CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

pronounced ARS and slower disease progression compared to subtype C or D infections. We set out to determine the impact of infecting HIV-1 subtypes on ARS and set point viral load. Methods: We compiled and analyzed longitudinal data from five well-characterized AHI cohorts. Archived samples from 100 participants with AHI (defined as HIV-1 antibody negative and RNA or p24 antigen positive) from Europe (Sweden [n=26]) and Africa (Kenya [n=32], Rwanda [n=14], Uganda [n=13], and Zambia [n=15] were included. Participants were followed during approximately one year post estimated date of infection (EDI). HIV-1 env sequencing was done for phylogenetic subtype determination. Clinical data were assessed for ARS, defined as any of 11 reported symptoms during AHI, whilst longitudinal HIV-1 viral load data was assessed for set-point viral load. Results: Most of the participants were male (n=83 [83.0%]). The median age at EDI was 30.3 (IQR 24.3-36.1) years. The infecting subtypes were A (n=41 [41%]), B (n=19 [19%]), C (n=17 [17%]), D (n=7 [7%]) G (n=2 [2%], F (n=2 [2%]) and different recombinant forms (n=12 [12%]). Subtype C-infected individuals were less likely to report ARS compared to those with non-C subtypes (n=8 [50.0%] vs. n=55 [78.6%], p=0.020), whilst subtype A-infected individuals were more likely to report ARS than those infected with non-A variants (n=34 [89.5%] vs. n=29 [60.4%], p=0.003). The median set-point viral load was 41,000 (IQR 16,000 – 80000) copies/ml. Subtype C-infected individuals were more likely to have higher viral set point than those infected with non-C variants (OR 5.6 [95% CI 1.6 – 19.3], p=0.003). Conclusion: Differences in ARS and set-point viral load were inversely associated with the HIV-1 subtype C. Expression of fewer symptoms during acute subtype C-infection and the subsequently higher set-point viral load may be linked to a less robust immune response followed with poor replication control. Further work is on-going to delineate the relationship between infecting subtype and innate immune responses, and their effect on ARS and disease progression. 203 GRANULOCYTIC MYELOID-DERIVED SUPPRESSOR CELLS IN PRIMARY HIV INFECTION Nicola Tumino, Maria Teresa Bilotta, Adriana Ammassari, Annalisa Mondi, Casetti Rita, Veronica Bordoni, Eleonora Cimini, Federico Martini, Chiara Agrati, Sacchi Alessandra Natl Inst for Infectious Diseases Lazzaro Spallanzani, Rome, Italy Background: It has been demonstrated that Myeloid Derived Suppressor Cells (MDSC) are expanded in HIV-1 chronically infected individuals. The phase of HIV infection during which MDSC expansion occurs, and the mechanisms that regulate this expansion remain to be established. In this study we evaluated the frequency of MDSC in patients during primary HIV infection, and factors involved in MDSC control. Methods: Patients with primary (PHI, n=51) and chronic (CHI, n=26) HIV infection were enrolled before and one year after therapy initiation. At baseline, median CD4 T cell count was 588 cells/mm3 (IQR 470-830) in PHI, and 499 cells/mm3 (IQR 148-644) in CHI. Median viral load was 5.31 Log RNA copies/ml (IQR 4.33-6.16) in PHI and 4.75 Log RNA copies/ml (IQR 4.44-5.34) in CHI. MDSC frequency and function were evaluated by flow cytometry. Cytokine levels were evaluated by Luminex technology. Spearman rho was calculated to evaluate correlations. Wilcoxon/Mann-Whitney test was used to compare continuous parameters. Results: We found that, before therapy initiation, granulocytic MDSC (Gr-MDSC) frequency was higher in PHI compared to healthy donors (p<0.0001), but lower than CHI (p=0.02). Interestingly, Gr-MDSC expansion was already observed in the early phases of HIV infection (Fiebig II/III), but it was not associated to HIV viral load and CD4 T cell count. As previously demonstrated in CHI, Gr-MDSC from PHI inhibit HIV-specific T cell response, suggesting a detrimental role of Gr-MDSC. Interestingly, in PHI Gr-MDSC frequency was inversely correlated with plasmatic level of TRAIL (r= -0.52, p= 0.003), while a direct correlation was observed in CHI (r= 0.6, p= 0.029). Further, lower level of GM-CSF was observed in PHI compared with CHI (p= 0.04). In vitro experiments demonstrated that, differently from CHI, recombinant TRAIL induced apoptosis of Gr-MDSC from PHI, an effect that can be abrogated by GM-CSF. Antiretroviral therapy was not able to affect Gr-MDSC frequency in both PHI and CHI. However, in PHI an inverse correlation between Gr-MDSC frequency and the number of CD4 T cells was observed (r= -0.39, p= 0.029), suggesting that Gr-MDSC persistence, after treatment of acute infection, could be associated with a worst CD4 T cell recovery. Conclusion: We found that suppressive Gr-MDSC are expanded very early during PHI, and correlate with CD4 T cell count after therapy. TRAIL and GM-CSF may play a role in regulating Gr-MDSC expansion, thus opening new perspectives for immune-based strategies. 204 HIV-1 EXPLOITS THE INTERPLAY BETWEEN EPITHELIAL AND TH17 CELLS FOR DISSEMINATION Tomas Raul Wiche Salinas 1 , Annie Gosselin 1 , Dragos Vlad 1 , Yuwei Zhang 1 , Huicheng Chen 1 , Cécile Tremblay 1 , Jean-Pierre Routy 2 , Petronela Ancuta 1 1 Cntr de Rsr du Cntr Hosp de l’Univ de Montréal, 2 McGill Univ Hlth Cntr, Glen site, Montréal, Canada Background: Epithelial cells (EC) are the first to capture HIV/SIV at portal sites of entry and transmit the virus to subjacent immune cells via transcytosis. The interplay between EC and Th17 cells is critical for the maintenance of immune homeostasis at mucosal level as well as viral dissemination. Th17 cells produce cytokines that act on EC to promote the production of CCL20/MIP-3α, an antimicrobial peptide and chemoattractant for CCR6+ Th17 cells. CCL20 was reported to limit HIV replication in T-cells by inducing APOBEC3G expression. Other studies demonstrated that CCL20 contributes to the establishment of HIV latency in CD4+ T-cells and promotes dissemination from the portal sites of entry. Herein, we investigated the impact of HIV-1 on the interplay between EC and Th17 cells and studied EC-T cell trans infection in an environment rich in CCL20. Methods: Intestinal EC line HT-29 was stimulated with recombinant human TNF-α and/or IL-17A in the presence or absence of the wild type R5 HIV strains NL4.3BaL and transmitted founder THRO. Memory CD4+ T-cells were isolated by magnetic beads from uninfected individuals and stimulated with CD3/CD28 Abs. EC-T cell trans infection was studied in co-culture experiments between HIV-exposed EC and activated T-cells. CCL20, CXCL8/IL-8, and HIV-p24 levels were quantified in cell culture supernatants by ELISA. The expression of IL-17 receptor A and C (IL-17RA/RC) on EC and the intracellular expression of HIV-p24 in T-cells were quantified by FACS. Results: IL-17A acted only in synergy with TNF-α to promote CCL20 but not CXCL8 production in EC. This synergy coincided with the TNF-α-mediated up-regulation of IL-17RA expression on EC. HIV exposure further increased CCL20 production by EC in response to IL-17A and TNF-α. Although CCL20 inhibited HIV replication in T-cells cultured alone, HIV trans infection of T-cells co-cultured with HIV-loaded EC occurred more robustly in the presence of high levels of CCL20 levels produced by EC in response to IL-17A and TNF-α. Conclusion: We demonstrate that IL-17A acts in synergy with TNF-α to promote CCL20 production in intestinal EC, HIV further amplifies this synergy, and HIV transmission from EC to T-cells is proportional to the magnitude of CCL20 production by EC. Together these results reveal that HIV-1 exploits the interplay between EC and Th17 cells for its own replicative advantage and that CCL20 plays an important role in HIV dissemination from the portal sites of entry. 205 PLASMA-SOLUBLE CD163 IS SUPPRESSED UPON EARLY ART INITIATION IN ACUTE HIV INFECTION Michelle L. D’Antoni 1 , Somporn Tipsuk 2 , Shelly J. Krebs 3 , Thep Chalermchai 2 , Duanghathai Suttichom 2 , Nittaya Phanuphak 2 , Victor Valcour 4 , Jintanat Ananworanich 3 , Lishomwa C. Ndhlovu 1 , for the RV254/SEARCH 010; SEARCH013 and SEARCH011 Study Groups 1 Univ of Hawaii, Honolulu, HI, USA, 2 SEARCH, South East Asia Rsr Collab with Hawaii, Bangkok, Thailand, 3 US Military HIV Rsr Prog, Silver Spring, MD, USA, 4 Univ of California San Francisco, San Francisco, CA, USA Background: Plasma soluble CD163 (sCD163), a marker of myeloid cell activation, is higher in cognitively impaired than unimpaired chronically HIV infected (CHI) adults on combination antiretroviral therapy (cART). Whether early cART initiation in acute HIV-infection (AHI) impacts CD163 shedding is unknown. Methods: We examined 51 AHI adults who were enrolled during Fiebig stage (F)I-IV and immediately initiated cART. sCD163 was measured in plasma and cerebrospinal fluid (CSF) by ELISA. For FI/II, 19/19 persons had plasma at all timepoints and for FIII, 30/32; for FI/II, 10/16 had CSF at all timepoints and for FIII, 21/22. Neuropsychological (NP) tests included Trail Making A (TM-A), Color Trails (CT1 and 2) and Grooved Pegboard (GP) to compute a summary NPZ-4. Magnetic resonance spectroscopy (MRS) assessed brain metabolites. CHI adults [N=33 pre-ART; n=48 post-ART (plasma); n=39 pre-ART; n=12 post-ART (CSF)] and 18 matched HIV- adults (CO) served as controls. Nonparametric statistics were used and a generalized estimating equation (GEE).

Poster and Themed Discussion Abstracts

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CROI 2017