Rapid Elimination of Broadly Neutralizing Antibodies Correlates with Treatment Failure in the Acute Phase of Simian-Human Immunodeficiency Virus Infection

Abstract

Early human immunodeficiency virus type 1 (HIV-1) treatment during the acute period of infection can significantly limit the seeding of viral reservoirs and modify the course of disease. However, while a number of HIV-1 broadly neutralizing antibodies (bnAbs) have demonstrated remarkable efficacy as prophylaxis in macaques chronically infected with simian-human immunodeficiency virus (SHIV), intriguingly, their inhibitory effects were largely attenuated in the acute period of SHIV infection. To investigate the mechanism for the disparate performance of bnAbs in different periods of SHIV infection, we used LSEVh-LS-F, a bispecific bnAb targeting the CD4 binding site and CD4-induced epitopes, as a representative bnAb and assessed its potential therapeutic benefit in controlling virus replication in acutely or chronically SHIV-infected macaques. We found that a single infusion of LSEVh-LS-F resulted in rapid decline of plasma viral loads to undetectable levels without emergence of viral resistance in the chronically infected macaques. In contrast, the inhibitory effect was robust but transient in the acutely infected macaques, despite the fact that all macaques had comparable plasma viral loads initially. Infusing multiple doses of LSEVh-LS-F did not extend its inhibitory duration. Furthermore, the pharmacokinetics of the infused LSEVh-LS-F in the acutely SHIV-infected macaques significantly differed from that in the uninfected or chronically infected macaques. Host SHIV-specific immune responses may play a role in the viremia-dependent pharmacokinetics. Our results highlight the correlation between the fast clearance of infused bnAbs and the treatment failure in the acute period of SHIV infection and may have important implications for the therapeutic use of bnAbs to treat acute HIV infections. IMPORTANCE Currently, there is no bnAb-based monotherapy that has been reported to clear the virus in the acute SHIV infection period. Since early HIV treatment is considered critical to restricting the establishment of viral reservoirs, investigation into the mechanism for treatment failure in acutely infected macaques would be important for the therapeutic use of bnAbs and eventually towards the functional cure of HIV/AIDS. Here we report the comparative study of the therapeutic efficacy of a bnAb in acutely and chronically SHIV-infected macaques. This study revealed the correlation between the fast clearance of infused bnAbs and treatment failure during the acute period of infection.

Rapid identification of a human antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 infection

“…One possible reason for the lower efficacy could be the larger amount of infectious virus produced in the animal after the first cycle(s) of replication and possibility for cell-to-cell spread. Another related contributing factor could be the decreased antibody concentration due to formation and removal of antigen/antibody complexes as we previously showed for HIV-1 ( 34 ). Indeed, the IgG1 ab1 concentration in the therapeutic group (20 to 30 μg/mL at day 1 and 0 to 15 μg/mL at day 5 after challenge) was significantly lower than that in the prophylactic group (30 to 50 μg/mL and 15 to 30 μg/mL, respectively) ( Fig.…”

Cross-Reactive Fc-Fused Single-Domain Antibodies to Hemagglutinin Stem Region Protect Mice from Group 1 Influenza a Virus Infection

“…Although therapy with a single dose of VHH-Fc 24 h post-infection did not offer complete protection against H1N1 infection, surviving mice gained weight and even exceeded their initial body mass up to the end of the experiment. Reduced potency of antibodies in the postexposure regimen is time-dependent, and may be associated with the larger amount of infectious viruses produced in the lungs after replication cycles [75] or with rapidly decreased VHH-Fc concentration in the result of formation and removal of immune complexes [76,77]. An improvement in the therapeutic effectiveness of VHH-Fc can be achieved by increasing the amount of delivered antibody, due to multiple injections with a certain interval or by obtaining an antibody cocktail [74,[78][79][80][81].…”

Pathways towards human immunodeficiency virus elimination

“…This delay in bnAbs production makes them highly specific as they undergo multiple iterations of somatic mutations [56,57]. Because of their longer half-lives and achievable effective therapeutic concentrations, a single infusion of bnAbs results in a rapid decline of plasma viral load (VL) that has been affirmed in long-term SIV infected macaques [58]. Moreover, modification of bnAbs by amino acid mutations has increased their half-lives even further and conferred protection against repeated viral challenges [59].…”