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HIV broadly neutralizing antibody escapability drives the therapeutic efficacy of vectored immunotherapy.

ABSTRACT: Broadly neutralizing antibodies (bNAbs) have shown great promise for prevention and treatment of HIV infection. Breadth of bNAb neutralization, measured in vitro across panels of diverse viral isolates, is often used as a predictor of clinical potential. However, recent prevention studies demonstrate that the clinical efficacy of a broad and potent bNAb (VRC01) is undermined by neutralization resistance of circulating strains. Using HIV-infected humanized mice, we find that therapeutic efficacy of bNAbs delivered as Vectored ImmunoTherapy (VIT) is a function of both the fitness cost and resistance benefit of mutations that emerge during viral escape, which we term 'escapability'. Applying this mechanistic framework, we find that the sequence of the envelope V5-loop alters the resistance benefits of mutants that arise during escape, thereby impacting the therapeutic efficacy of VIT-mediated viral suppression. We also find that an emtricitabine-based antiretroviral drug regimen dramatically enhances the efficacy of VIT, by reducing the fitness of mutants along the escape path. Our findings demonstrate that bNAb escapability is a key determinant to consider in the rational design of antibody regimens with maximal efficacy and illustrates a tractable means of minimizing viral escape from existing bNAbs.

SUBMITTER: Galvez NMS

PROVIDER: S-EPMC11257540 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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HIV broadly neutralizing antibody escape dynamics drive the outcome of AAV vectored immunotherapy in humanized mice.

Galvez Nicolas M S NMS Nitido Adam D AD Yoo Seo Bin SB Cao Yi Y Deal Cailin E CE Boutros Christine L CL MacDonald Scott W SW Albrecht Yentli E Soto YES Lam Evan C EC Sheehan Maegan L ML Parsons Dylan D Lin Allen Z AZ Deymier Martin J MJ Brady Jacqueline M JM Moon Benjamin B Bullock Christopher B CB Tanno Serah S Pegu Amarendra A Chen Xuejun X Liu Cuiping C Koup Richard A RA Mascola John R JR Vrbanac Vladimir D VD Lingwood Daniel D Balazs Alejandro B AB

bioRxiv : the preprint server for biology 20250614

Broadly neutralizing antibodies (bNAbs) have shown promise for prevention and treatment of HIV. Potency and breadth measured <i>in vitro</i> are often used as predictors of clinical potential; however, human studies demonstrate that clinical efficacy of bNAbs is undermined by both pre-existing and <i>de novo</i> resistance. Here we find that HIV-infected humanized mice receiving bNAbs delivered via AAV as Vectored ImmunoTherapy (VIT) can be used to identify antibody escape paths, which are large ...[more]

PMID: 39026699

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Project description:BackgroundHIV-1 infections occur following viral exposure at anogenital mucosal surfaces in the presence of semen. Semen contains immunosuppressive and pro-inflammatory factors. Semen from HIV-1-infected donors contains anti-HIV-1 antibodies. We assessed if passively infused anti-HIV-1 neutralizing antibody conferred protection from rectal SHIVSF162P3 challenge at semen exposed mucosae.MethodsWe pooled seminal plasma from HIV-1-infected donors. The pool was screened by ELISA for antibodies against HIV-1SF162 gp140. The ability of seminal plasma to inhibit macaque NK cells from responding to direct and antibody-dependent stimulation was assessed. The ability of seminal plasma to inhibit macaque granulocytes from mediating oxidative burst was also assessed. To demonstrate viral infectivity in the presence of seminal plasma, macaques (n = 4) were rectally challenged with SHIVSF162P3 following exposure to 2.5 mL of seminal plasma. To evaluate if anti-HIV-1 neutralizing antibody confers protection against rectal SHIV challenge at semen exposed mucosae, eight macaques were intravenously infused with PGT121, either wild type (n = 4) or the Fc receptor binding deficient LALA variant (n = 4), and rectally challenged with SHIVSF162P3 following exposure to 2.5 mL of seminal plasma.FindingsAnti-HIV-1SF162 gp140 antibodies were detected in seminal plasma. Seminal plasma inhibited direct and antibody-dependent NK cell activation and granulocyte oxidative burst in vitro. Rectal SHIVSF162P3 challenge of control macaques following seminal plasma exposure resulted in infection of all animals. All macaques infused with wild type or LALA PGT121 and challenged with SHIVSF162P3 following seminal plasma exposure were protected.InterpretationPGT121 conferred protection against rectal SHIVSF162P3 challenge at semen exposed mucosae. Future research should investigate if semen alters protection conferred by antibodies more dependent on non-neutralizing functions.FundingThis work was supported by a grant from the Australian National Health and Medical Research Council (APP1124680).

Dataset Information

HIV broadly neutralizing antibody escapability drives the therapeutic efficacy of vectored immunotherapy.

Publications

HIV broadly neutralizing antibody escape dynamics drive the outcome of AAV vectored immunotherapy in humanized mice.

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