Use of broadly neutralizing antibodies for HIV-1 prevention

Abstract

Antibodies have a long history in antiviral therapy, but until recently, they have not been actively pursued for HIV-1 due to modest potency and breadth of early human monoclonal antibodies (MAbs) and perceived insurmountable technical, financial, and logistical hurdles. Recent advances in the identification and characterization of MAbs with the ability to potently neutralize diverse HIV-1 isolates have reinvigorated discussion and testing of these products in humans, since new broadly neutralizing MAbs (bnMAbs) are more likely to be effective against worldwide strains of HIV-1. In animal models, there is abundant evidence that bnMAbs can block infection in a dose-dependent manner, and the more potent bnMAbs will allow clinical testing at infusion doses that are practically achievable. Moreover, recent advances in antibody engineering are providing further improvements in MAb potency, breadth, and half-life. This review summarizes the current state of the field of bnMAb protection in animal models as well as a review of variables that are critical for antiviral activity. Several bnMAbs are currently in clinical testing, and we offer perspectives on their use as pre-exposure prophylaxis (PrEP), potential benefits beyond sterilizing immunity, and a discussion of future approaches to engineer novel molecules.

Keywords: Fc-effector functions; HIV-1 antibodies; Neutralizing antibodies; SHIV protection; pre-exposure prophylaxis.

Figure 1. Timing and complexity of neutralizing antibodies in human subjects with different virus levels

HIV-1 accumulates at least one mutation every time it replicates and thus, develops into a swarm of closely related viruses called the quasispecies that differs in each individual. The number of variants in the quasispecies depends upon the interplay between the virus and the adaptive immune response. Progressors have moderate to high viremia that is accompanied by the development of variants and antibodies that become diverse within a few years. Slow Progressors have low or undetectable viremia for 10 years or more, and they develop nAbs slowly and at low titers as a result of exposure to less antigen, and less diverse antigen.

Figure 2. HIV-1 Env divergence and variation during infection

Following infection, the autologous or “type specific” response develops first, with low affinity Abs against the T/F viruses (gray) and early variants (light blue). This occurs in essentially all individuals and affinity and neutralization against the autologous virus increase over time. As the virus responds to autologous NAbs, escape variants emerge that are divergent from the T/F virus, creating more Env sequence diversity, which in turn becomes subject to the host humoral responses. As the quasispecies diverges, the nAb responses become higher affinity and broadens to accommodate resistant variants. This results in the ability of an individual sera to neutralize viruses from other individuals. After a number of years, some sera are able to cross-react with a range of heterologous strains by targeting one or more shared epitopes. This results and “broad” nAbs (bnAbs) that can neutralize many diverse Tier 2 viruses. A small percentage of individuals are “elite” neutralizers or have antibodies that can potently neutralize the large majority of virus isolates.

Figure 3. Neutralization sensitivity of SHIVs to anti-HIV-1 bnMAbs

The IC₅₀ titers of the bnMAbs shown were determined against a panel of replication competent SHIVs in a single-round of infection assay with TZM-bl target cells. The SHIV stocks were made in rhesus PBMCs. The clade of each SHIV is indicated in parenthesis.

Figure 4. VRC01 serum concentrations needed to protect against SHIV infection

The neutralization sensitivity (IC₅₀) of a panel of 177 HIV-1 strains to VRC01 is shown (red) along with the sensitivity of two SHIVs (SHIV_SF162P3 and SHIV_BaL.P4) (black). The plasma concentration of VRC01 needed to protect 50% of animals (EC₅₀) after mucosal challenge is indicated for each SHIV.

Figure 5. Antiviral activities of antibodies against HIV

The two panels depict scenarios of the protection outcome of HIV-1 exposure at mucosal sites when non-neutralizing or weakly neutralizing antibodies are present, compared to exposure in the presence of potently neutralizing antibodies. The former may be unable to block virus entry into cells, but can kill infected cells via Fc-mediated functions. These anti-viral activities are important for blunting viremia and slowing viral replication, but may not be sufficient to prevent eventual infection that overwhelms the antibody response. Conversely, neutralizing antibodies block entry into cells and also mediate Fc effector functions to kill and clear any infected cells, thus preventing establishment of infection.

Figure 6. Biodistribution of bnMAb cocktail following subcutaneous (s.c.) injection

A cocktail containing 5 mg/kg of each PGT121 and VRC07-523 was delivered s.c. in the upper back to infant (~1 month old) rhesus macaques. Multiple tissues were collected one day later, homogenized, and assayed for bnMAb cocktail concentration. Two representative animals are shown from experiments with no SHIV inoculation.