Human immunodeficiency virus type-1 (HIV-1) is a retrovirus that infects CD4+ T cells of the immunesystem. If left untreated, people living with HIV-1 (PLWH) will progress to AIDS and may ultimately die as aresult. Combination antiretroviral therapy (ART) with small-molecule drugs is extremely effective at stoppingthe replication of HIV-1 in infected individuals but requires daily dosing often with considerable side effects.Importantly, despite the success of this approach at suppressing HIV-1 replication to clinically undetectablelevels, antiretroviral therapy is not curative. This is due to the persistence of HIV-1 in a silent, or latent, statewithin long-lived CD4+ T cells at extremely low frequencies. These latently infected cells are not targeted bycurrent small-molecule ART regimens. As a result, PLWH must remain on lifelong antiretroviral therapy. Broadly neutralizing antibodies targeting critical epitopes in HIV-1 Env (HIV-1 bNAbs) are currentlybeing developed as a potential approach to eliminate latent HIV-1 and/or as an alternative to small-moleculeART. HIV-1 bNAbs offer several advantages over traditional small-molecule ART, including the potential forlong-acting formulations, reduced side effects, and the potential to eliminate latently infected cells over time.However, a major challenge to the implementation of HIV-1 bNAbs in treatment and cure is pre-existingvariation or resistance in the bNAb-targeted epitopes. Scalable clinical tests are needed to determine (1)whether people who will receive HIV-1 bNAbs have pre-existing resistance, and (2) personalize HIV-1 bNAbcombinations to each individual. To address this critical unmet need, AccelevirDx is developing the HIV-1EnvLRS assay as the first scalable sequence-based test to assess HIV-1 bNAb resistance and predictantibody efficacy by in-depth env sequence analysis. Broadly, this proposal aims to (1) analytically qualifyAccelevirDx's novel, proprietary HiFi-dePCR approach for env amplification underlying HIV-1 EnvLRS, (2)determine the reproducibility of the HIV-1 EnvLRS assay of samples from PLWH, and (3) apply the assay to arecently completed ACTG A5340 clinical trial of the HIV-1 bNAb VRC01 in PLWH to assess assayperformance and utility. PROJECT NARRATIVE
Broadly neutralizing antibodies targeting the HIV Envelope protein (HIV bNAbs) are being developed as
a new therapeutic approach to suppress HIV replication and potentially eliminate latent HIV infection in people
living with HIV. Scalable clinical tests are needed to determine (1) whether people who will receive HIV bNAbs
have pre-existing resistance, and (2) personalize HIV bNAb combinations to each individual. To address this
unmet need, Accelevir Diagnostics is developing the HIV-1 EnvLRS assay as the first molecular test to assess
HIV bNAb resistance and predict antibody efficacy by in-depth analysis of an HIV-positive person's HIV
envelope gene sequences. Acquired Immunodeficiency Syndrome ; AIDS ; Acquired Immune Deficiency ; Acquired Immune Deficiency Syndrome ; Acquired Immuno-Deficiency Syndrome ; Acquired Immunologic Deficiency Syndrome ; Antibodies ; Epitopes ; Antigenic Determinants ; Binding Determinants ; Archives ; Base Sequence ; Nucleotide Sequence ; nucleic acid sequence ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Cells ; Cell Body ; Chemistry ; Clinical Trials ; DNA ; Deoxyribonucleic Acid ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Dyes ; Coloring Agents ; Emulsions ; Foundations ; Genes ; HIV ; AIDS Virus ; Acquired Immune Deficiency Syndrome Virus ; Acquired Immunodeficiency Syndrome Virus ; Human Immunodeficiency Viruses ; LAV-HTLV-III ; Lymphadenopathy-Associated Virus ; Virus-HIV ; HIV Infections ; HTLV-III Infections ; HTLV-III-LAV Infections ; Human T-Lymphotropic Virus Type III Infections ; HIV Seropositivity ; Anti-HIV Positivity ; HIV Positive ; HIV Positivity ; HIV Seroconversion ; HIV antibody positive ; HTLV-III Seroconversion ; HTLV-III Seropositivity ; HIV-1 ; HIV-I ; HIV1 ; Human Immunodeficiency Virus Type 1 ; Human immunodeficiency virus 1 ; Immune system ; allergic/immunologic body system ; allergic/immunologic organ system ; Institutes ; Leukapheresis ; Leukocytapheresis ; Therapeutic Leukopheresis ; Minor ; Persons ; Phenotype ; Plasmids ; Genetic Recombination ; DNA Recombination ; Recombination ; Retroviridae ; Retroviruses ; Virus-Retrovirus ; Safety ; CD4 Positive T Lymphocytes ; CD4 Cells ; CD4 T cells ; CD4 helper T cell ; CD4 lymphocyte ; CD4+ T-Lymphocyte ; CD4-Positive Lymphocytes ; T4 Cells ; T4 Lymphocytes ; Testing ; Time ; virology ; Virus Replication ; viral multiplication ; viral replication ; virus multiplication ; Wisconsin ; Generations ; Sequence Analysis ; SEQ-AN ; Sequence Analyses ; base ; Left ; Clinical ; Phase ; Variant ; Variation ; Series ; Individual ; Recovery ; Measurement ; Disease Progression ; Diagnostic ; Frequencies ; System ; neutralizing antibody ; Viral ; HIV envelope protein ; Performance ; success ; Antiretroviral Agents ; anti-retroviral ; antiretroviral ; Anti-Retroviral Agents ; PBMC ; Peripheral Blood Mononuclear Cell ; novel ; Participant ; Clonality ; Sampling ; assay development ; single molecule ; µfluidic ; Microfluidics ; AACTG ; ACTG ; acquired immunodeficiency syndrome clinical trial group ; AIDS clinical trial group ; small molecule ; Address ; Dose ; Data ; Reproducibility ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Viral Vector ; Molecular ; Development ; developmental ; antiretroviral therapy ; anti-retroviral therapy ; anti-retroviral treatment ; antiretroviral treatment ; novel strategies ; new approaches ; novel approaches ; novel strategy ; Population ; Resistance ; resistant ; novel therapeutic intervention ; new therapeutic approach ; new therapeutic intervention ; new therapeutic strategies ; new therapy approaches ; novel therapeutic approach ; novel therapeutic strategies ; novel therapy approach ; resistance mutation ; resistant mutation ; Regimen ; Genomic DNA ; gDNA ; phase I trial ; phase 1 trial ; individual patient ; Formulation ; prediction algorithm ; predictive algorithm ; predictor algorithm ; clinical implementation ; side effect ; bioinformatics pipeline ; bio-informatics pipeline ;
