We have engineered a synthetic antibody that neutralizes 100% of HIV strains. This antibody is built from the parts of CD4 and CCR5 that are recognized by HIV, and is named "eCD4-Ig." The goal of our research program is now to maximize its efficacy. A fundamental question for our effort-and for the field as a whole-is: Which isotype of IgG has the properties that are most important for suppressing viral replication? To answer this question, we will eliminate problematic features of IgG2 and IgG3 that have historically presented a barrier to their use as therapeutics in humans, and we will compare the ability of rhesus IgG1, IgG2, and IgG3 forms of eCD4-Ig to suppress SIV replication in macaques. The isotype of eCD4-Ig that most completely suppresses viral replication will be advanced to human clinical trials.
Public Health Relevance Statement: Public Health Relevance: The HIV-1 pandemic continues to be a catastrophe for global health. We are developing approaches based on a synthetic antibody, named "eCD4-Ig," for treating and preventing HIV infection. The proposed project will resolve a fundamental scientific question about how to most effectively treat or prevent HIV infection, and indicate which is the best embodiment of eCD4-Ig to advance to human clinical trials.
NIH Spending Category: Biotechnology; HIV/AIDS; Infectious Diseases; Prevention
Project Terms: adeno-associated viral vector; Affect; Affinity; Animal Experiments; Antibodies; antiretroviral therapy; Antiviral Agents; antiviral immunity; base; Binding; Biological Assay; Blood Circulation; CCR5 gene; Cell Line; Chinese Hamster Ovary Cell; Clinical Trials; Complement; Dependovirus; Engineering; Exhibits; Fc Receptor; global health; Goals; HIV; HIV Infections; HIV-1; Human; IgG1; IgG2; IgG3; Immune; immunogenicity; Immunoglobulin G; Infusion procedures; Intravenous; Killings; Macaca; Macaca mulatta; macrophage; Measures; Mediating; Names; Natural Killer Cells; Nature; overexpression; pandemic disease; Pharmaceutical Preparations; Plasma Cells; prevent; Production; programs; Property; Prophylactic treatment; protein-tyrosine sulfotransferase; Proteins; Protocols documentation; public health relevance; Publishing; Quality Control; Recombinant Proteins; Recombinants; Recrudescences; Regimen; Research; scale up; Shock; SIV; synthetic antibodies; Testing; Therapeutic; Transgenes; Variant; Viral; Viral Load result; Viral reservoir; Virus; Virus Diseases; Virus Replication
