R5 HIV gp120-mediated cellular contacts induce the death of single CCR5-expressing CD4 T cells by a gp41-dependent mechanism
- 16 July 2004
- journal article
- Published by Oxford University Press (OUP) in Journal of Leukocyte Biology
- Vol. 76 (4) , 804-811
- https://doi.org/10.1189/jlb.0204100
Abstract
The use of CXC chemokine receptor 4 (CXCR4) and CC chemokine receptor 5 (CCR5) by X4 and R5 human immunodeficiency virus (HIV) envelopes (Env) influences HIV cytopathicity. Here, we have evaluated the role of CCR5 and gp41 in Env-induced cell death occurring during the contacts of uninfected, primary cells with MOLT cells infected with different R5 and X4 HIV isolates. As reported for X4-Env, R5 HIV-infected cells destroyed CD4 T cells expressing the appropriate coreceptor by inducing the formation of syncytia and the death of single target cells. Therefore, only the small (+ subset of primary CD4 T cells was sensitive to cellular presentation of R5-Env, and CCR5–CD4 T cells showed complete resistance to R5-Env-mediated cell death. X4- and R5-infected cells killed single primary cells by a common mechanism that was dependent on gp41 function and induced a rapid loss of mitochondrial membrane potential and plasma membrane integrity in target cells. Single-cell death was not affected by the blockade of HIV replication in target cells or G-protein signaling through CXCR4/CCR5. In contrast, caspase inhibition (Z-Val-Ala-Asp-fluoromethylketone) profoundly changed the outcome of cell-to-cell contacts by reducing the number of single dead CD4 T cells and increasing the rate of syncytium formation. In conclusion, X4 and R5 HIV Env share a common gp41-dependent mechanism to kill CD4 T cells during cellular contacts. Env tropism and coreceptor expression but not differential killing mechanisms seem to govern the extent of cytopathic effects induced by HIV infection.Keywords
Funding Information
- Fondo de Investigaciones Sanitarias (02/0798)
- Red Cooperativa de Investigación en SIDA
- Ministerio de Ciencia y Tecnología (BFI 03-00405)
- fundacio marato de TV3 (020930)
- European Comission Project (LSHG-CT-2003-503480)
- Fundació IGTP (FIS 98/3047)
This publication has 52 references indexed in Scilit:
- Apoptosis of Bystander T Cells Induced by Human Immunodeficiency Virus Type 1 with Increased Envelope/Receptor Affinity and Coreceptor Binding Site ExposureJournal of Virology, 2004
- Depletion of naive CD4 T cells by CXCR4-using HIV-1 variants occurs mainly through increased T-cell death and activationAIDS, 2003
- Cytolysis by CCR5-Using Human Immunodeficiency Virus Type 1 Envelope Glycoproteins Is Dependent on Membrane Fusion and Can Be Inhibited by High Levels of CD4 ExpressionJournal of Virology, 2003
- Cytopathic Killing of Peripheral Blood CD4+T Lymphocytes by Human Immunodeficiency Virus Type 1 Appears Necrotic rather than Apoptotic and Does Not RequireenvJournal of Virology, 2002
- Death of CD4+T-Cell Lines Caused by Human Immunodeficiency Virus Type 1 Does Not Depend on Caspases or ApoptosisJournal of Virology, 2002
- CD4+ T-cell depletion in HIV infection: Are we closer to understanding the cause?Nature Medicine, 2002
- Preferential and persistent depletion of CCR5+T-helper lymphocytes with nonlymphoid homing potential despite early treatment of primary HIV infectionBlood, 2001
- Chemokine-receptor activation by env determines the mechanism of death in HIV-infected and uninfected T lymphocytesJournal of Clinical Investigation, 2001
- CHEMOKINE RECEPTORS AS HIV-1 CORECEPTORS: Roles in Viral Entry, Tropism, and DiseaseAnnual Review of Immunology, 1999
- Role of the HTLV-III/LAV envelope in syncytium formation and cytopathicityNature, 1986