CROI 2020 Abstract eBook

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Oral Abstracts

17 days except for 1 RM in Group B that rebounded at day 31, indicating PD-1 blockade did not affect time to virus rebound. Moreover, rebound pvl peaked by day 21 post-ART at 4.5 logs in Group A, 4.8 logs in Group B and 4.8 logs in Group C controls. However, by 42 post-ART, we observed a ~2 log reduction of pvl in both anti-PD1 treatment groups A and B relative to Group C controls (2.5 logs and 2.6 logs vs. 4.5 logs, respectively). RM are continuing to be followed to determine long-term pvl set points. Conclusion: PD-1 blockade had no effect on reactivation and early spread of virus following ART release, but maintaining PD-1 blockade following ART release appears to facilitate early control of virus replication, likely by enhancing the functional activity of SIV-specific T cells expanding in response to SIV replication. 118 TRACKING AND PREDICTING REBOUND IN SHIV-INFECTED INFANT MACAQUES AFTER LONG-TERM ART Veronica Obregon-Perko 1 , Katherine Bricker 1 , Ferzan Uddin 1 , Laura Rotolo 2 , Daryll Vanover 2 , Philip Santangelo 2 , Stella Berendam 3 , Genevieve Fouda 3 , Shan Liang 4 , Thomas Vanderford 4 , Katharine J. Bar 5 , George Shaw 5 , Guido Silvestri 4 , Sallie Permar 3 , Ann Chahroudi 1 1 Emory University, Atlanta, GA, USA, 2 Georgia Institute of Technology, Atlanta, GA, USA, 3 Duke Human Vaccine Institute, Durham, NC, USA, 4 Yerkes National Primate Research Center, Atlanta, GA, USA, 5 University of Pennsylvania, Philadelphia, PA, USA Background: Breastfeeding transmission accounts for the majority of new pediatric infections and commits infants to lifelong ART, as interruption is typically followed by return of replication and repopulation of reservoirs. A better understanding of the anatomic origin and kinetics of viral rebound during analytical treatment interruption (ATI) could inform the development of alternatives to ART-based strategies to achieve long-term viral remission in the pediatric population. Methods: At 4 wks old, 10 rhesus macaques were orally-administered SHIV. CH505.375H.dCT and placed on daily ART at 8 wpi. ART was interrupted after 1 yr in a subset of animals (n=6) to assess viral rebound. Blood and tissue were collected throughout the study for flow cytometry and viral measurements. For whole-body ImmunoPET, macaques were infused with 68Ga-labeled PGT145 F(ab) and imaged by PET/CT. Scans were done once on long-term ART and twice weekly following ATI. Results: Median viral loads at peak infection and just prior to ART were 5x105 and 1x105 copies/mL, respectively. During ATI, rebound viremia was detected within 10-24 d, with variable peak viral loads that reached levels seen at ART initiation. Post-treatment control within 4 wks of rebound was seen in 1/2 Mamu A01+macaques. Various parameters were evaluated for their ability to predict time to viral rebound. In our model, we did not see an association between PD-1 expression on CD4+ T cells and time to rebound, as previously reported for HIV-1 infection. SHIV-DNA and -RNA persistence in blood, lymph node, and colorectal CD4+ T cells was also evaluated. Just prior to ATI, the highest levels of SHIV-RNA were found in the colorectal compartment, suggesting this region could be an early site of viral reactivation following ART interruption. Indeed, longitudinal imaging of SHIV Env expressing cells in tissues by ImmunoPET before and immediately following ATI showed an expansion of infected cells in the GI tract prior to SHIV RNA reaching detectable levels in the plasma. A similar trend was observed in the lungs, where tissue-resident macrophages have been found to be the principal target cells of infection. Conclusion: This work provides novel insight into the kinetics, anatomic origin, and predictors of viral rebound in a pre-clinical NHP model of pediatric HIV infection. Our preliminary data implicates the GI tract as a key site to be studied for the development of remission strategies and one to be monitored in HIV- infected children being considered for ATI. 119 PERIPHERAL BLOOD SIV/HIV ORIGINATES FROM INFECTED CELLS IN TISSUES Leticia Kuri Cervantes 1 , Maria B. Pampena 1 , Marcus Buggert 2 , Meagan Watkins 3 , David S. Khoury 4 , Kevin McCormick 1 , Felicity Mampe 1 , Emily Lindemuth 1 , Ian Frank 1 , Max G. Itkin 1 , Miles Davenport 4 , Brandon F. Keele 5 , Katharine J. Bar 1 , Ronald Veazey 3 , Michael R. Betts 1 1 University of Pennsylvania, Philadelphia, PA, USA, 2Karolinska Institute, Stockholm, Sweden, 3 Tulane University, Metairie, LA, USA, 4 Kirby Institute, Sydney, NSW, Australia, 5 NIH, Frederick, MD, USA Background: HIV and SIV infected CD4 T cells localize primarily to lymphoid and mucosal tissues, where they constitute >90% of infected cells in chronic

infection. While largely assumed, it remains to be established if peripheral blood (PB) viremia originates from these tissues, or from infected cells directly within the vasculature. Here we assessed in rhesus macaques (RM) and humans the potential contribution of tissue-based virus production to plasma viremia (VL). Methods: Four RM were infected i.v. with barcoded SIVmac239, and treated with the lymphocyte migration inhibitor FTY720 daily from day 7 or 28 until day 90. PB and lymphoid tissue (LT) samples were collected for cell and virus quantification. In parallel, we collected PB and thoracic duct lymph (TDL) from 11 HIV+ donors (3 viremic, 8 ART) and assessed VL in each compartment. Viral phylogeny was characterized by SGS gp160 env sequencing of plasma and TDL. Results: In the FTY720-treated RM we observed near complete redistribution of circulating CD4 T cells into tissues within 7 days of FTY720 treatment (pre- FTY720: 513±283 CD4 T cells/µl, post-FTY720: 5±2 CD4 T cells/µl). Despite the absence of PB CD4 T cells, all animals, regardless FTY720 administration, had peak and set point plasma VL similar to historical controls. Barcode sequencing of cell-associated virus from LT and plasma virus during FTY720 treatment revealed substantial overlap in the dominant virus populations replicating in the LT and circulating in plasma. Together, these results suggest that the circulating plasma virus originated from tissues. We next assessed paired TDL and plasma from HIV+ donors. HIV RNA copies were higher in TDL vs. PB (p=0.0137; up to 10-fold higher in viremic), and the virus populations were phylogenetically indistinguishable between the compartments. Based upon the differential VLs, and incorporating viral clearance rate, plasma volume, and lymph output we calculated that ~50% of plasma virus originates from thoracic duct output, in some individuals reaching a 100% contribution. Conclusion: Our results indicate that HIV infected cells within LT and non-LT, rather than the vasculature, are the major source of PB viremia. A large proportion of this viremia is maintained through thoracic duct lymphatic efflux, indicating that virus released from infected cells in tissues travels through lymphatics into PB. 120LB CD4+ T-CELL DEPLETION IN AFRICAN GREEN MONKEYS DOES NOT ALTER DISEASE PROGRESSION Egidio Brocca-Cofano 1 , Paola Sette 1 , Ranjit Sivanandham 1 , Cui Ling Xu 1 , Adam J. Kleinman 1 , Sindhuja Murali Kilapandal Venkatraman 1 , Haritha Annapureddy 1 , Colin McAndrews 1 , Tammy Dunsmore 1 , Jason Brenchley 2 , Jacob D. Estes 3 , Cristian Apetrei 1 , Ivona Pandrea 1 1 University of Pittsburgh, Pittsburgh, PA, USA, 2 NIAID, Bethesda, MD, USA, 3 Oregon Health and Sciences University, Portland, OR, USA Background: Massive and persistent CD4+ T cell depletion is a hallmark of HIV infection, being associated with impairment of cellular immunity and opportunistic infections. The contribution of CD4+ T cell depletion to SIV/ HIV-associated gut dysfunction is unknown. African Green Monkeys (AGMs), a species that do not progress to AIDS, partially recover mucosal CD4+ T cells during chronic infection and maintain gut integrity. We assessed the impact of prolonged experimental CD4+ T cell depletion on the gut integrity and natural history of SIV infection in AGMs. Methods: Six AGMs were infected intravenously with 300TCID50 SIVsab. All animals received an anti α-CD4 antibody intravenously every three weeks, starting from 21 days post infection (dpi). Plasma viral loads (PVLs), absolute counts, proliferation and activation status of T cells, systemic and local immune activation and inflammation, gut integrity, and cardiovascular disease onset were monitored throughout the follow-up. Results: Complete ablation of CD4+ T cells in blood and greater than 90% depletion in intestine and lymph nodes was achieved. PVLs peaked at 107 viral RNA copies/mL at 10 dpi, followed by a 4-log decrease by 28 dpi. PVLs were lower compared to SIV-infected historical AGM controls and were even undetectable in some CD4-depleted AGMs. No significant changes in T cell immune activation and proliferation levels occurred in the CD4-depleted AGMs. A transient increase of the inflammatory cytokines and chemokines (IL-1RA, Rantes, Eotoxin, MCP-1, I-TAC, MIF and IP-10) occurred only during acute infection but was resolved prior to chronic infection. Absence of gut damage was observed in situ and through the testing of iFABP, Zonulin, and sCD14 which remained stable during the follow up. sCD163 transiently increased during acute infection. Conclusion: Despite a major and persistent (over 1 year) depletion of CD4+ T cells in blood and tissues, AGMs remained healthy and did not progress to AIDS. Gut integrity was maintained in spite of profound CD4+ T cell loss. As such, our results suggest that CD4+ T cell depletion, in the absence of increased

Oral Abstracts

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CROI 2020