1 HIV Curative Strategies: Key Research Priorities Deeks S, et al., (2013) Nat Rev Immunol. 12(8): 607-614.

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Presentation transcript:

1 HIV Curative Strategies: Key Research Priorities Deeks S, et al., (2013) Nat Rev Immunol. 12(8):

2 HIV/AIDS Curative Treatment: “Shock and Kill” Strategies SHOCK: Re-activation of HIV-1 replication in latent resting memory T-cells Chromatin remodeling: HDACi (vorinostat, panobinostat, romidepsin) γ-chain cytokines: IL-2, IL-7 Protein kinase C (PKC) activators: bryostatin-1, prostratin Transcriptional activators: NFκB activators, farnesyl transferase inhibitors KILL: HIV specific T-cell activation CD4 helper & CD8 T-effector cell killing: Immune checkpoint modulators Viral vaccines (CMV vectors that express HIV proteins) Antibody drug conjugates (ADC) cART: combination antiretroviral therapy Inhibitors of HIV entry and integration

3 HIV/AIDS Curative Treatment: “Shock and Kill” Assays SHOCK Assays: HIV RNA expression Genomic vs multiply spliced RNA Plasma vs cell-associated RNA HIV protein expression, virus production/infection (Flow cytometry, ELISA, reporter viruses) KILL Assays: CTL killing: reduction in HIV proteins or reporters or RNA expression Reservoir Depletion Assays: Direct: viral outgrowth assays (under-estimate), HIV DNA (over- estimate) Indirect (biomarker): HIV expression profiles, gene signatures, Cytokine expression: Flow cytometry, ELISA,

4 HIV Curative Strategy Assays: Viral Outgrowth Assays Statement of Use: Virus outgrowth assays (Q-VOA) that quantify the size of the latent HIV-1 reservoir pre- and post-treatment with potential curative therapies (e.g. HDAC inhibitors). Application: Support clinical development of HIV-1 curative therapies in patient populations that have achieved long term suppression of viral replication. Status: Currently supporting pharma-sponsored clinical investigations of curative therapies. Awarded 2 NIH grant applications to fund support of assay enhancements and automation. Client Support: Primary testing opportunity is support of HIV curative strategy (functional cure) efforts. Future potential patient management applications are uncertain at this time.

5 HIV Curative Strategy Assays: Cytotoxic T-cell Killing Assay Statement of Use: Cytotoxic T-cell assay that quantifies effector T-cell killing of HIV infected cells. Application: Support clinical development of antibody mediated T-cell therapies that induce killing of HIV infected cells Status: In preliminary discussions to develop standardized, high- throughput methods to measure T-cell killing of HIV infected cells. Client Support: Primary testing opportunity is support of HIV curative strategy (functional cure) efforts. Future potential patient management applications are uncertain at this time.

6 VeraTag Proteomics Platform Accurate quantification of immune checkpoint receptors, ligands and complexes (e.g. CTLA-1, B7, PD-1, PD-L1, OX40, OX40-L, TRAF) Patented dual antibody detection method; more sensitive and specific than IHC, ELISA, Flow Cyt Adaptable to the detection of any protein or protein complex

7 HIV/AIDS Curative Treatment Efforts at Monogram Biosciences Monogram Biosciences is highly-proficient in developing validated, high complexity and high throughput antiviral drug resistance assays. Notably, Monogram offers a comprehensive portfolio of cell-based infectivity assays that measure susceptibility to antiviral compounds and antibodies that target various stages of viral replication. Monogram has a dedicated interest in developing assays to support the growing Curative Strategy effort. Currently, Monogram performs a conventional Quantitative Viral Outgrowth Assay (Q-VOA). On July 15, Monogram was awarded two NIH/NIAID grants to support efforts to improve/simplify and automate the Q-VOA and to develop novel approaches for quantifying the HIV latent reservoir. Recognized as having the ability to standardize and automate Curative Strategy assays, Monogram scientists contribute to the DARE collaboratory and the IAS HIV Cure Industry Collaboration Group (ICG).