Related Experiment Video
Updated: Jun 18, 2025
New Tools to Expand Regulatory T Cells from HIV-1-infected Individuals
Published on: May 30, 2013
MARCH2, a T cell specific factor that restricts HIV-1 infection
Supawadee Umthong1,2, Uddhav Timilsina1, Mary R D'Angelo1
1Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, United States of America.
Abstract:
Membrane-associated RING-CH (MARCH) 2 is a member of the MARCH protein family of RING-CH finger E3 ubiquitin ligases that play important roles in regulating the levels of proteins found on the cell surface. MARCH1, 2 and 8 inhibit HIV-1 infection by preventing the incorporation of the envelope glycoproteins into nascent virions. However, a better understanding of the mechanism utilized by MARCH proteins to restrict HIV-1 infection is needed. In this report, we identify an amino acid in human MARCH2, absent in mouse MARCH2, critical for its antiretroviral function. Moreover, we map the domains of human MARCH2 critical for restricting as well as binding to the HIV-1 envelope glycoproteins. In addition, we demonstrate that MARCH2 is present inside nascent virions and reduces particle infectivity by blocking virus entry in a RING-CH-independent manner. Finally, we show that MARCH2 acts as an HIV-1 restriction factor only in primary CD4+ T cells and can prevent cell-to-cell transmission of HIV-1. Our findings reveal important new aspects of the antiviral mechanism utilized by human MARCH2 to restrict HIV-1 that have potential implications to all MARCH proteins with antiviral functions and their viral targets.
Insights
Human Membrane-associated RING-CH (MARCH) 2 protein restricts HIV-1 infection by blocking viral entry and cell-to-cell transmission, particularly in CD4+ T cells. This antiviral function involves specific amino acids and domains critical for its activity.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Membrane-associated RING-CH (MARCH) 2 is an E3 ubiquitin ligase regulating cell surface proteins.
- MARCH proteins, including MARCH1, 2, and 8, inhibit HIV-1 by preventing envelope glycoprotein incorporation into virions.
- The precise mechanism of MARCH protein-mediated HIV-1 restriction requires further elucidation.
Purpose of the Study:
- To identify key features of human MARCH2 essential for its antiretroviral function.
- To investigate the mechanism by which MARCH2 restricts HIV-1 infection.
- To determine the cellular context and transmission routes affected by MARCH2.
Main Methods:
- Amino acid and domain mapping of human MARCH2.
- Analysis of MARCH2 localization within nascent virions.
- Assessment of MARCH2's impact on HIV-1 infectivity and entry.
- Evaluation of MARCH2's role in primary CD4+ T cells and cell-to-cell transmission.
Main Results:
- A specific amino acid in human MARCH2, absent in mouse MARCH2, is critical for antiretroviral activity.
- Domains of human MARCH2 essential for HIV-1 envelope glycoprotein binding and restriction were identified.
- MARCH2 was found within nascent virions, reducing infectivity by blocking virus entry independently of its RING-CH domain.
- MARCH2 functions as an HIV-1 restriction factor specifically in primary CD4+ T cells, inhibiting cell-to-cell transmission.
Conclusions:
- Human MARCH2 possesses a unique antiretroviral mechanism involving intracellular localization and entry inhibition.
- Specific molecular determinants within MARCH2 dictate its interaction with HIV-1 and its restriction capability.
- MARCH2's role as a restriction factor in CD4+ T cells highlights its importance in controlling HIV-1 spread and has implications for other MARCH proteins and viral targets.
Related Concept Videos
01:22T Cell Activation and Clonal Selection
Naive T cells that have not yet encountered an antigen express two primary CD...
01:24T Cell Types and Functions
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
01:29Immune Response Against Viral Pathogens
NK Cells
NK cells are a crucial part of our innate immune system, acting as the first line of defense against viral infections. These cells can recognize and kill infected cells without prior exposure to the virus, effectively slowing down the spread of infection. Additionally, NK cells produce proinflammatory...
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...