CROI 2020 Abstract eBook
1 University of Miami, Miami, FL, USA, 2 University of Louisiana at Lafayette, Lafayette, LA, USA, 3 Vaccine Research Center, NIAID, Bethesda, MD, USA Background: HIV/aging contribute to inflammaging (chronic low-grade systemic inflammation) and immune senescence (accelerated aging of the immune system). Immune dysfunction, in the form of impaired antibody (Ab) responses to vaccines such as influenza (flu) vaccination, is observed in aging and HIV infection. Given the central role of IL-21 in Ab responses we hypothesized that administration of IL-21 as a flu vaccine adjuvant in aged, ART treated, SIV+ Rhesus Macaques (RM) would result in significant improvement in the quality of pTfh and B cell function alongside improved germinal center reactions, resulting in improved Ab responses to vaccination. Methods: In this study flu vaccination was administered with (N=4) and without (N=4) subcutaneous IL-21 in a prime, boost, boost series at 3-month intervals to old ART treated, SIV+ (IV SIVmac239) RM. IL-21 was given (50µg/kg) on d-2, d0, d5 post each vaccine dose. Blood was collected on d0, d5, d14 and d42; and lymph node tissue was collected on d14 after each vaccine dose. Serumwas analyzed for flu Ab titers, and PBMC with multicolor flow cytometry using panels for detailed phenotypic characterization of peripheral blood T follicular helper (pTfh) cells and CD4 memory populations. Results: In results analyzed to date, pre-prime H3N2 HAI titers of controls (mean=1:55) did not differ from IL-21 treated animals (mean=1:100). Titers increased significantly (p=0.0018) in IL-21 treated animals from 1:100 at baseline to 1:283 post boost 1 (PB1) and were significantly higher (P=<0.0001) than the PB1 control mean titer of 1:60 (Fig. 1A). We did not observe baseline differences in pTfh frequency between groups (Fig. 1A). IL-21 treated animals had significant (p=0.0118) expansion of pTfh, as measured by the fold change of pTfh frequency from day of Boost 1 (B1) to 14 days PB1, correlating with H3N2 HAI titers 14 days PB1 (R2=0.6978, P=0.0193, Fig. 1B). We also observed that the frequency of PD1+ pTfh cells was significantly higher (p=0.0188) in IL-21 treated animals (mean=27%) compared to controls (mean=16.7%) on the day of B1 and correlated with H3N2 HAI titers 14 days PB1 (R2=0.728, P=0.0146). Conclusion: These findings suggest IL-21 has a significant adjuvant effect, improving flu vaccine titers in old, ART treated, SIV+ RM. As no baseline pTfh differences were observed, these results highlight that IL-21 may be directly or indirectly inducing a shift in pTfh cell kinetics and phenotype, warranting further investigation as a potential vaccine adjuvant.
277 LOSARTAN DOES NOT IMPROVE LYMPHATIC TISSUE FIBROSIS OR T-CELL RECOVERY IN HIV Jason V. Baker 1 , Julian Wolfson 2 , Caryn G. Morse 3 , Frank S. Rhame 4 , Caitlin David 2 , Jodi Anderson 2 , Gary Collins 2 , Greg Knowlton 2 , Jennifer Czachura 2 , Cavan Reilly 2 , Jeffrey Chipman 2 , Gregory Beilman 2 , Russell Tracy 5 , Irini Sereti 3 , Timothy Schacker 2 1 Hennepin Healthcare Research Institute, Minneapolis, MN, USA, 2 University of Minnesota, Minneapolis, MN, USA, 3 NIAID, Bethesda, MD, USA, 4 Allina Health, Minneapolis, MN, USA, 5 University of Vermont, Burlington, VT, USA Background: Incomplete immune recovery despite HIV viral suppression is associated with excess clinical risk, and is, in part a consequence of fibrosis within secondary lymphoid tissues. We hypothesized that the angiotensin receptor blocker losartan would inhibit fibrosis and improve T-cell recovery within lymphatic tissue, given its established effects in blocking TGF-b. Methods: We pooled data from two randomized (1:1), double-blind, placebo- controlled trials of losartan (100mg) versus placebo among persons with HIV on ART with plasma HIV RNA <200 copies/mL. Participants underwent an inguinal lymph node (LN) biopsy at baseline and after 12 months. The percent area of collagen and CD4+ T-cells were quantified in the LN parafollicular T-cell zone, using quantitative image analysis. Fibrosis biomarkers in blood were measured using ELISA and electrochemiluminescence (Table). Baseline associations estimated the difference in LN percent area collagen associated with a 1-SD difference in T-cell measures. The treatment effect was defined as change on losartan minus change on placebo over 12 months. Results: Forty-eight participants had LN tissue available for analysis at both baseline and month 12 (n=23 on losartan; n=25 on placebo). Median age was 55 years, years of HIV diagnosis was 17, and current and nadir CD4+ count were 450 and 59 cells/mm 3 , respectively; 97%were male, 59%white. The table reports baseline and month 12 levels of study measures. LN collagen was inversely associated with LN CD4+ T-cells (est: -3.8, p<0.001), though did not reach significance with blood CD4+ count (est: -1.3, p=0.18), and was positively associated with blood CD8+ count (est: 2.5, p<0.01). Losartan treatment was not associated with a significant difference in change of LN collagen, LN CD4+ T-cells, or blood measures of fibrosis activity or T-cell recovery over 12 months (Table). Neither LN collagen nor LN CD4+ T-cells changed over 12 months within losartan or placebo groups. Conclusion: Among older persons with longstanding HIV disease, losartan did not alter lymphatic tissue fibrosis or T-cell immune recovery over one year. Future research is needed to identify treatments that reduce lymphatic tissue fibrosis and/or improve the associated T-cell immune depletion, given the importance for restoring health among persons living with HIV.
279 BUTYROPHILINS: NOVEL IMMUNE CHECKPOINT TARGETS FOR HIV Sai Vemula 1 , Morgan Monslow 1 , Guoxin Wu 1 , Luca Micci 2 , Laura Garvin-Queen 2 , Min Xu 1 , Lei Ba 1 , Shuo Quan 3 , Yvonne Meng 3 , Steve Carroll 1 , Hussam Shaheen 3 , Daniel Gorman 2 , Daria Hazuda 1 , Bonnie J. Howell 1 1 Merck & Co, Inc, West Point, PA, USA, 2 Merck & Co, Inc, Palo Alto, CA, USA, 3 Merck & Co, Inc, Kenilworth, NJ, USA Background: Overexpression of immune-checkpoint receptors (IRs) has been associated with T-cell exhaustion and overall dysfunction in HIV. CD4 T-cells expressing IRs (e.g, PD-1, CTLA-4, LAG-3) enrich for integrated provirus and likely contribute to viral persistence during ART suppression. We identified a class of IRs, buytrophilins (BTNs), with high homology to B7 family members (e.g., PD-L1 and PD-L2) and the capability to modulate T-cell activation and HIV expression. We postulate BTNs can be exploited to induce both latent virus reactivation and/or T-cell function and serve as novel immunomodulatory targets for HIV cure research.
278 IL-21 ALTERS TFH DYNAMICS, IMPROVES FLU VACCINE RESPONSE IN OLD SIV+ NHPS UNDER ART Daniel Kvistad 1 , Suresh Pallikkuth 1 , Tirupataiah Sirupangi 2 , Kyle Russell 1 , Rajendra Pahwa 1 , Constantinos Petrovas 3 , Francois Villinger 2 , Savita Pahwa 1
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