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J Virol. 2019 Mar 6. pii: JVI.01901-18. doi: 10.1128/JVI.01901-18. [Epub ahead of print]

CD4- and time-dependent susceptibility of HIV-1-infected cells to ADCC.

Author information

1
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
2
Centre de Recherche du CHUM, Montreal, QC, Canada.
3
Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada.
4
Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.
5
Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC, Australia.
6
Infectious Diseases Division, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
7
Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
8
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia skent@unimelb.edu.au.
9
Melbourne Sexual Health Centre and Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia.
10
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Melbourne, VIC, Australia.

Abstract

HIV-1-specific antibody-dependent cellular cytotoxicity (ADCC) antibodies within HIV-1+ individuals predominantly target CD4-induced (CD4i) epitopes on HIV-1 envelope glycoprotein (Env). These CD4i epitopes are usually concealed on the surface of infected cells due to CD4-downregulation by the HIV-1 accessory proteins Nef and Vpu. We hypothesized that early-stage infected cells in the process of downregulating CD4 could be more susceptible to ADCC compared to late-stage infected cells that have fully downregulated CD4. There was significantly higher binding of antibodies within plasma from HIV-1-infected individuals to early-stage CD4-intermediate infected cells compared to late-stage CD4-low infected cells. However, we noted HIV-1-uninfected bystander cells and HIV-1-infected cells, at various stages of downregulating CD4, were all susceptible to NK cell-mediated ADCC. Importantly, we observed that the cytolysis of bystander cells and early infected cells in this culture system was driven by sensitization of target cells by inoculum-derived HIV-1 Env or virions. This phenomenon provided Env to target cells prior to de novo Env expression, resulting in artefactual ADCC measurements. Future studies should take into consideration the inherent caveats of in vitro infection systems and develop improved models to address the potential role for ADCC against cells with nascent HIV-1 infection.IMPORTANCEAn increasing body of evidence suggests that ADCC contributes to protection against HIV-1 acquisition and slower HIV-1 disease progression. Targeting cells early during the infection cycle would be most effective in limiting virus production and spread. We hypothesized that there could be a time-dependent susceptibility of HIV-1-infected cells to ADCC in regard to CD4 expression. We observed NK cell-mediated ADCC of HIV-1-infected cells at multiple stages of CD4 downregulation. Importantly, ADCC of early infected cells appeared to be driven by a previously unappreciated problem of soluble Env and virions from the viral inoculum sensitizing uninfected cells to ADCC prior to de novo Env expression. These results have implications for studies examining ADCC against cells with nascent HIV-1 infection.

PMID:
30842324
DOI:
10.1128/JVI.01901-18

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