CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

activation), CD25/FoxP3 (Tregs), CCR6 (Th17), CCR5 (HIV co-receptor) and CCR7/ CD45RA (memory subsets). HIV shedders and non-shedders were compared by Mann-Whitney (SPSS). Results: Fifteen (27.8%) of 54 ART-treated men had detectable anorectal HIV shedding despite plasma HIV suppression, albeit at low levels (median 206 copies/swab). Surprisingly, HIV shedders did not have increased levels of activated (CD38+HLA-DR+) CD4+ T cells (p= 0.401). However, we observed differences in anorectal CD4+ T cells memory subsets: HIV shedders had a significantly higher proportion of central memory cells (CCR7+CD45RA-; Shedders= 34.5%, Non-shedders= 17.9%; p= 0.004). All other mucosal memory subsets were enriched in HIV non-shedders, including terminally differentiated cells (CCR7-CD45RA+; p= 0.024). No other mucosal T cell differences were observed between HIV shedders and HIV non-shedders. Conclusion: An increased proportion of central memory cells (TCM), but not of activated mucosal CD4+ T cells, was associated with HIV shedding. This suggests that non-inflammatory mechanisms, such as the homeostatic proliferation of latently infected cells, may be driving mucosal HIV shedding in ART-treated individuals. While the low-level HIV shedding that we observed is unlikely to contribute to sexual transmission of HIV, understanding immune correlates of compartmentalized HIV production in ART-treated individuals may help to optimize strategies for HIV eradication.

enhancing migration to other lymphoid sites via modulation of homing receptor expression. 216 VAGINAL BACTERIA REGULATE MICRO-RNAs TARGETING THE HIV-HOST INTERACTOME Raina Fichorova 1 , Hidemi Yamamoto 1 , Yashini Govender 1 , Andrea R. Thurman 2 , Sharon Anderson 2 , Jennifer Deese 3 , Charles S. Morrison 4 , Pai-Lien Chen 4 , Jonathan Dreyfuss 5 , Robert Barbieri 1 , Robert A. Salata 6 , Gustavo Doncel 2 1 Brigham and Women's Hospital, Boston, MA, USA, 2 Eastern Virginia Medical School, Norfolk, VA, USA, 3 École Normale Supérieure de Cachan, Cachan, France, 4 FHI 360, Durham, NC, USA, 5 Joslin Diabetes Center, Boston, MA, USA, 6 Case Western Reserve University, Cleveland, OH, USA Background: Understanding the molecular mechanisms underlying the role of the vaginal microbiome in HIV acquisition risk is an essential step toward safer and more effective HIV prevention. We hypothesized that the resident microbiota regulates micro(mi)-RNAs that can interfere with host pathways exploited by the virus. MiRNAs are endogenous short non-coding RNA molecules that are stably carried in circulation by extracellular vesicles and exert post-transcriptional epigenetic regulation with emerging significance in HIV infection. Their role in the anti-viral mucosal barrier function is unknown. Methods: The study utilized 112 cervicovaginal specimens from healthy reproductive-age women collected during the luteal phase of the menstrual cycle. All subjects were confirmed negative for sexually transmitted infections at the time of sampling. Vaginal microbiota was classified by Nugent scores and microbiome sequencing. Levels of miRNAs were quantified in extracellular vesicles isolated from the cervicovaginal secretions using the EdgeSeq global transcriptome platform. Differential expression (DE) was determined using Bioconductor DESeq2. miRNA target prediction was performed using miRNAtap Bioconductor package. Results: Cervicovaginal miRNA profiles varied by both Nugent score categories (0-3 scores – normal, 4-6 – intermediate, and 7-10 – bacterial vaginosis, BV) and by metagenome classification. Higher microbiome diversity was associated with higher number of significantly dysregulated miRNAs (373 in BV versus 119 in Nugent 4-6 compared to Nugent 0-3, FDR<0.1, p<0.01). The miRNAs dysregulated by BV overlapped with 66% of the miRNAs which were up or down regulated in G. vaginalis-dominated compared to L. crispatus-dominated metagenomes. The gene ontology predictions based on BV-dysregulated miRNAs identified enrichment for 88 genes previously validated as part of the HIV-host interactome facilitating infection. Gene clusters identified with highest stringency included proteasome and chaperonin pathways, virus entry receptor clusters, host signaling pathways downstream from NF-KB, TNFα, T-cell receptor and the MAPK cascade. Highest enrichment scores were achieved for the TCP-1 ring complex which interacts with the HIV Vif. Conclusion: We identified miRNAs regulated by vaginal dysbiosis that may facilitate immune imbalance and cellular pathways associated with HIV risk. 217 LONG-TERM SEX-DIFFERENCES IN OUTCOMES FOLLOWING ACUTE HIV-1 INFECTION Sophie Novelli 1 , Pierre Delobel 2 , Olivier Bouchaud 3 , Veronique Avettand- Fenoel 4 , Pascale Fialaire 5 , Sylvie Abel 6 , Faouzi Souala 7 , François Raffi 8 , Pilartxo Catalan 9 , Laurence Weiss 10 , Laurence Meyer 1 , Cécile Goujard 9 , for the ANRS Primo Cohort Study Group 1 INSERM, Le Kremlin-Bicetre, France, 2 Toulouse University Hospital, Toulouse, France, 3 Hôpital Avicenne, Bobigny, France, 4 Necker Hospital, Paris, France, 5 CHU de Angers, Angers, France, 6 CHU Fort de France, Fort de France, Martinique, 7 CHU de Rennes, Rennes, France, 8 CHU de Nantes, Nantes, France, 9 Hôpital Bicêtre, Le Kremlin-Bicetre, France, 10 Georges Pompidou European Hospital, Paris, France Background: Women have shown more favorable immunovirological characteristics than men around seroconversion. Here we investigated whether differences persisted under long-term antiretroviral therapy (ART) in individuals treated since acute and early HIV-1 infection (AHI). Methods: Data was obtained for 262 women and 1783 men enrolled in the French multicenter ANRS PRIMO cohort between 1996 and 2017. We modelled the viral response, long-term immune recovery and total HIV DNA decay in the 143 women and 1126 men who initiated ART within the first three months of infection. Models were adjusted for age, geographical origin, viral load at ART initiation, time from infection to ART initiation and calendar period. Results: The 1269 participants were mostly white (85%). The median age at AHI diagnosis was 36 years (IQR: 29–44). The median ART duration was 62 months

Poster Abstracts

215 HIV HIGHLY INFECTS GENITAL CD4+ T CELLS WITH REMODELING FOR SURVIVAL AND MIGRATION Tongcui Ma 1 , Xiaoyu Luo 1 , Ashley George 1 , Trimble Spitzer 2 , Linda Giudice 3 , Warner C. Greene 1 , Nadia R. Roan 1 1 Gladstone Institute of Virology and Immunology, San Francisco, CA, USA, 2 Naval Medical Center Portsmouth, Portsmouth, VA, USA, 3 University of California San Francisco, San Francisco, CA, USA Background: The female reproductive tract is one of the most common sites of initial HIV transmission yet we lack a detailed understanding of the cells that are most susceptible to infection. One challenge involves the extensive remodeling of host cells by HIV, rendering it difficult to classify infected cells into traditional T cell subsets. Methods: We exposed specimens of endometrial biopsies and PBMCs from the same donors to a CCR5-tropic transmitted/founder HIV-1 reporter virus, and conducted an extensive phenotypic analysis of uninfected and infected cells using CyTOF. Using bioinformatics analyses of the resultant high-dimensional single-cell datasets, we were able to characterize the subsets of cells that were most susceptible to HIV infection independent of remodeling. Results: Memory CD4+ T cells were almost exclusively targeted for infection in both the tissue and blood specimens, but those from the endometriumwere significantly more susceptible (p<0.01). While a diverse array of endometrial memory CD4+ T cells were targeted for infection, only a small subset of the unstimulated PBMC-derived CD4+ T cells could be infected. In-depth analyses of the features of the endometrial memory CD4+ cells targeted for infection revealed preferential infection of T effector memory (Tem) cells polarized towards the Th1 and Th2 lineages, as well as preferential infection of T resident memory (Trm) and T follicular helper (Tfh) cells. Upon infection, HIV interfered with the TCR signaling apparatus by downregulating CD4, CD45RO, CD28, and ICOS, and upregulated BIRC5 promoting survival of infected cells. Infection also upregulated the chemokine receptors CCR7 and CXCR5 and the tissue retention receptor CD69 while downregulating expression of the CD49d integrin. Conclusion: These data suggest that unique phenotypic features of memory CD4+ T cells in the genital tract renders these cells highly susceptible to infection by HIV-1, and that upon infection the virus remodels the cell in a manner than undermines TCR signaling while promoting survival and

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