Decoupling HIV-1 antiretroviral drug inhibition from plasma antibody activity to evaluate broadly neutralizing antibody therapeutics and vaccines

• Published in: Cell reports. Medicine 2024-09, Vol.5 (9), p.101702, Article 101702
• Main Authors: Schwarzmüller, Magdalena, Lozano, Cristina, Schanz, Merle, Abela, Irene A., Grosse-Holz, Silvan, Epp, Selina, Curcio, Martina, Greshake, Jule, Rusert, Peter, Huber, Michael, Kouyos, Roger D., Günthard, Huldrych F., Trkola, Alexandra
• Format: Article
• Language: English
• Subjects: AIDS Vaccines - immunology; AIDS Vaccines - therapeutic use; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Anti-Retroviral Agents - therapeutic use; Antibodies, Neutralizing - blood; Antibodies, Neutralizing - immunology; antiretroviral therapy; Broadly Neutralizing Antibodies - immunology; Broadly Neutralizing Antibodies - therapeutic use; HIV Antibodies - blood; HIV Antibodies - immunology; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - virology; HIV-1; HIV-1 - drug effects; HIV-1 - immunology; Humans; Neutralization Tests - methods; neutralizing antibody
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101702

The development of broadly neutralizing antibody (bnAb)-based therapeutic HIV-1 vaccines and cure concepts depends on monitoring bnAb plasma activity in people with HIV (PWH) on suppressive antiretroviral therapy (ART). To enable this, analytical strategies must be defined to reliably distinguish antibody-based neutralization from drug inhibition. Here, we explore strategies that either utilize drug-resistant viruses or remove drugs from plasma. We develop ART-DEX (ART dissociation and size exclusion), an approach which quantitatively separates drugs from plasma proteins following pH-triggered release allowing accurate definition of antibody-based neutralization. We demonstrate that ART-DEX, alone or combined with ART-resistant viruses, provides a highly effective and scalable means of assessing antibody neutralization during ART. Implementation of ART-DEX in standard neutralization protocols should be considered to enhance the analytical capabilities of studies evaluating bnAb therapeutics and therapeutic vaccines, furthering the development of advanced ART and HIV-1 cure strategies. [Display omitted] •ART-DEX is a high-throughput strategy to separate HIV drugs from plasma proteins•ART-DEX is compatible with standard HIV-1 neutralization protocols•ART-DEX advances monitoring of neutralizing antibody activity in people with HIV•Implementing ART-DEX aids therapeutic evaluation of bnAbs and HIV cure strategies Schwarzmüller et al. report the development of the ART-DEX, a high-throughput method for removing antiretrovirals from the plasma of people with HIV allowing reliable monitoring of antibody-mediated neutralization with conventional neutralization assays. ART-DEX, used alone or with ART-resistant viruses, enhances the ability to evaluate bnAb activity in therapeutic and cure strategies.