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M-Sec facilitates intercellular transmission of HIV-1 through multiple mechanisms
Sameh Lotfi1,2, Hesham Nasser1,2,3, Osamu Noyori1,2
1Division of Infection & Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811, Japan.
Background:
HIV-1 promotes the formation of tunneling nanotubes (TNTs) that connect distant cells, aiding cell-to-cell viral transmission between macrophages. Our recent study suggests that the cellular protein M-Sec plays a role in these processes. However, the timing, mechanism, and to what extent M-Sec contributes to HIV-1 transmission is not fully understood, and the lack of a cell line model that mimics macrophages has hindered in-depth analysis.
Results:
We found that HIV-1 increased the number, length and thickness of TNTs in a manner dependent on its pathogenic protein Nef and M-Sec in U87 cells, as observed in macrophages. In addition, we found that M-Sec was required not only for TNT formation but also motility of U87 cells, both of which are beneficial for viral transmission. In fact, M-Sec knockdown in U87 cells led to a significantly delayed viral production in both cellular and extracellular fractions. This inhibition was observed for wild-type virus, but not for a mutant virus lacking Nef, which is known to promote not only TNT formation but also migration of infected macrophages.
Conclusions:
By taking advantage of useful features of U87 cells, we provided evidence that M-Sec mediates a rapid and efficient cell-cell transmission of HIV-1 at an early phase of infection by enhancing both TNT formation and cell motility.
Insights
The cellular protein M-Sec enhances human immunodeficiency virus type 1 (HIV-1) transmission by promoting tunneling nanotubes (TNTs) and cell motility. M-Sec is crucial for early-stage viral spread, particularly when the Nef protein is present.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Human immunodeficiency virus type 1 (HIV-1) utilizes tunneling nanotubes (TNTs) for cell-to-cell transmission, particularly between macrophages.
- The cellular protein M-Sec is implicated in TNT formation and viral spread, but its precise role in HIV-1 transmission remains unclear.
- A lack of suitable cell models has limited detailed investigation into M-Sec's function in HIV-1 transmission.
Purpose of the Study:
- To investigate the role of M-Sec in HIV-1 transmission using a U87 cell line model.
- To elucidate the mechanism by which M-Sec influences TNT formation and cell motility during HIV-1 infection.
- To determine the contribution of M-Sec to early-stage viral spread.
Main Methods:
- Utilized U87 cells, a glioblastoma cell line, as a model system to study HIV-1 and M-Sec interactions.
- Analyzed the impact of HIV-1 infection on TNT formation (number, length, thickness) in U87 cells.
- Assessed the requirement of M-Sec and the viral Nef protein for TNT formation and cell motility.
- Quantified viral production in cellular and extracellular fractions following M-Sec knockdown.
Main Results:
- HIV-1 infection increased TNT formation in U87 cells, dependent on both M-Sec and the viral Nef protein.
- M-Sec was essential for both TNT formation and U87 cell motility, facilitating viral transmission.
- M-Sec knockdown significantly delayed viral production in both cellular and extracellular compartments.
- The inhibitory effect of M-Sec knockdown was observed for wild-type HIV-1 but not for Nef-deficient virus.
Conclusions:
- M-Sec plays a critical role in mediating rapid and efficient cell-to-cell transmission of HIV-1.
- M-Sec enhances HIV-1 spread by promoting both TNT formation and host cell motility.
- The findings highlight M-Sec's importance in early-stage HIV-1 infection, particularly in the context of Nef activity.
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