CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

347 RAPID DECAY OF HIV PERSISTENCE MARKERS IN ACUTELY ART-TREATED INDIVIDUALS IN PERU Marta Massanella 1 , Rachel A. Bender Ignacio 2 , Javier R. Lama 3 , Amelie Pagliuzza 1 , Ricardo Alfaro 3 , Jessica Rios 3 , Carmela Ganoza 3 , Delia Pinto-Santini 2 , Trupti I. Gilada 2 , Ann Duerr 2 , Nicolas Chomont 1 1 Centre de Research du Centre Hospitalier de l’Université de Montreal, Montreal, QC, Canada, 2 Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 3 Asociacion Civil Impacta Salud y Educacion, Lima, Peru Background: Early ART initiation confers several benefits on HIV-related morbidity and clinical outcomes and can lead to natural control of HIV replication upon ART interruption in a subset of individuals. We evaluated how timing of ART initiation impacts the size of the HIV reservoir during early infection in a subset of the Sabes study, a randomized clinical trial in Peru. Methods: HIV-infected MSM and transgender women who were diagnosed while sero-negative (acute, n=12), or were sero-positive and <90 days from last negative RNA test (recent, n=16), were randomized to receive ART immediately (acute immediate [AI], n=8 and recent immediate [RI], n=11) or after 24 weeks deferral (D, n=9). We quantified total and integrated HIV DNA in CD4 T cells by real-time PCR, and used TILDA (Tat/rev Induced Limiting Dilution Assay) to measure the frequency of CD4 T cells producing multiply spliced RNA (msRNA) as a proxy for virus production, with and without stimulation. Results: As expected, viral loads measured before ART initiation (week 0: Acute & Recent, week 24: D) were significantly higher in the acute group compared to either recent or D groups (6.78, 5.71 and 5.05 log 10 copies/ml, respectively, p<0.01 both comparisons). Total and integrated HIV DNA did not differ in the 3 groups prior to ART, although TILDA frequencies with and without stimulation were higher in the acute and recent groups than the D group (p<0.05 all comparisons). After 6 months of ART, levels of integrated HIV DNA were significantly lower in the AI group than in the RI group (p=0.03); the inducible reservoir measured by TILDA was smaller in the AI group than in the RI or D groups (p=0.005 and 0.02, respectively, Figure 1a). During the first 6 months of ART, all three measurements of HIV persistence decreased more in the AI group than in those treated later (Figure 1b, all p<0.02). The TILDA/integrated HIV DNA ratio at study entry and 24 weeks later were highly correlated (R=0.87, p<0.001), suggesting that the relative proportion of inducible and defective proviruses was maintained over 6 months. Conclusion: ART initiation during acute infection limits the size of the inducible reservoir, but the apparent benefit does not extend to persons who initiated ART after seroconversion. Markers of HIV persistence had a steeper decay in acutely treated individuals than in the two groups treated slightly later. Initiating ART during acute infection may facilitate HIV remission in concert with additional eradication strategies.

the anti-inflammatory functions of IL-21 with the antiviral properties of IFNα to reinvigorate antiviral responses. We hypothesize that increased antiviral responses in a context of lower inflammation would impact on viral persistence on ART and viral rebound following ART treatment interruption (ATI). Methods: 21 RMs infected with SIVmac239 started TDF/FTC/DTG treatment at day 35 post-infection; ART was continued for 12 months. 14 RMs received Macaquized (M)-IL-21-IgFc (100 μg/kg, SC, weekly for 4 weeks) at initiation and mid-way thru ART. This group also received M-IFNα-IgFc (500,000 IU, SC, weekly for 5 weeks) prior to ATI. The remaining seven RMs served as ART-only controls. Five controls and eight treated RMs underwent ATI. Upon ART-discontinuation, the eight IL-21/IFNα-treated RMs received PEGylated-IFNα-2a, 7 μg/kg, SC, weekly for 7 weeks. Results: ART suppressed plasma viremia (pVL) (<30 RNA copies/mL) in all RMs. During ART, IL-21 reduced levels of activated (HLA-DR+CD38+) and proliferating (Ki-67+) T cells in PB, RB, and LN as compared to ART-only controls (P<0.01). Levels of inflammation remained lower during and after addition of IFNα (P<0.01). Gut SIV-DNA levels (P<0.05) and the frequency of LN CD4+ T cells harboring replication-competent SIV (P<0.01) were reduced in IL-21/IFNα treated RMs as compared to controls. Upon ART-interruption, IL-21/IFNα-treated RMs exhibited delayed viral rebound with a median of 21 days as compared to 9 days in controls (P=0.0009). Moreover, IL-21/IFNα-treated RMs maintained reduced viremia in comparison to controls up to 45 days after ATI (1.3 log lower; P=0.0004). The increased viral control was temporally limited, with IFNα interruption leading to pVL in treated RMs at levels no longer different from controls. Conclusion: These data support the safety of a combined IL-21 and IFNα treatment for HIV infection. While IL-21 effectively reduces inflammation, addition of IFNα prior and after ART-discontinuation resulted in a more effective control of viral rebound. The synergy of such therapeutics may promote reinvigoration of host responses toward reduction of latent HIV reservoirs. 349 CD4 DEPLETION IN SIV-INFECTED MACAQUES ON EARLY ART HAS NO IMPACT ON VIRAL REBOUND Adrienne E. Swanstrom, Taina T. Immonen, Claire Deleage, Kelli Oswald, William J. Bosche, Douglas K. Schneider, Sirish Khanal, James A. Thomas, Cathi Pyle, Charles M. Trubey, Jacob D. Estes, Jeffrey D. Lifson, Brandon Keele, Gregory Q. Del Prete Frederick National Laboratory for Cancer Research, Frederick, MD, USA Background: To date, no approaches have been identified that reduce the replication-competent viral reservoir that persists during suppressive combination antiretroviral therapy (cART) by a degree large enough to consistently delay off-cART viral rebound. Early initiation of cART limits the size of the persistent viral reservoir that is established, making for a more tractable target for subsequent interventions. To evaluate the impact of substantial ablation of the viral reservoir in the setting of limited initial reservoir establishment, we administered a CD4-depleting antibody to SIV infected rhesus macaques that had initiated early cART. Methods: Ten rhesus macaques started daily cART (TDF/FTC/DTG) 4 days post-infection (IV) with molecularly-barcoded SIVmac239M. Beginning at 30 weeks post-cART initiation, 5 animals received 5-6 biweekly doses of rhesusized CD4-depleting antibody; 5 animals served as controls. CD4+ cell depletion and cell-associated viral DNA (vDNA) levels were monitored in blood and lymph nodes (LN). Following the last dose of anti-CD4 antibody, animals remained on cART for 1 year. cART was then discontinued, with monitoring for viral rebound, rebounding viral variants in plasma, and estimation of viral reactivation rates. Results: By ~7 weeks post-cART initiation, plasma viral loads in all animals were stably suppressed to <15 viral RNA copies/ml. Consistent with limited reservoir establishment, cell-associated vDNA measurements were low in PBMC (median 1.7 vDNA copies/10 6 cells) and LN (median 2.1 vDNA copies/10 6 cells) pre-anti-CD4 administration, with no significant differences between experimental groups. Following anti-CD4 administration, CD4 T cell counts in blood declined by 96.3-99.9% and in LN by 78-91%. By one year after the last anti-CD4 treatment, CD4 counts returned in depleted animals to levels 23-65% lower than pre-depletion. Upon cART cessation, there was no significant difference between depleted and control groups, respectively, in time to first positive plasma viral load (median 27 days vs 17 days), unique rebounding variants (median 2 vs 4), or calculated reactivation rates (mean once per 6 days vs once per 3 days).

Poster Abstracts

348 IL-21 PLUS IFNΑ LIMITS VIRAL PERSISTENCE AND REBOUND IN SIV- INFECTED RHESUS MACAQUES Maria Pino 1 , Luca Micci 1 , Justin L. Harper 1 , Colin T. King 1 , Guido Silvestri 1 , Jeffrey D. Lifson 2 , Mirko Paiardini 1 1 Yerkes National Primate Research Center, Atlanta, GA, USA, 2 Leidos Biomedical Research, Inc, Frederick, MD, USA Background: Although ART suppresses HIV replication, residual inflammation persists, and contributes to non-AIDS-related morbidity in infected subjects. Inflammation can also promote HIV persistence during ART. We showed that administration of IL-21 reduces chronic inflammation in ART-treated, SIV-infected rhesus macaques (RMs). In this study, we sought to combine

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