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

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.

Quick COVID-19 Healers Sustain Anti-SARS-CoV-2 Antibody Production.

Antibodies are key immune effectors that confer protection against pathogenic threats. The nature and longevity of the antibody response to SARS-CoV-2 infection are not well defined. We charted longitudinal antibody responses to SARS-CoV-2 in 92 subjects after symptomatic COVID-19. Antibody responses to SARS-CoV-2 are unimodally distributed over a broad range, with symptom severity correlating directly with virus-specific antibody magnitude. Seventy-six subjects followed longitudinally to ∼100 days demonstrated marked heterogeneity in antibody duration dynamics. Virus-specific IgG decayed substantially in most individuals, whereas a distinct subset had stable or increasing antibody levels in the same time frame despite similar initial antibody magnitudes. These individuals with increasing responses recovered rapidly from symptomatic COVID-19 disease, harbored increased somatic mutations in virus-specific memory B cell antibody genes, and had persistent higher frequencies of previously activated CD4+ T cells. These findings illuminate an efficient immune phenotype that connects symptom clearance speed to differential antibody durability dynamics.

Dimeric 2G12 as a potent protection against HIV-1.

We previously showed that broadly neutralizing anti-HIV-1 antibody 2G12 (human IgG1) naturally forms dimers that are more potent than monomeric 2G12 in in vitro neutralization of various strains of HIV-1. In this study, we have investigated the protective effects of monomeric versus dimeric 2G12 against HIV-1 infection in vivo using a humanized mouse model. Our results showed that passively transferred, purified 2G12 dimer is more potent than 2G12 monomer at preventing CD4 T cell loss and suppressing the increase of viral load following HIV-1 infection of humanized mice. Using humanized mice bearing IgG "backpack" tumors that provided 2G12 antibodies continuously, we found that a sustained dimer concentration of 5-25 µg/ml during the course of infection provides effective protection against HIV-1. Importantly, 2G12 dimer at this concentration does not favor mutations of the HIV-1 envelope that would cause the virus to completely escape 2G12 neutralization. We have therefore identified dimeric 2G12 as a potent prophylactic reagent against HIV-1 in vivo, which could be used as part of an antibody cocktail to prevent HIV-1 infection.