HIV-1 inhibits IFITM3 expression to promote the infection of megakaryocytes

Area of Science:

• Virology
• Immunology
• Hematology

Background:

• Despite effective antiretroviral therapy (ART), some individuals with human immunodeficiency virus type 1 (HIV-1) exhibit poor immune reconstitution and harbor infectious HIV-1 in platelets.
• Megakaryocytes, the precursors to platelets, are implicated as the cellular origin of these HIV-1-containing platelets.

Purpose of the Study:

• To investigate the mechanisms by which megakaryocytes support HIV-1 infection.
• To determine the role of interferon-induced transmembrane protein 3 (IFITM3) in HIV-1 infection of megakaryocytes.

Main Methods:

• Established in vitro models using hematopoietic stem cell-derived megakaryocytes and the MEG-01 cell line.
• Analyzed HIV-1 DNA integration, viral production, protein/RNA compartmentalization, and IFITM3 expression.
• Utilized IFITM3 knockdown in MEG-01 cells to assess its impact on HIV-1 infection.

Main Results:

• HIV-1 proviral DNA integrated into the megakaryocyte genome.
• HIV-1 production was self-limiting, with viral components compartmentalized within infected cells.
• Interferon-induced transmembrane protein 3 (IFITM3) expression was suppressed in terminally differentiated HIV-1-infected megakaryocytes.
• IFITM3 knockdown enhanced HIV-1 infection, identifying IFITM3 as an HIV-1 restriction factor in megakaryocytes.

Conclusions:

• Megakaryocyte precursors are susceptible to HIV-1 infection.
• Terminally differentiated megakaryocytes can harbor HIV-1, potentially forming a neglected viral reservoir.
• IFITM3 plays a crucial role in restricting HIV-1 replication within megakaryocytes.
• Further research into megakaryocytes as an HIV-1 reservoir may inform improved therapies and eradication strategies.