Research ArticleHIV

Effector function does not contribute to protection from virus challenge by a highly potent HIV broadly neutralizing antibody in nonhuman primates

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Science Translational Medicine  17 Mar 2021:
Vol. 13, Issue 585, eabe3349
DOI: 10.1126/scitranslmed.abe3349

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Fc function in focus

There are multiple mechanisms by which broadly neutralizing antibodies (bnAbs) promote protection against HIV, including neutralization of virions and Fc receptor–mediated induction of effector functions on immune cells. Here, Hangartner et al. used variants of the potent HIV bnAb, PGT121, to investigate whether Fc receptor function is required for the protective effects elicited by antibody treatment. The authors showed that variants of PGT121 that could not bind to Fc receptors still protected female macaques against intravaginal simian-HIV infection. These findings underpin the importance of neutralization in determining effectiveness of bnAb treatment for HIV.

Abstract

Protection from immunodeficiency virus challenge in nonhuman primates (NHPs) by a first-generation HIV broadly neutralizing antibody (bnAb) b12 has previously been shown to benefit from interaction between the bnAb and Fcγ receptors (FcγRs) on immune cells. To investigate the mechanism of protection for a more potent second-generation bnAb currently in clinical trials, PGT121, we carried out a series of NHP studies. These studies included treating with PGT121 at a concentration at which only half of the animals were protected to avoid potential masking of FcγR effector function benefits by dominant neutralization and using a new variant that more completely eliminated all rhesus FcγR binding than earlier variants. In contrast to b12, which required FcγR binding for optimal protection, we concluded that PGT121-mediated protection is not augmented by FcγR interaction. Thus, for HIV-passive antibody prophylaxis, these results, together with existing literature, emphasize the importance of neutralization potency for clinical antibodies, with effector function requiring evaluation for individual antibodies.

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