CROI 2020 Abstract eBook

Abstract eBook

Oral Abstracts

cells and antibody responses is a major function of CD4+ T cells. It has been 10 years since the publication of Bcl6 as the lineage defining transcription factor for T follicular helper (Tfh) differentiation and the requirement of Tfh cells as the specialized subset of CD4+ T cells needed for germinal centers and related B cell responses. A great deal has been learned about Tfh cells in the past 10 years. Using longitudinal tracking of GCs in draining lymph nodes, using fine needle aspirates (FNAs), we found that two independent methods of slow delivery immunization of rhesus monkeys (RM) resulted in larger GCs, more robust and sustained GC-Tfh cell responses, and GC B cells with improved Env-binding. These GC-associated cell differences correlated with the development of ~20- to 30-fold higher titers of tier 2 HIV nAbs in animals immunized via slow delivery modalities. By analyzing IgV gene usage, we were able to determine that slow delivery immunization enhances HIV neutralizing antibody and GC responses via modulation of immunodominance (Cell, 2019). Slow delivery immunization therefore engages the immune system in unique ways, and novel strategies to accomplish slow delivery immunization in human vaccines will be discussed. 113 IL-6 BLOCKADE DECREASES INFLAMMATION AND INCREASES CD127 EXPRESSION IN HIV INFECTION Benigno Rodriguez 1 , Zhengyi Chen 1 , Curtis Tatsuoka 1 , Scott F Sieg 1 , Alan Landay 2 , Grace A. McComsey 1 , Brian Clagett 1 , Chris T.Longenecker 1 , Carey Shive 1 , Keith W. Crawford 3 , Daniela Moisi 1 , Michael L.Freeman 1 , Nicholas Funderburg 4 , Leonard Calabrese 5 , Michael M. Lederman 1 1 Case Western Reserve University, Cleveland, OH, USA, 2 Rush University, Chicago, IL, USA, 3 NIAID, Rockville, MD, USA, 4 The Ohio State University, Columbus, OH, USA, 5 Cleveland Clinic, Cleveland, OH, USA Background: Interleukin-6 (IL6) is a key inflammatory mediator in treated HIV infection. In vitro, we have shown that IL6 drives cell cycling and blocks responsiveness to interleukin-7 (IL-7). In vivo, plasma levels of IL6 are linked to cardiovascular risk and other end-organ complications. We hypothesized that blocking IL6 signaling in vivo could attenuate these effects. Methods: HIV-infected persons with suppressed viremia and CD4 T cell counts >350 were enrolled in a 2x2 crossover trial of 3 monthly IV doses of the anti-IL6 receptor monoclonal antibody tocilizumab (TCZ) and matching placebo. T cell subpopulations, expression of markers of activation, senescence, cycling, and survival were quantified by flow cytometry. Soluble vascular, metabolic, and inflammation indices were measured by ELISA. Significance of treatment- induced changes was assessed by Wilcoxon signed-rank test. Mixed effects models were fitted to generate effect estimates and for covariate adjustment. Results: Thirty-four participants were enrolled; 29 continued treatment through the crossover visit at week 20. Two discontinued due to adverse events: grade 3 rash and neutropenia. Both resolved without treatment. IL-6 receptor blockade by TCZ led to a profound decrease in plasma C-reactive protein (CRP) (-2037 ng/mL, p<0.001) and a dramatic increase in plasma IL-6 (42 pg/mL, p<0.001). PD-1 expression on naïve (-2%, p<0.001) and central memory (-3%, p,0.01) CD4 T cells decreased significantly; this was accompanied by a significant decrease in naïve CD4 T cell cycling (Ki-67 expression, -0.2 %, p=0.01) and by a significant increase in IL-7 receptor (CD127) expression on naïve (0.7%, p=0.02) and terminally differentiated (3%, p=0.03) CD8 T cells, as well as a significant decrease in plasma IL7 levels (-1 pg/mL, p<0.001). TCZ also led to significant decreases in soluble TNF receptor-1, soluble CD14, soluble CD40, and p-selectin. E-selectin, adiponectin. Most lipid species in plasma including oxidized LDL increased with TCZ. Lp-PLA-2 also increased modestly. Conclusion: Blockade of IL-6 activity markedly decreases soluble markers of inflammation and indices of CD4 T activation/regulation that have been linked to morbidities in treated HIV infection. TCZ enhances expression of the IL7 receptor CD127 on some CD8 subpopulations, which may explain decreased plasma IL7 levels. The combination of these effects may result in reduced turnover and dysfunction of T cells in treated HIV infection.

Oral Abstracts

114 NEUTRALIZING ANTIBODIES AND TRMS PROVIDE ENHANCED AND DURABLE RESISTANCE AGAINST HIV Prabhu S Arunachalam 1 , Tysheena P. Charles 2 , Vineet Joag 3 , Satish V. Bollimpelli 2 , Madeleine K. Scott 1 , Shakti Gupta 4 , Shankar Subramaniam 4 , Purvesh Khatri 1 , Pamela A. Kozlowski 5 , Cynthia Derdeyn 2 , Eric Hunter 2 , David Masopust 3 , Rama R. Amara 2 , Bali Pulendran 1 , for the Emory Consortium for Innovative AIDS Research 1 Stanford University, Stanford, CA, USA, 2 Emory Vaccine Center, Atlanta, GA, USA, 3 University of Minnesota, Minneapolis, MN, USA, 4 University of California San Diego, La Jolla, CA, USA, 5 Louisiana State University, New Orleans, LA, USA Background: A broadly cross-reactive neutralizing antibody response is necessary to prevent infection from diverse strains of HIV. Induction of such broadly neutralizing antibodies by vaccination has been challenging but current approaches can induce autologous neutralizing antibodies (nAbs) in various animal models. Here we tested if vaccine-induced nAbs alone or in combination with cellular immune responses can protect rhesus macaques (RMs) against intravaginal challenges with the autologous strain of virus representative of circulating HIV-1 strains. Methods: We immunized three groups of RMs as follows: group 1 with a trimeric HIV envelope protein (BG505 SOSIP.664) adjuvanted with the TLR7/8 ligand 3M-052, alone to induce nAbs; group 2 with a heterologous viral vector regimen expressing SIVmac239 Gag to induce tissue-resident memory CD8 T cells (TRMs, which traffic to and reside in mucosal tissues), as well as with BG505 SOSIP.664/3M-052 as in group 1; and group 3 as controls with 3M-052 alone. One month after the final protein vaccination, we challenged the animals weekly, in total 10 times, with SHIV-BG505 via the intravaginal route to measure vaccine-induced protection. We then identified immune correlates of protection. Finally, vaginal tissues were isolated from four protected animals from group 2 following necropsy, and were stimulated ex vivo with cognate Gag peptides to reactivate TRMs. The impact of TRM activation was analyzed by CITE-seq single-cell RNA sequencing to identify a possible mechanism(s) by which the TRMs enhanced protection. Results: The protein and HVV immunizations were immunogenic as measured by high autologous nAb titers and Gag-specific T cell responses, respectively. Following 10 weekly vaginal challenges with SHIV-BG505, protection was observed in both immunization groups: 53.3% and 66.7% in groups 1 and 2, respectively. A nAb titer above ~300 represented the primary correlate of protection in group 1 animals. Surprisingly, in group 2, nAb response was not the primary correlate. A majority of the protected animals had nAb titers <300 suggesting that the TRMs reduced the nAb threshold associated with protection. Furthermore, protection observed in group 2 was durable as these animals resisted six additional challenges five months later with the same virus. Ex vivo restimulation of TRMs in vaginal tissues revealed rapid induction of local antiviral immunity. Conclusion: TRMs can reduce nAb threshold and provide durable protection against HIV.

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CROI 2020