller 4 ; David Asmuth 4 1 University Hospital Ramón y Cajal, Madrid, Spain; 2 University Hospital La Paz, Madrid, Spain; 3 National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, US; 4 University of California Davis, Davis, CA, US; 5 University of Texas, Galveston, TX, US; 6 Rush University Medical Center, Chicago, IL, US; 7 University of California San Francisco, San Francisco, CA, US Background: The CD4/CD8 ratio correlates with persistent T-cell dysfunction and mortality. We examined the impact of changes (∆) in the HIV reservoir, systemic inflammation/ bacterial translocation and mucosal immunity following ART initiation on CD4/CD8 ratio. Methods: 33 ART naïve HIV subjects were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with tenofovir/emtricitabine. Colon and duodenal biopsies were obtained at baseline (BL) and after 9 months of suppressive ART. Duodenal CD4 T-cell density (cells/mm 2 ) was counted by immunofluorescence antibody (IFA) labeling. Tissue was digested into single-cell suspensions for immunophenotyping. Cell-associated HIV RNA and proviral DNA, lymphocyte subsets and activation phenotypes (CD38 + /HLA-DR + ) were measured in duodenum, and colon, and in peripheral blood (PB) at BL, month 3, 6, and 9. Plasma IL-6, lipoteichoic acid (LTA), sCD14 and zonulin were measured by ELISA. Associations between ∆CD4/CD8 ratio and variations of continuous variables were analyzed using linear mixed models with random intercepts. Results: The CD4/CD8 ratio significantly improved during ART in all compartments but recovered less in duodenum (all P<0.001). No difference was observed between the regimens (P=0.102) (Figure 1). Higher PB ∆CD4/CD8 ratio was associated with greater decay of HIV-DNA and HIV-RNA. In PB these correlations were significant for both HIV-RNA and HIV-DNA levels (P<0.001), but only PB ∆CD4/CD8 increments predicted colonic RNA-HIV declines (P=0.001). Increases in CD4/CD8 ratio were related to increased zonulin levels (P=0.076). Higher CD4/CD8 was consistently associated with a lower % of activated CD8 T-cells in PB (Rho -0.74, P<0.001) and colon (Rho -0.48, P=0.002). PB ∆CD4/CD8 increases predicted comparable declines of T-cell activation in PB and colon (P<0.001) and ∆naïve/memory increases in PB and colon (P<0.001), but not any of these phenotypes of CD4 T-cells in duodenum. A higher PB ∆CD4/CD8 ratio was associated with significant improvements of duodenal CD4-T cells/mm 2 , which still remained profoundly impaired at the end of follow-up (mean CD4 cells/mm 2 : at baseline, 48, at month 9, 151; in controls: 674; P<0.001).

Poster Abstracts

Figure 1. Changes in CD4/CD8 ratio in three compartments during first-line ART. Individual participant trajectories are represented by grey lines. Dash lines represent levels observed in HIV-uninfected individuals. Red, green and blue lines represent mean changes for each treatment arm predicted by linear mixed-effects models adjusted for baseline CD4 counts. P values for the interaction between treatment arms and time did not reach statistical significance in any compartment. Conclusions: CD4/CD8 recovery during ART correlates with improvements in markers of viral persistence, T cell activation and T cell maturation in PB and colon. The duodenum may represent a unique compartment for impairment of CD4 maturation and depletion. A quadruple ART regimen did not add detectable benefit to triple ART. 268 Monocyte/Macrophage Activation and Recruitment to Mucosal Sites in SIV Pathogenesis Background: Monocytes/macrophages (Mo/Ma) assume unique functions in HIV infection, being linked to microbial translocation, immune activation and inflammation (IA/ INFL). We compared the fate of Mo/Ma in pathogenic, nonpathogenic and controlled SIVsab infection of pigtailed macaque (PTM), African green monkey (AGM) and rhesus macaques (RM) to better define their role in SIV pathogenesis. Methods: We assessed Mo/Ma subsets (CD14, CD163, CD16), mobilization (CCR5, a4b7, CCR7, CXCR3), IA (CD80, 86, Ki-67, CCR5, TF), apoptosis (Cas-3), cytokine production (IL-6, IL-10, IL-12 and TNF-a), and phagocytic capacity of Mo/Ma in blood, LNs and intestine. We measured soluble Mo activation markers (sCD14, sCD163, sTF). Tissue infiltration of Ma was assessed by HAM56, CD68, CD163, CD16. Ma trafficking in tissues was assessed by administration of iron oxide microparticles. Results: Increased CCR5 Mo expression correlated with their loss in circulation and increases in the gut in SV-infected PTMs. Increased CCR7 Mo expression was associated with Ma increase in the LNs in AGMs. No significant Mo/Ma variations were observed in RMs. Increased Mo/Ma proliferation occurred at all sites in PTMs, only in LNs in AGMs, and mainly in blood in RMs. Increased CCR5, CD80, CD86 and TF were observed on Mo/Ma from PTMs, while no changes occurred in AGMs. In RMs CD80 only increased in blood, while CD86 was decreased. Increased Mo/Ma apoptosis occurred early in PTMs and RMs, but was absent in AGMs. Phagocytic activity increased in PTMs but not in AGMs or RMs. Mo produced higher amounts of IL-6 and IL-12 in PTMs, IL-10 and 12 in RMs, while inflammatory cytokine did not increase in AGMs. In the gut AGMMa produced IL-10, while PTMMa produced IL-6 and TNF in addition to lL-10. RMs Ma did not show increases in cytokine production in the gut. Soluble markers of monocyte activation and sTF increased throughout infection in PTMs, but not AGMs. Massive infiltration with Ma was observed in LNs, gut, liver, lung and heart in chronically-infected PTMs but not in AGMs and RMs. Ma containing microparticles were found in liver, spleen, myocardium and pericardium in progressive hosts. Conclusions: Progressive SIV infection is associated with increased activation, apoptosis and massive Mo recruitment to mucosal and nonmucosal tissues. These data suggest that Mo/Ma fuel immune activation and inflammation and development of comorbidities that distinguish progressive from nonprogressive SIV infection. Jan Kristoff 1 ; Jenny Stock 1 ;Tianyu He 1 ; Bruno Andrade 2 ; Benjamin Policicchio 1 ; Alan Landay 3 ; Ivo Francischetti 2 ; Cristian Apetrei 1 ; Irini Sereti 2 ; Ivona Pandrea 1 1 University of Pittsburgh, Pittsburgh, PA, US; 2 National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, US; 3 Rush University, Chicago, IL, US

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CROI 2015