The mammalian genome encodes a variety of pathogen recognition receptors (PRRs) specifically involved in the recognition of nucleic acids. Efforts to identify sensors and decipher the mechanisms underlying the innate immune responses that follow nucleic acid detection have largely revolved around studying the interactions of viruses and mammalian cells. Viruses replicate their genomes within host cells and must avoid detection of their nucleic acids by the host cell. The lentivirus HIV-1 is no exception. HIV-1 converts its ssRNA genome into a linear dsDNA within a complex of virion proteins that facilitates the import of the vDNA into the host nucleus where it is integrated into the host genome. Upon entry into host cells, HIV-1 genomic RNA is surrounded by a core composed primarily of CA. Before the HIV-1 core is imported into the nucleus, it appears to shed at least a portion of its CA molecules in a process known as uncoating. Uncoating is thought to be required for the dsDNA contained in the PIC to engage and pass through the host NPC. The precise mechanism and kinetics of HIV-1 uncoating remain unclear. There is evidence to suggest that HIV-1 uncoats after completing reverse transcription and docking at the NPC, suggesting that reverse transcription and uncoating are tightly coupled. It is during the uncoating process that the HIV-1 reverse transcription products would be susceptible to sensing by host cell innate signaling machinery. Thus, the viral and host factors that contribute to HIV uncoating are of particular interest. The mechanism of CA loss during HIV-1 infection appears to be a regulated process. Certain mutations in CA have been shown to negatively impact overall stability of the core and are thought to lead to premature uncoating. In addition, CA variants that either enhance or reduce the stability of the core impair reverse transcription, reinforcing the idea that reverse transcription and uncoating are tightly coupled. Although uncoating has not been directly linked to the induction of innate immune responses in cells, several studies have implicated CA. The retroviral restriction factor TRIM5 was found to initiate MAP kinase and NF-kB signaling in response to sensing of HIV-1 CA. Studies in dendritic cells have shown that newly synthesized HIV-1 CA has a role in the stimulation of an IFN response. Capsid proteins from other viruses have been shown to play a role in preventing type I IFN induction. Degradation of Herpes Simplex Virus capsid led to detection of viral DNA by macrophages. In addition, MLV glycosylated Gag protein was shown to enhance the stability of the viral core and prevent detection of viral reverse transcription products by host cytosolic sensors. There is evidence that HIV-1 reverse transcription products are able to trigger an innate immune response during infection, and it is reasonable to predict that HIV-1 CA prevents the detection of viral DNA prior to uncoating. Cells deficient in the DNA 3' repair exonuclease 1 (TREX1) produce high levels of type I IFN in response to HIV-1 infection, suggesting that viral DNA products can stimulate an immune response if they are not degraded by this exonuclease. In addition, a recent study identified cyclic-GMP-AMP synthase (cGAS) as an HIV-1 DNA sensor whose activation leads to type I IFN induction. It has also been suggested that CA-interacting host factors, such as CypA and CPSF6, could modulate the cytoplasmic exposure of HIV-1 DNA to cGAS or other cytoplasmic DNA receptors. We are investigating the coordination between HIV-1 reverse transcription and uncoating in minimizing exposure of vDNA to sensors such as cGAS.
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