Bystander CD4 T-cell death is inhibited by broadly neutralizing anti-HIV antibodies only at levels blocking cell-to-cell viral transmission

Xiaoyu Luo,Hugo Mouquet,Olivier Schwartz,Warner C Greene

doi:10.1016/j.jbc.2021.101098

Abstract

The progressive loss of CD4+ T cells during HIV infection of lymphoid tissues involves both the apoptotic death of activated and productively infected CD4 T cells and the pyroptotic death of large numbers of resting and abortively infected bystander CD4 T cells. HIV spreads both through cellular release of virions and cell-to-cell transmission involving the formation of virological synapses. Cell-to-cell transmission results in high-level transfer of large quantities of virions to the target cell exceeding that achieved with cell-free virions. Broadly neutralizing anti-HIV antibodies (bNAbs) binding to HIV envelope protein capably block cell-free virus spread, and when added at higher concentrations can also interdict cell-to-cell transmission. Exploiting these distinct dose–response differences, we now show that four different bNAbs block the pyroptotic death of bystander cells, but only when added at concentrations sufficient to block cell-to-cell transmission. These findings further support the conclusion that HIV killing of abortively infected bystander CD4 T cells requires cell-to-cell transfer of virions. As bNAbs attract more interest as potential therapeutics, it will be important to consider the higher concentrations of these antibodies required to block the inflammatory death of bystander CD4 T cells.

Highlights

In the absence of treatment, HIV infection leads to the progressive depletion of CD4 T cells and emergence of the AIDS [1,2,3,4]
Using a human lymphoid aggregate culture (HLAC) coculture system formed with cells from lymphoid tissue, we have suggested that abortive HIV infection and bystander cell pyroptosis require cell-to-cell virus transmission based on transwell experiments, antibody-mediated interruption of leukocyte function–associated antigen-1/intercellular adhesion molecule-1–dependent virological synapses, and alterations in surface area of cell cultures that favor or disfavor cell-to-cell interactions [26]
Application of multiple t tests indicated that Broadly neutralizing anti-HIV antibodies (bNAbs) inhibition of cell-cell transmission and bNAb inhibition of killing were statistically indistinguishable (Fig. 3, cyan), whereas significant differences existed in the level of inhibition with an adjusted p value (q) >0.01 between cell killing and bNAb inhibition of cell-free viral infection (Fig. 3, purple) for each bNAb and concentration tested

Summary

Introduction

In the absence of treatment, HIV infection leads to the progressive depletion of CD4 T cells and emergence of the AIDS [1,2,3,4]. These bNAbs are capable of potently blocking infection by cell-free HIV virions [32,33,34]. We have analyzed the ability of four different potent bNAbs (NIH45–46, 3BNC117, VRC01, and 10E8) to block cell-free HIV transmission, cell-to-cell HIV transmission, and pyroptotic CD4 T-cell death in lymphoid tissues.

Results

Conclusion