CROI 2017 Abstract e-Book

Abstract eBook

Oral Abstracts

kg no-RUSF, +1.4 versus +1.1 kg/m2, and +1.2 versus +1.0 cm respectively. Changes in weight with RUSF were predominantly due to gains in fat mass by bioimpedance analysis. There were no differences in grip strength between groups (p=0.36). 96 (10.9%) RUSF versus 92 (10.3%) no-RUSF died before 24 weeks (stratified hazard ratio=1.05 (95% CI 0.79- 1.40) p=0.75) (to 48-weeks p=0.87), with no evidence of interaction with the two other randomizations (p>0.7). There was no difference in time to first WHO 3/4 event or death (p=0.82). Conclusion: RUSF supplementation at ART initiation in advanced disease improved nutritional status but did not impact mortality.

Oral Abstracts

118 TLR7 AGONIST GS-9620 INCREASES IMMUNE-MEDIATED CLEARANCE OF HIV-INFECTED CELLS Alivelu Irrinki 1 , Angela Tsai 1 , Jasmine Kaur 1 , Jay Lalezari 2 , Tomas Cihlar 1 , George Kukolj 1 , Derek D. Sloan 3 , Jeffrey Murry 1 1 Gilead Scis, Inc, Foster City, CA, USA, 2 Quest Clinical Rsr, San Francisco, CA, USA, 3 Agenovir, South San Francisco, CA, USA

Background: Reactivation of latent HIV may be necessary to efficiently clear long-lived HIV reservoirs. As reactivation alone may not induce the death of infected cells, it is important that potential reactivating agents do not impede immune mechanisms required for clearing infected cells. GS-9620 is a selective TLR7 agonist that has previously been shown to induce latent virus in vitro and in SIV-infected ART-suppressed rhesus macaques. Here, the effect of GS-9620 on the activity of immune effectors required to clear infected cells was investigated. Methods: Peripheral blood mononuclear cells (PBMCs) isolated from ART-suppressed HIV-infected patients were treated with GS-9620 in the presence or absence of HIV peptides. To assess the role of type I interferons in the effects mediated by GS-9620, an antibody blocking IFN-α/β receptor (anti-IFNAR1) was used. HIV RNA was assessed by quantitative PCR in supernatants and flow cytometry was used to assess CD8 T cell activation. Cytolytic activity of CD8 T cells was assessed by monitoring caspase 3 activation in CD4 target cells coated with HIV peptides and co-cultured with activated CD8 T cells. Antibody-mediated killing was assessed by co-culturing GS-9620-treated PBMCs with the HIV Env-specific antibody PGT121 and autologous HIV-infected CD4 T cells. Results: Consistent with TLR7 agonist activity, GS-9620 strongly induced IFN-α in PBMCs. GS-9620 increased IFN-γ and TNF-α production in HIV-specific proliferating CD8 T cells by 100-230% (n = 23; p < 0.001). Stimulation of intracellular cytokines correlated with increased CD8 T cell cytolytic activity. GS-9620 induced 1.5-2 fold increases in HIV RNA in cell culture supernatants compared to cells treated with vehicle control (n = 43; p = 0.0002). Blockade with anti-IFNAR1 decreased GS-9620-mediated activation of T cells as well as HIV RNA induction, suggesting these effects require signaling through type I interferons. Antibody-mediated killing of HIV-infected CD4 T cells by PGT121 was enhanced by GS-9620 treatment, demonstrating that TLR7 activation can stimulate multiple mechanisms for eliminating infected cells. Conclusion: GS-9620 stimulated both HIV production by infected CD4 T cells and the elimination of infected cells by activation of cytolytic CD8 T cells or improved killing by an effector Ab. This indicates that GS-9620 may effectively complement orthogonal therapies designed to stimulate antiviral immunity, such as therapeutic vaccines or broadly neutralizing antibodies.

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CROI 2017