Background:

HIV envelope (env) diversity may result in resistance to broadly neutralizing antibodies (bNAbs). Assessment of genotypic or phenotypic susceptibility to antiretroviral treatment is often performed in people with HIV-1 (PWH) and used for clinical trial screening for HIV-1 bNAb susceptibility. Optimal bNAb susceptibility screening methods are not yet clear.

Methods:

Phenotypic and genotypic analyses were conducted on 124 screening samples from a phase 1b study of bNAbs teropavimab (3BNC117-LS) and zinlirvimab (10-1074-LS) administered with lenacapavir in virally suppressed PWH. Phenotypic analysis was conducted on integrated HIV-1 provirus and stimulated outgrowth virus, with susceptibility to bNAbs defined as 90% inhibitory concentration ≤2 μg/mL. The proviral DNA HIV env gene was genotyped using deep sequencing, and bNAb susceptibility predicted using published env amino acid signatures.

Results:

Proviral phenotypic results were reported for 109 of 124 samples; 75% (82/109) were susceptible to teropavimab, 65% (71/109) to zinlirvimab, and 50% (55/109) to both bNAbs. Phenotypic susceptibility of outgrowth viruses was available for 39 samples; 56% (22/39) were susceptible to teropavimab, and 64% (25/39) to zinlirvimab. Phenotypic susceptibilities correlated between these methods: teropavimab r = 0.82 (P < 0.0001); zinlirvimab r = 0.77 (P < 0.0001). Sixty-seven samples had genotypic and phenotypic data. Proviral genotypic signatures predicted proviral phenotypic susceptibility with high positive predictive value (68%–86% teropavimab; 63%–90% zinlirvimab).

Conclusions:

bNAb susceptibility was correlated among all 3 in vitro assays used to determine teropavimab and zinlirvimab susceptibility in virally suppressed PWH. These findings may help refine PWH selection criteria for eligibility for future studies.