Contribution to HIV Prevention and Treatment by Antibody-Mediated Effector Function and Advances in Broadly Neutralizing Antibody Delivery by Vectored Immunoprophylaxis.

Meredith Phelps,Alejandro Benjamin Balazs

doi:10.3389/fimmu.2021.734304

Meredith Phelps, Alejandro Benjamin Balazs

Open Access

https://doi.org/10.3389/fimmu.2021.734304

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Abstract

HIV-1 broadly neutralizing antibodies (bNAbs) targeting the viral envelope have shown significant promise in both HIV prevention and viral clearance, including pivotal results against sensitive strains in the recent Antibody Mediated Prevention (AMP) trial. Studies of bNAb passive transfer in infected patients have demonstrated transient reduction of viral load at high concentrations that rebounds as bNAb is cleared from circulation. While neutralization is a crucial component of therapeutic efficacy, numerous studies have demonstrated that bNAbs can also mediate effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent complement deposition (ADCD). These functions have been shown to contribute towards protection in several models of HIV acquisition and in viral clearance during chronic infection, however the role of target epitope in facilitating these functions, as well as the contribution of individual innate functions in protection and viral clearance remain areas of active investigation. Despite their potential, the transient nature of antibody passive transfer limits the widespread use of bNAbs. To overcome this, we and others have demonstrated vectored antibody delivery capable of yielding long-lasting expression of bNAbs in vivo. Two clinical trials have shown that adeno-associated virus (AAV) delivery of bNAbs is safe and capable of sustained bNAb expression for over 18 months following a single intramuscular administration. Here, we review key concepts of effector functions mediated by bNAbs against HIV infection and the potential for vectored immunoprophylaxis as a means of producing bNAbs in patients.

Highlights

Despite the success of pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) in reducing HIV incidence in developed countries, the HIV pandemic remains a major burden in developing nations [1]
Passive administration of Broadly neutralizing antibodies (bNAbs) have demonstrated that antibody concentration and potency are important parameters correlated with protection against HIV acquisition
Other nonneutralizing functions, including antibodydependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent complement deposition (ADCD) have been shown to be critical in this context

Summary

INTRODUCTION

Despite the success of pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) in reducing HIV incidence in developed countries, the HIV pandemic remains a major burden in developing nations [1]. More recent studies investigating the correlates of protection in a phase 1B trial attempting to replicate the RV144 regimen in South Africa (HVTN 097) found that innate immune pathways were highly upregulated, including signatures of ADCC and ADCP it failed to demonstrate significant protection [53] These findings suggest antibodies capable of driving Fc-mediated effector functions may hold promise in future interventions designed to prevent HIV transmission. A study by Dugast et al [55] demonstrated that passive transfer of ADCCinducing non-neutralizing antibodies isolated from elite controllers failed to protect rhesus monkeys from SHIV challenge, suggesting that Fc-mediated effector functions alone are insufficient to protect against viral acquisition [55].

I.V. SHIV-325c rectal

I.V. SHIV-BalP4 rectal

I.V. SHIV-327c rectal

Findings

DISCUSSION