CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

routine anal pap and HPV-testing (DNA and E6/E7 mRNA) were also tested for rectal HIV-RNA. A backward stepwise multivariate logistic regression analysis was performed to verify the association of multiple HPV infections with the detection of rectal HIV-RNA by including confounders and other variables significantly related with the outcome at univariate regression (at a p-value <0.100). Results: One hundred and one pts were eligible for the analysis. They were mostly men (92.1%), mainly with homosexual intercourses as risk factor for HIV infection (80.2%) and with 50 years of median age. The median duration of HIV disease and of exposure to antiretrovirals was 12 and 10 years, respectively; 32 pts (31.7%) had a history of AIDS-defining events. Median time since last HIV-RNA ≥50 copies/mL was 72 months, but 26 pts (25.7%) had a residual viremia (defined as target detected <50 copies/mL) and 11 (10.9%) a detectable rectal HIV-RNA. Median number of HPV infections was 4, with the most frequent among high-risk genotypes being HPV 16 (26.7%), and among low-risk genotypes HPV 42 (33.7%). No other symptomatic sexually-transmitted infections were reported. Pts were divided into two groups, based on having 4 or less HPV infections (62 pts) versus more than 4 (39 pts). Differences between study groups are summarized in table 1. At multivariate analysis, the presence of more than 4 HPV infections did not confirm any statistically-significant association with detectable rectal HIV-RNA (aOR 2.79, 95% CI 0.49-15.77; p=0.247). Conversely, residual plasma viremia (versus undetectable HIV-RNA, aOR 16.45, 95% CI 2.43-111.40; p=0.004) and older age (per 10 years more, aOR 4.64, 95% CI 1.12-19.24; p=0.034) had an independent association with rectal HIV shedding, after adjusting for ethnicity, previous AIDS-events and months since last plasma HIV-RNA>50 copies/mL. Conclusion: Rectal HIV shedding was independently associated with residual viremia and older age, but not to a higher number of HPV genotypes. Larger studies are needed to confirm these results.

over time and qualitatively compared across individuals. Cellular features of 2 participants who later develop spontaneous control of HIV were also described. Results: Across all individuals we profiled >59,000 single cells. Onset of viremia induced conserved ISG responses integrated across multiple lymphocyte and myeloid lineages, wherein monocytes and natural killer (NK) cells significantly contributed to the cytokine milieu. Otherwise obscured in bulk analyses, we describe a second layer of responses following ISG upregulation: pro- inflammatory T cell differentiation, prolonged monocyte MHC-II upregulation, and persistent NK cytolytic killing. Predicting upstream drivers, we propose both shared and cell subset specific intra- and inter-cellular regulation by several key cytokines. Two participants who later develop viremic control associated with elevated frequencies of proliferating cytotoxic cells following HIV detection, inclusive of a previously unappreciated proliferating NK cell subset. Conclusion: We present an experimental and computational framework to longitudinally characterize multicellular responses in viral infection at high-resolution in humans. Applied to hyper-acute HIV infection, our approach reveals both cooperative and cell subset specific immune responses with temporal resolution. We nominate cell subsets and signaling pathways to perturb in future vaccines and therapeutics and highlight the importance of monocytes and NK cells in driving coordination and potentially influencing clinical trajectory.

Poster Abstracts

259 UNCOUPLED CELLULAR AND PLASMA MARKERS OF MONOCYTE ACTIVATION IN EARLY HIV INFECTION

Montse Jiménez 1 , Lucia Pastor Palomo 2 , Victor Urrea 1 , Nuria Izquierdo-Useros 1 , Javier Martinez-Picado 1 , Inacio Mandomando 3 , Chenjerai Jairoce 3 , Bonaventura Clotet 1 , Jorge Carrillo1, Denise Naniche 2 , Julià Blanco 1 1 IrsiCaixa Institute for AIDS Research, Badalona, Spain, 2 ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain, 3 Centro de Investigação em Saúde da Manhiça (CISM), Maputo, Mozambique Background: Monocytes are chronically activated in HIV infection, showing increased expression of CD16 and downregulation of CD14. This observation is concomitant to increased plasma levels of sCD14 and sCD163, which are considered surrogate markers of monocyte activation. Nevertheless, phenotypic abnormalities of monocytes during primary HIV infection (PHI) are not fully characterized. Methods: We longitudinally studied monocytes in individuals at PHI (n=40) followed for 1 year. HIV-uninfected individuals (n=58) and treated or untreated chronic HIV infected individuals (CHI;n=56) were also cross-sectionally analyzed. Participants were recruited at the Manhiça District Hospital in Mozambique. Monocyte activation was assessed by multicolor flow-cytometry, while plasma levels of sCD14, sCD163 and IFN-a were assessed by ELISA or Luminex. Results: Plasma HIV viremia peaked at one month after infection and immunological (CD4 and CD8 counts) and virological (VL) plateau was reached after month 4 of infection. The percentage of circulating monocytes was stable during PHI. Activated (CD14+CD16+) and highly activated (CD14–CD16+) monocytes were significantly increased in untreated CHI patients compared to HIV-uninfected individuals (p<0.005). During PHI, the frequency of these subsets remained similar to that of uninfected individuals for the first five months, rising after. In contrast, plasma sCD163 levels peaked at month 2-3 after infection, while the levels of sCD14 showed the highest value at one month after infection and then decreased to reach the levels observed in chronic patients. The expression of the Type-I IFN regulated protein Siglec-1 on monocytes showed a kinetics similar to VL and plasma IFN-a, showing the highest percentage at month 2 after infection and remaining at high levels during the

258 INTEGRATED ANALYSIS OF MULTICELLULAR IMMUNE DYNAMICS DURING HYPERACUTE HIV INFECTION Samuel W. Kazer 1 , Toby P. Aicher 1 , Daniel M. Muema 2 , Vincent N. Miao 3 , Carly G. Ziegler 3 , Sarah K. Nyquist 3 , Amber D. Moodley 1 , Krista Dong 1 , Zaza Ndhlovu 4 , Thumbi Ndungú 2 , Bruce D. Walker, Alex K. Shalek 3 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 KwaZulu-Natal Research Institute for TB and HIV, Durban, South Africa, 3 MIT Institute for Medical Engineering & Science, Cambridge, MA, USA, 4 University of KwaZulu-Natal, Durban, South Africa Background: Development of effective vaccines and therapeutics is facilitated by understanding the earliest moments of infection. Studies in S(H)IV models have characterized the quality and duration of the interferon-stimulated gene (ISG) response in acute infection. However, longitudinal immune responses to acute HIV infection are underexplored. Moreover, contributions and interactions of different cell subsets are unknown. Here, we longitudinally profile multicellular immune responses in hyper-acute HIV infection detected in Fiebig Stage I. Methods: High-throughput single-cell RNA-sequencing was performed on peripheral immune cells throughout acute HIV-1 infection (pre-infection, HIV detection – 1 year) on 4 FRESH participants (Dong, The Lancet, 2018). Cell subsets were identified by unsupervised clustering analyses. Shared and cell subset specific immune responses were elucidated using a gene-module discovery approach. Modules were tested for significant changes in expression

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CROI 2020