Triple broadly neutralizing antibody (bnAb) combination therapy: a cure for pediatric HIV?
Authors: Bahadir Zeynep , Pahountis Ioanna , Vuong Kenneth , Kosman Christina , Dankwa Sedem , Dennis Maria , McCarthy Janice , Ngo Julia T , Enemuo Chiamaka A , Carnathan Diane G , Nelson Ashley , Berendam Stella J , Silvestri Guido , Amara Rama , Permar Sallie , Goswami Ria , Chahroudi Ann , Fouda Genevieve G 
Published: October 2024

Abstract

Background
In 2022, UNAIDS estimated out of the 1.7 million children living with HIV, only 57.1% had access to antiretroviral therapy (ART). Though ART has significantly decreased HIV-associated morbidity and mortality, it cannot eliminate the latent viral reservoir. Consequently, most people living with HIV demonstrate viral rebound when ART is interrupted. There is therefore a critical need for alternative therapeutic to achieve long term ART free viral control. Broadly neutralizing antibodies (bnAb) have shown promising results in preclinical and clinical studies, but their potential efficacy is limited by the emergence of escape variants, especially with monotherapy. We previously tested the neutralizing and non-neutralizing functions of different bnAb combinations and identified a triple bnAb combination that showed robust neutralization potency and breadth, as well as non-neutralizing functions. In this project, we investigated the impact of combination bnAb therapy on viral rebound in SHIV infected infant rhesus macaques (RMs).

Methods
Ten infant rhesus macaques were orally challenged with SHIV.C.CH505 at 4 weeks of age. Oral challenge is a well-established method that is used to mimic breastmilk transmission of HIV, which contributes to almost 50% of pediatric HIV infections every year. A triple bnAb combination of simianized 3BNC117 (CD4 binding site), PGDM1400 (V2 glycan dependent), and PGT151 (interface) was subcutaneously administered twice at 40 mg/kg of each antibody. The initial infusion was administered at ART initiation (8 weeks post-infection) while the second infusion with administered at the time of analytical treatment interruption (ATI) (49 weeks post-infection). RMs were monitored weekly from the beginning of infection until 12 weeks post-ATI. Enzyme-linked Immunosorbent Assay (ELISA) was used to monitor plasma concentrations of each bNab and Env-specific IgG binding responses.

Results
Env-specific antibody binding levels against HIV envelope proteins gp120 and gp41 peaked in plasma 8 weeks after infection. The antibody levels then slightly decreased during ART and increased again after viral rebound following ATI. BnAb plasma concentrations peaked 1-2 weeks after each bnAb infusion, then slowly declined. After the initial infusion, all RMs had undetectable levels of 3BNC117 and PGT151 by 8 weeks post initial infusion, and only 2/10 RMs had detectable PGDM1400 levels. All animals experienced viral rebound following ATI.). Importantly, the average time to virus rebound (7 weeks, range 3-10 weeks) was significantly longer than a s control group of RMs without any immune-based intervention (~2.5 weeks). By the time of viral rebound, most animals had undetectable plasma levels of 3BNC117, PGDM1400 or PGT151. However, in some animals, rebound occurs when passively administered antibodies were still detectable, suggesting the emergence of bnAb resistant variants.

Conclusion
Passive immunization with a triple-bnAb combination of 3BNC117, PGT151 and PGDM1400 was associated with delayed viral rebound, but more investigation is needed to understand the potential role of this strategy in the HIV therapeutic portfolio. Future work will investigate the sensitivity of the rebound viruses to the bnAb combination to evaluate the contribution of bnAb escape to viral rebound.