CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Conclusion: In contrast to other studies, our large longitudinal study in a well characterized patient group did not reveal any effect of pIFNα on the latent reservoir as measured by a HIV-1 DNA qPCR assay in PBMCs. Notably, repeated pIFNα treatment did not affect HIV-1 DNA levels. Cumulatively, no discernible effect of pIFNa on HIV-1 DNA in HIV-1/HCV co-infected individuals was detected.

Poster and Themed Discussion Abstracts

328 IN VIVO CONTROL OF HIV INFECTION BY AN ENGINEERED BI-SPECIFIC ANTI-HIV FUSION PROTEIN Ariola Bardhi 1 , Weizao Chen 2 , Yanping Wang 2 , Jennifer Jones 3 , John C. Kappes 3 , Christina Ochsenbauer 3 , Dimiter S. Dimitrov 2 , Harris Goldstein 1 1 Albert Einstein Coll of Med, Bronx, NY, USA, 2 NIH, Frederick, MD, USA, 3 Univ of Alabama at Birmingham, Birmingham, AL, USA

Background: No single natural broadly neutralizing antibody (bNAb) neutralizes all clinical isolates, enabling the recurrence of viremia by immune escape mutants thereby limiting the therapeutic efficacy of passive bNAb treatment. In addition, the avidity and potency of natural bNAb are reduced by their monospecific recognition of Env, limiting their capacity to bivalently bind to the widely dispersed Env molecules in the HIV membrane. We circumvented these limitations by engineering a multivalent bi-specific anti-HIV fusion protein, LSEVh-LS, which utilizes a human IgG1 Fc scaffold linking 4 gp120-specific CD4 domains (mD1.22) and 2 human antibody VH domains (m36.4) specific for the highly conserved, CD4-inducible HIV-1 co-receptor binding region (Figure). We also enhanced LSEVh-LS antibody dependent cellular cytotoxicity (ADCC) activity by increasing its FcγR IIIa binding affinity by rendering its Fc domain fucose-free. Methods: LSEVh-LS neutralizing breadth was determined by in vitro infection inhibition assays using human PBMC and HIV isolates resistant to other bNAb, VRC01 and 3BNC117. LSEVh-LS in vivo neutralizing and ADCC activity was examined by infecting humanized mice constructed by intrasplenically injecting activated human PBMC into NOD-SCID- IL2rγ-/- mice (hu-spl-PBMC-NSG mice) with VRC01-sensitive and resistant isolates expressing a luciferase reporter gene. Results: LSEVh-LS equivalently neutralized in vitro infection by 3 VRC01-sensitive, 3 VRC01-resistant and 1 VRC01/3BNC117-resistant HIV strains at lower concentrations than VRC01. Thus, LSEVh-LS has more potent and broader inhibitory activity than VRC01. These results were extended by in vivo studies in hu-spl-PBMC-NSG mice demonstrating potent in vivo reduction (>90%) of infection by an HIV expressing a VRC01-resistant Env. We investigated in vivo ADCC activity by measuring the elimination of HIV infected cells in hu-spl- PBMC-NSG mice. One day after LSEVh-LS treatment of hu-spl-PBMC-NSG mice with established in vivo infection, infection was reduced 90%, compared to a ~40% reduction of HIV infection by VRC01 treatment. LSEVh-LS treatment did not reduce HIV-infection in NSG mice intrasplenically injected with NK cell-depleted PBMC, indicating that its in vivo ADCC activity was NK cell-mediated. Conclusion: LSEVh-LS, an engineered bi-specific multivalent antibody with more potent and broader neutralizing and ADCC activity than natural bNAb, may represent a more effective therapeutic strategy.

CROI 2017 129