Immunodeficiency virus uptake, turnover, and 2-phase transfer in human dendritic cells

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Human immunodeficiency virus type 1 (HIV-1) infection involves dendritic cells (DCs) in viral uptake, infection, and subsequent transfer to T cells.
• DCs play a critical role in initiating adaptive immune responses, but HIV-1 exploits them for viral dissemination.
• Understanding the mechanisms of HIV-1 transfer from DCs to lymphocytes is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To elucidate the distinct phases and mechanisms by which dendritic cells (DCs) transfer HIV-1 to CD4+ lymphocytes.
• To investigate the role of endolysosomal trafficking and de novo viral production in HIV-1 transfer.
• To resolve the controversy regarding DC infection status in the context of HIV-1 transfer dynamics.

Main Methods:

• Comparative analysis of monomeric gp120 and HIV-1 binding and colocalization with endolysosomal markers in DCs.
• Tracking of viral intracellular trafficking and movement to DC-CD4+ lymphocyte synapses.
• Assessment of viral transfer kinetics and dependence on de novo HIV-1 production using assays like zidovudine sensitivity.
• Distinguishing transfer phases in immature versus mature DCs.

Main Results:

• HIV-1, unlike gp120, rarely colocalized with endolysosomal markers, indicating altered trafficking pathways.
• An initial transient transfer of HIV-1 to CD4+ lymphocytes occurred within 24 hours from nonlysosomal compartments via the DC-T-cell synapse.
• A second, long-term transfer phase was observed in immature DCs after 48 hours, characterized by a zidovudine-sensitive increase in proviral DNA, suggesting de novo HIV-1 production.

Conclusions:

• Dendritic cells (DCs) mediate HIV-1 transfer to CD4+ lymphocytes through two distinct temporal phases.
• The early phase involves rapid transfer from nonlysosomal compartments to the DC-T-cell synapse.
• The later phase, particularly in immature DCs, is dependent on de novo HIV-1 production, clarifying the role of DC infection in viral transmission.