CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

Background: Combination antiretroviral therapy (cART) disrupts the fatal course of infection but does not eradicate the HIV reservoir. Previously we have shown that 4 weeks treatment with the TLR9 agonist lefitolimod (MGN1703, Mologen AG) adjunctive to cART functions as both a latency reversing agent and as activator of cytotoxic NK cells. In this 2nd part of the trial, we assessed safety and evaluated if extended administration of lefitolimod could enhance the HIV-specific T cell responses, decrease the latent reservoir and prolong time to rebound. Methods: This was a phase Ib/IIa, open label, investigator-initiated clinical trial (NCT02443935). We included 13 HIV-infected individuals on cART. Lefitolimod (60 mg s.c.) was administered twice weekly for 24 weeks while participants remained on cART. Safety was assessed at each visit. After the 24-week dosing period, most participants initiated an analytical treatment interruption (ATI) until viral rebound occurred (two consecutive plasma HIV RNA >5000 c/mL). Blood samples were collected at baseline, after 12 and 24 weeks and at time of rebound. HIV-specific immunity was assessed by CD8+ T cell intracellular cytokine stain (ICS) for IFN-γ, TNF-α and IL-2. Total HIV DNA was measured by ddPCR. Plasma HIV RNA was measured by Cobas Taqman assay. Results: Lefitolimod was safe and well tolerated. ICS revealed a significant (p=0.0068) cohort-wide increase in IFN-γ response in HIV-specific CD8+ T Effector Memory (TEM) and Terminally Differentiated (TTD) cells from baseline to after 24 weeks treatment. On a cohort level, HIV DNA did not change significantly during the treatment period. During the ATI, one individual who initiated cART during chronic infection (pre-cART HIV RNA >100,000 c/mL and nadir CD4 of 29 cells/µL) demonstrated plasma HIV RNA levels below limits of detection (20 c/mL) for >21 weeks. Notably, this person had the highest percentage of polyfunctional HIV-specific CD8+ TEM (IFN-γ+, TNF-α+ and IL-2+) which further increased 3-fold from baseline to end of treatment, indicating that polyfunctional HIV-specific CD8+ T cells might have contributed to the observed virological control. Time to rebound for the remaining 8 individuals participating in the ATI was comparable to historical data. Conclusion: In conclusion, 24 week adjunctive TLR9 agonist therapy was safe, enhanced HIV-specific T cell responses and might increase time to rebound in some individuals with strong polyfunctional HIV-specific CD8+ TEM responses. 358 IFN-Α INDUCES NK-DEPENDENT HIV DNA DECLINE IN ART-TREATED HIV/ HCV COINFECTED PATIENTS Stephane Hua 1 , Selena Vigano 1 , Samantha Tse 1 , Zhengyu Ouyang 1 , Sean Harrington 1 , Jordi Negron 1 , Pilar Garcia-Broncano 1 , Giulia Marchetti 2 , Miguel Genebat 3 , Manuel Leal 3 , Salvador Resino 4 , Ezequiel Ruiz-Mateos 3 , Mathias Lichterfeld 1 , Xu G. Yu 1 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 University of Milan, Milan, Italy, 3 Institute of Biomedicine of Seville, Sevilla, Spain, 4 Institute de Salud Carlos III, Majadahonda, Spain Background: IFN-α can potently reduce HIV-1 replication in tissue culture and animal models, but may also modulate residual viral reservoirs that persist despite suppressive antiretroviral combination therapy. However, mechanisms leading to viral reservoir reduction during IFN-α treatment are unclear. Methods: We analyzed HIV-1 gag DNA levels in CD4 T cells by digital droplet PCR and CD8 T and NK cell phenotypes by flow cytometry in a cohort of ART- treated HIV-1/HCV co-infected patients (n=67) undergoing treatment for Hepatitis C infection with pegylated IFN-α and Ribavirin for an average of 11 months. Results: We observed that IFN-α treatment induced a significant decrease in CD4 T cells counts (p<0.0001), in CD4 T cell-associated HIV-1 DNA copies (p=0.002) and in HIV-1 DNA copies per microliter of blood (p<0.0001) in our study patients. Notably, HIV-1 DNA levels were unrelated to HIV-1-specific CD8 T cells responses. In contrast, proportions of total NK cells, of CD56brightCD16- NK cells and of CD56brightCD16+ NK cells were significantly associated with reduced levels of CD4 T cell associated HIV-1 DNA during IFN-α treatment, especially when co-expressing the activation markers NKG2D and NKp30. Conclusion: These data suggest that the reduction of viral reservoir cells during treatment with IFN-α is primarily attributable to antiviral activities of NK cells.

death. We also found that IFNAR blockade rescued anti–HIV-1 T cells response. Most strikingly, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1–infected hu-mice. Finally, we found that CD8 T cells rescued by IFNAR blockade were essential for HIV-1 reservoir reduction. Conclusion: We conclude that low levels of IFN-I signaling contribute to HIV-1– specific CD8 T cell dysfunction and foster HIV-1 persistence in cART treated hosts. 356 A PHASE 1 STUDY OF ALT-803 (IL-15 SUPERAGONIST) TO CLEAR LATENT HIV RESERVOIRS Zachary Davis 1 , Ann Thorkelson 1 , Jodi Anderson 1 , Hing C. Wong 2 , Jonathan Karn 3 , Curtis Dobrowlski 3 , Jeffrey S. Miller 1 , Sarah Cooley 1 , Daniel Douek 4 , Timothy Schacker 1 1 University of Minnesota, Minneapolis, MN, USA, 2 Altor Bioscience, Miramar, FL, USA, 3 Case Western Reserve University, Cleveland, OH, USA, 4 NIH, Bethesda, MD, USA Background: A primary barrier to HIV cure is the large latent reservoir in tissues. Efforts to clear these cells are hampered by defects in both adaptive and cellular immune responses. IL-15, a cytokine that stimulates NK and T cells has potential to reverse these defects and to clear virus infected cells. Methods: We are conducting a Phase 1 dose escalation trial of ALT-803 in HIV+ adults. ALT-803 is an IL-15 superagonist/IL-15 receptor α complex (IL-15N72D/IL-15Rα-Fc) and is in clinical trials for hematologic and solid organ malignancies. Clinical trials in cancer patients have shown that subcutaneous (SQ) administration (compared to intravenous (IV)) is well tolerated and gives favorable pharmacokinetics at doses between 10-20 mcg/kg weekly. HIV+ people on ART with plasma viral load < 20 copies/ml and CD4 T cells > 500 cells/ µl receive an IV or SQ injection of ALT-803 weekly for 3 weeks. Blood is obtained for assessments of cell activation and proliferation, and changes to the virus reservoir. Three people are planned to receive the drug at each dose level. The dose escalation scheme is 0.3 mcg/kg IV then 1, 3, and 6 mcg/kg SQ. Results: A total of 7 individuals have been dosed to date. The mean age was 42 and mean CD4 T cell count was 865 cell/µl. The mean time from diagnosis was 9.7 years and the mean time on ART was 5.3 years. The first 2 participants received 0.3 mcg/kg IV and the remaining 5 received 1.0 mcg/kg SQ. SQ dosing was associated with an injection site rash and adenopathy. Eight of the first 13 doses were associated with transient low-level plasma viremia. We measured a 7.6-fold increase in NK cell activation, a 23-fold increase in CD4 activation and a 10-fold increase in CD8 T cell activation in LN 48 hours after dosing. We used the EDITS assay (Envelope Detection by Induced Transcription-based Sequencing, developed by Dr. Karn, CWRU) to measure inducible cell-associated HIV RNA. Prior to Con A stimulation we measured a significant increase in HIV transcription after the first 2 ALT-803 doses but after dose 3 there were fewer transcription events. With ConA stimulation there was a trend towards decreasing transcription events (Figure). Conclusion: At these relatively low doses of ALT-803, the drug is safe and well- tolerated. The drug is biologically active and causes activation and proliferation of CD4, CD8 T cells and NK cells and induces transcription of HIV. These studies suggest ALT-803 reactivates virus from latency and activates NK and T cells.

Poster Abstracts

357 EFFECT OF 24 WEEKS TLR9 AGONIST THERAPY ON CTL RESPONSES AND VIRAL REBOUND DURING ATI Line K. Vibholm 1 , Giacomo Frattari 1 , Mariane H. Schleimann 1 , Rikke Olesen 1 , Mathias Lichterfeld 2 , Anni Winckelmann 1 , Christina V. Konrad 1 , Vibeke Klastrup 1 , Thomas A. Rasmussen 1 , Manuel Schmidt 3 , Burghardt Wittig 4 , Lars Østergaard 1 , Paul W. Denton 1 , Martin Tolstrup 1 , Ole S. Søgaard 1 1 Aarhus University Hospital, Aarhus, Denmark, 2 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 3 Mologen AG, Berlin, Germany, 4 Freie Universität Berlin, Berlin, Germany

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