Activation and lysis of human CD4 cells latently infected with HIV-1.

Amarendra Pegu,Richard A Koup,John-Paul Todd,Gary J Nabel,Lan Wu,John R Mascola,Sijy O’Dell,Tongqing Zhou,Wei Shi,Peter D Kwong,Ivelin Georgiev,Mangaiarkarasi Asokan,Srinivas S Rao,Zhi-Yong Yang,Keyun Wang,Xuejun Chen,Jason Hataye,Xiaoti Guo,Joseph P Casazza

doi:10.1038/ncomms9447

Abstract

The treatment of AIDS with combination antiretroviral therapy (cART) remains lifelong largely because the virus persists in latent reservoirs. Elimination of latently infected cells could therefore reduce treatment duration and facilitate immune reconstitution. Here we report an approach to reduce the viral reservoir by activating dormant viral gene expression and directing T lymphocytes to lyse previously latent, HIV-1-infected cells. An immunomodulatory protein was created that combines the specificity of a HIV-1 broadly neutralizing antibody with that of an antibody to the CD3 component of the T-cell receptor. CD3 engagement by the protein can stimulate T-cell activation that induces proviral gene expression in latently infected T cells. It further stimulates CD8 T-cell effector function and redirects T cells to lyse these previously latent-infected cells through recognition of newly expressed Env. This immunomodulatory protein could potentially help to eliminate latently infected cells and deplete the viral reservoir in HIV-1-infected individuals.

Highlights

The treatment of AIDS with combination antiretroviral therapy remains lifelong largely because the virus persists in latent reservoirs
The persistence of latently infected cells during long-term combination antiretroviral therapy in HIV-1infected individuals represents a significant hurdle towards a functional cure for HIV-1
Latent HIV-1 infection of resting memory CD4 þ T cells is established when activated CD4 þ T cells return to a quiescent state or through infection of quiescent T cells

Summary

Introduction

The treatment of AIDS with combination antiretroviral therapy (cART) remains lifelong largely because the virus persists in latent reservoirs. CD3 engagement by the protein can stimulate T-cell activation that induces proviral gene expression in latently infected T cells. A variety of strategies aim to activate HIV gene expression in latently infected cells, which might be eliminated by antiviral drugs or the immune system The ability of an anti-HIV-1/CD3-bispecific protein to activate and redirect T cells to lyse latently infected T cells provides an immunotherapy that may help to reduce the levels of latently infected cells in HIV-1-infected subjects. This immunomodulatory protein was able to both activate CD4 þ T cells latently infected with HIV-1 and redirect CD8 þ T cells to lyse these infected cells through recognition of HIV-1 Env expressed on these previously latent cells

Methods

Results

Conclusion