SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Monocyte-derived dendritic cells (MDDC) present viral antigens via MHC-I molecules to CD8 cytotoxic T lymphocytes (CTL).
• Human immunodeficiency virus type 1 (HIV-1) infection of MDDC is restricted by SAMHD1, an enzyme depleting deoxynucleoside triphosphates (dNTPs) and degrading viral RNA.
• Vpx protein antagonizes SAMHD1 by inducing its degradation, but SAMHD1's role in adaptive immunity is unclear.

Purpose of the Study:

• To investigate whether SAMHD1 modulates MHC-I-restricted HIV-1 antigen presentation in MDDC.
• To understand the impact of SAMHD1 on HIV-1 replication and subsequent adaptive cellular immune responses.

Main Methods:

• MDDC were exposed to HIV-1, with or without Vpx pretreatment to deplete SAMHD1.
• Antigen presentation was assessed by monitoring the activation of an HIV-1 Gag-specific CTL clone.
• Time-lapse microscopy was used to observe CTL-mediated killing of infected MDDC.
• Transmitted/founder (T/F) HIV-1 strains and VSV-G pseudotyped T/F viruses were used to study entry-dependent antigen presentation.

Main Results:

• SAMHD1 depletion significantly enhanced productive HIV-1 infection and endogenous antigen presentation in MDDC.
• Absence of SAMHD1 led to rapid killing of infected MDDC by CTL.
• Most T/F HIV-1 strains poorly infected MDDC and did not stimulate CTL.
• VSV-G pseudotyping of T/F HIV-1 induced antigen presentation only in SAMHD1-depleted MDDC.
• SAMHD1 did not affect exogenous viral antigen presentation.

Conclusions:

• The antiviral SAMHD1 restricts HIV-1 antigen presentation by DCs, impacting adaptive immune responses.
• SAMHD1's role in restricting viral replication is directly linked to its influence on antigen presentation and CTL activation.
• These findings highlight the interplay between viral restriction factors and the adaptive cellular immune system.