Innate immune sensing of HIV-1 by dendritic cells

Abstract

HIV-1-specific antibodies and CD8(+) cytotoxic T cells are detected in most HIV-1-infected people, yet HIV-1 infection is not eradicated. Contributing to the failure to mount a sterilizing immune response may be the inability of antigen-presenting dendritic cells (DCs) to sense HIV-1 during acute infection, and thus the inability to effectively prime naive, HIV-1-specific T cells. Recent findings related to DC-expressed innate immune factors including SAMHD1, TREX1, and TRIM5 provide a molecular basis for understanding why DCs fail to adequately sense invasion by this deadly pathogen and suggest experimental approaches to improve T cell priming to HIV-1 in prophylactic vaccination protocols.

Figure 1. Dendritic cells provide multiple signals to naïve T cells

The innate immune system instructs the acquired immune system via a diverse set of signals that dendritic cells provide to naïve, antigen-specific T cells. A range of outcomes are possible - from tolerance to potent antiviral immunity - depending upon the exact signals provided. Protective antiviral immunity requires that naïve T cells specific for viral antigens receive 3 signals from DCs (Reis e Sousa, 2006). Elaboration of the three signals requires DC maturation, most effectively attained by activation of cell-intrinsic pattern recognition receptors. The first signal involves antigen presentation via MHC. The second signal is provided by cell surface molecules that include CD80 and CD86. The third signal is delivered by cytokines that include IL-12, the structure of which is shown (PDB:1F45) (Yoon et al., 2000); the two IL-12 subunits are distinguished from each other by red (IL12A, p35) and blue (IL12B, p40).

Figure 2. HIV-1 virion interaction with dendritic cells is dominated by non-productive entry pathways

Productive infection requires that HIV-1 virions gain access to the target cell cytoplasm via HIV-1 glycoprotein (gp120/gp41) interacting with host cell receptors (CD4 and either CCR5 or CXCR4). Cell surface levels of CD4 are low on many types of dendritic cells, and HIV-1 virions are endocytosed via interaction with cell surface lectins such as DC-SIGN. Replication of the HIV-1 genomic RNA (green lines) does not occur within the endocytic compartment and innate immune signaling is not activated within conventional, antigen-presenting DCs. However, the endocytosed virion is degraded and HIV-1 proteins are therefore efficiently presented in the absence of DC maturation. Alternatively, the glycosphingolipid GM3 in the HIV-1 virion membrane is recognized by an unknown receptor on DCs (designated X). This results in virion capture and transfer to susceptible CD4⁺ T cells via infectious synapses.

Figure 3. Bypass of the block to productive entry reveals a block to HIV-1 reverse transcription in DCs due to SAMHD1

The block to productive entry can be overcome experimentally by producing HIV-1 virions bearing the vesicular stomatitis virus glycoprotein (VSV G). Once in the dendritic cell cytoplasm, HIV-1 virions fail to reverse transcribe the viral genomic RNA template (green), into viral cDNA (red), because the dNTP concentration is too low to support cDNA synthesis. This block to reverse transcription is due to the dNTP triphosphohydrolase SAMHD1.

Figure 4. The human exonuclease TREX1 limits the level of HIV-1 cDNA

HIV-1 reverse transcriptase generates a cDNA (red lines) from the HIV-1 genomic RNA (green) in the target cell cytoplasm. Normally, the HIV-1 cDNA is not detected by pattern recognition receptors (PRRs) that recognize DNA in the cytoplasm. When the host cell TREX1 nuclease is disrupted, either by mutation or by siRNA, HIV-1 cDNA accumulates to supra-normal levels and activates type 1 IFN. Though several candidate receptors exist (e.g., IFI16), the cell intrinsic PRR that recognizes HIV-1 cDNA under these conditions has not been identified.

Figure 5. TRIM5 is a pattern recognition receptor specific for the retrovirus capsid lattice

The cytoplasmic E3 ubiquitin ligase TRIM5 exists as a dimer in the cytoplasm where it signals weakly or not at all. Upon infection with a retrovirus, if avidity for the capsid lattice is great enough, TRIM5 multimerizes to form a complementary lattice (Ganser-Pornillos et al., 2011) and E3 ubiquitin ligase activity is increased (Pertel et al., 2011a). In complex with the heterodimeric E2 (UBC13/UEV1A), TRIM5 synthesizes unattached K63-linked ubiquitin chains that activate the TAK1 kinase complex and innate immune signaling (Pertel et al., 2011a). Most HIV-1 strains (blue capsid) are only weakly detected by the human TRIM5 orthologue. HIV-1 capsid variants that are better recognized by human TRIM5 (orange capsid) would increase innate immune signaling, and might make better immunogens.