Genotypic challenges in implementing broadly neutralizing antibody-based long-acting HIV-1 therapies

Broadly neutralizing antibodies (bnAbs) against HIV-1 are promising components of long-acting antiretroviral treatment (ART) due to their prolonged activity and potential for recruiting additional immune effector functions. Their use is most advanced in virologically suppressed people living with HIV-1 switching from a standard daily ART regimen to a long-acting regimen comprising one or two bnAbs combined with one of the currently approved long-acting small-molecule inhibitors: cabotegravir or lenacapavir. Implementation of bnAb-based therapies, however, requires accurate assessment of viral susceptibility. Although phenotypic assays provide the most direct and reliable measures of bnAb activity, their limited scalability has prompted interest in genotypic approaches. Here we summarize evidence linking HIV-1 Env sequence characteristics to reduced bnAb susceptibility, including in vivo selection data in animal models and human studies, and in vitro selection and susceptibility data. Although genotypic analysis of HIV-1 Env may reliably identify resistance in some viruses, more research is required before genotypic methods can reliably predict susceptibility in clinical settings. Tao et al. review clinical and experimental data linking HIV-1 Env sequence features to reduced broadly neutralizing Ab susceptibility. While genotypic analysis identifies many predictors of reduced susceptibility, larger datasets and more advanced models will be required before genetic methods can reliably predict susceptibility in clinical settings.