CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

at baseline and at study end in each patient. Activation of CD4 and CD8 cells significantly decreased in G6 (p<0.05, 2-way Anova). There was a significant increase in interleukins measurement from 1st DCv dose to last dose at CD4+ T cells, and a significant increase in IL2 and TNF at CD8 from 1st to last dose (Kruskal-Wallis), with no changes in the control experiment. Conclusion: NA+Au+antiretroviral intensification in combination with DCv reduced the viral reservoir size and cell activation markers among individuals on ART.

400 IMPACT OF EVEROLIMUS THERAPY ON HIV PERSISTENCE, IMMUNE FUNCTION, AND GENE EXPRESSION Corinna N. Schreiner 1 , Cheryl A. Cameron 2 , Louise Hogan 3 , Rachel L. Rutishauser 3 , Simon Chu 3 , Brian Richardson 2 , Rodney Rogers 3 , Cassandra Thanh 3 , Sonia Bakkour 4 , Michael P. Busch 3 , Jeffrey M. Milush 3 , Rafick-Pierre Sekaly 2 , Peter Stock 3 , Steven G. Deeks 3 , Timothy J. Henrich 3 1 Ulm University Medical Center, Ulm, Germany, 2 Case Western Reserve University, Cleveland, OH, USA, 3 University of California San Francisco, San Francisco, CA, USA, 4 Vitalant Research Institute, San Francisco, CA, USA Background: mTOR inhibition may have beneficial effects on HIV persistence, including reducing T Cell CCR5 and PD-1 expression and promoting HIV transcriptional silencing. We previously observed lower cell-associated HIV DNA levels in renal transplant recipients that received sirolimus, an mTOR complex 1 (mTORC1) inhibitor, but prospective data are lacking. Therefore, we conducted a single-arm study of the impact of everolimus, an mTORC1/2 inhibitor on HIV persistence and immune function in ART-suppressed solid organ (SOT) recipients. Methods: Ten HIV-infected SOT recipients on stable, suppressive antiretroviral therapy switched to or added everolimus for 6 months. Cellular and plasma HIV burden, lymphocyte immune phenotype and function, and gene expression/ transcriptomic profiles were evaluated before, during and following everolimus treatment. Results: Everolimus was well tolerated, with one participant stopping at month 2 for diarrhea. Most participants remained on long-term calcineurin inhibitors and mycophenolate anti-proliferative therapy. No overall changes in bulk measures of CD4+ T-cell-associated HIV total DNA, unspliced RNA, and residual viremia were observed, but treatment-mediated downregulation in hallmark mTOR signaling pathway gene expression at month 2 was observed in participants that experienced sustained decreases in CD4+ T-cell-associated DNA 6 months following completion of everolimus therapy. In addition, everolimus treatment was highly associated with downregulation of histone complex genes in network analyses, and the frequency of individual HIV transcriptionally active CD4+ T-cells measured directly by a single-cell encapsulation assay significantly increased from baseline to month 6 of therapy (186 to 309 RNA+ cells/10^6 CD4+ T-cells; P=0.02) across all participants. A significant decrease in PD-1 expression on terminally differentiated CD4+ TEMRA cells was observed (P<0.01), but no differences were observed in CD4+ or CD8+ T-cell intracellular cytokine responses to HIV or CMV peptide stimulations. Conclusion: Everolimus therapy reduced mTOR gene expression in some individuals, which was associated with sustained reductions in CD4+ T cell HIV DNA levels. Everolimus also increased the frequency of individual HIV transcriptionally active cells during therapy in all participants which may have

Poster Abstracts

399 RANDOMIZED TRIAL OF IMPACT OF MULTIPLE INTERVENTIONS ON HIV RESERVOIR: SPARC-7 TRIAL Ricardo S. Diaz 1 , Leila B. Giron 1 , James Hunter 1 , Juliana Galinskas 1 , Danilo A. Dias 1 , Sadia Samer 1 , Muhammad S. Arif 1 , Juliana T. Maricato 1 , Maria A. Juliano 1 , Maria Cecilia Araripe Sucupira 1 , Luis M. Janini 1 , Andrea Savarino 2 , Luiz Rodolfo R. Travassos 1 , for the SPARC WORKING GROUP 1 Universidade Federal de São Paulo, Sao Paulo, Brazil, 2 Istituto Superiore di Sanità, Rome, Italy Background: Multiple interventional strategies may be required to decrease HIV-1 reservoir along with antiretroviral therapy (ART). We investigated the effect of treatment intensification with Dolutegravir (DTG) with and without Maraviroc (MVC), the HDAC inhibitor Nicotinamide (NA), and Auranofin (Au), and a dendritic cell vaccine pulsed with autologous HIV (DCv). Au had decreased viral DNA of ART treated SIV infected macaques. Methods: 30 ART suppressed individuals for >2 years (CD4 nadir >350) were randomized to six arms of SPARC-7 TRIAL followed for 48 weeks. Patients from two arms received 3 doses of DCv after 48 weeks and were followed for additional 24 weeks. Groups: G1) continuation of ART, G2) intensified ART (ART+DTG+MVC), G3) intensified ART and HDACi (ART+DTG+MVC+NA), G4) intensified ART and Au (ART+DTG+MVC+Au), G5) partially intensified ART (DTG)+DCv, G6) partially intensified ART (DTG)+NA+Auranofin+DCv. Au was used for the first 24 weeks. DC was pulsed with autologous Gag256- 367 peptides (nanomers, 3-6 peptides each patient) according to the best immunogenicity based in specific HLA of everyone. Total viral DNA was measured by qPCR in PBMCs and rectal biopsy tissues, and T cell activation by HLADR and CD38 on CD4 and CD8. In vitro immunogenicity of DCv was measured by pulsing patients’ cells with autologous peptides used in DCv or S aureus enterotoxin B and brefaldine (control). IL2, TNF and interferon (IFN) were measured by flow cytometry in CD4 and CD8 collected at 1st 2nd and 3rd DCv dose and 30 days after 3rd dose (dose interval=2 weeks). Results: There was no virologic failure or intervention-related SAE. Decrease in viral DNA was observed in G6 but not in other groups. (p=0.022; Odds ratio: 9.75, 95%CL: 1.1-72.39), and G1 showed a linear increase of proviral DNA (p<.05). One G6 patient evolved to undetectable proviral DNA during 48-week period and another after receiving the DCv. Rectal biopsy viral DNA was positive

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