Reduced Potency and Incomplete Neutralization of Broadly Neutralizing Antibodies against Cell-to-Cell Transmission of HIV-1 with Transmitted Founder Envs

Abstract

Broadly neutralizing antibodies (bNAbs) have been isolated from HIV-1 patients and can potently block infection of a wide spectrum of HIV-1 subtypes. These antibodies define common epitopes shared by many viral isolates. While bNAbs potently antagonize infection with cell-free virus, inhibition of HIV-1 transmission from infected to uninfected CD4 ϩ T cells through virological synapses (VS) has been found to require greater amounts of antibody. In this study, we examined two well-studied molecular clones and two transmitted/founder (T/F) clones for their sensitivities to a panel of bNAbs in cell-free and cell-to-cell infection assays. We observed resistance of cell-to-cell transmission to antibody neutralization that was reflected not only by reductions of antibody potency but also by decreases in maximum neutralization capacity relative to the levels seen with cell-free infections. BNAbs targeting different epitopes exhibited incomplete neutralization against cellassociated virus with T/F Envs, which was not observed with the cell-free form of the same virus. We further identified the membrane-proximal internal tyrosine-based sorting motif as a determinant that can affect the incomplete neutralization of these T/F clones in cell-to-cell infection. These findings indicate that the signal that affects surface expression and/or internalization of Env from the plasma membrane can modulate the presentation of neutralizing epitopes on infected cells. These results highlight that a fraction of virus can escape from high concentrations of antibody through cell-to-cell infection while remaining sensitive to neutralization in cell-free infection. The ability to fully inhibit cell-to-cell transmission may represent an important consideration in the development of antibodies for treatment or prophylaxis.

Neutralization Synergy between HIV-1 Attachment Inhibitor Fostemsavir and Anti-CD4 Binding Site Broadly Neutralizing Antibodies against HIV

“…For pseudotyping, cells are infected with cell-free, replication-defective virus, which is easily neutralized by bNAbs. In the case of replication-competent virus, however, cells are also infected via cell-to-cell transmission, which is both highly efficient and more difficult for bNAbs to neutralize (23). The mutations most resistant to BMS-626529, i.e., M426L, S375M, and S375M/M434I, were introduced into Env sequence of HIV-1 NL43-ΔR1 , which has a frameshift in vpr, rendering that gene nonfunctional.…”

Broadly neutralizing antibodies for HIV-1: efficacies, challenges and opportunities

“…Recent studies have suggested that the capacity of bNAbs in cell-to-cell transmission varies depending on their mode of action and virus strains [10,53]. A range of bNAbs and virus tests revealed decreased inhibitory activity against HIV-1 cell-to-cell transmission compared with cell-free transmission, and potent capacity in neutralizing free virus spread cannot predict equally relevant for inhibiting cell-to-cell transmission [53,54]. More recently, Parsons examined the efficacy of bNAbs PGT121 against cellassociated SHIV infection and reported partial prevention of infection after cell-associated viral challenge [55].…”

“…Notably, the full-length heavy chain-reconstituted VHH (J3-Fc) effectively neutralizes cell-to-cell spread, suggesting that small size is not the only determinant of potency and that other factors are worthy of further exploration [77]. Additionally, due to the higher multiplicity of infection (MOI) during cell-tocell transmission, maintaining high concentrations of bNAbs is crucial for protecting against cell-associated viruses [54]. Alternatively, mAbs that target CD4 or coreceptors competitively or uncompetitively bind to CD4/CCR5 with higher affinity than to HIV glycoprotein 120 (gp120) and might inhibit viral entry as well as cell-to-cell spread [78][79][80].…”

Masters of manipulation: Viral modulation of the immunological synapse

“…For example, HIV‐1 transmitted cell to cell requires greater concentrations of broadly neutralising antibodies to neutralise virus when compared with cell‐free virus. In a recent study, several broadly neutralising antibodies were found to have a decreased capacity to neutralise virus isolated from HIV‐1 patients in a transfer assay compared with cell‐free virus (Li, Zony, Chen, & Chen, ). Moreover, even though virus transferred via VS is still susceptible to antiretroviral treatment, it is thought to be less sensitive to some commonly used antiretrovirals than cell‐free virus (Sigal et al, ).…”