Viral evasion of DNA-stimulated innate immune responses

Christensen, Maria H; Paludan, Søren R

mediating cell proliferation and oncogenesis. 71 Lau et al. speculated that the LXCXE motifs evolved in these viruses to inhibit STING and hence to facilitate the establishment of infection, and that the oncogenic function of the LXCXE motif may be a secondary effect. This hypothesis is supported by the fact that only a minor group of viruses expressing LXCXE-containing proteins have oncogenic properties. 70 HIV-1 replicates efficiently in human macrophages, and this replication stimulates only modest innate immune responses. 30, 72 Upon cell entry the viral capsid plays an important role in preventing immediate recognition of the viral genome. More host proteins, including the cofactors cleavage and polyadenylation specificity factor subunit 6 (CPSF6) and cyclophilin A (CypA), are known to be recruited to the viral capsid to facilitate virus replication in myeloid cells. [73] [74] [75] The recruitment of CPSF6 to the capsid explains the ability of the pharmaceutical molecule PF-3450074 to block HIV-1 replication. PF-3450074 competes with CPSF6 for binding to the HIV-1 capsid, thus blocking virus replication. 76, 77 Findings by Rasaiyaah et al. 72 showed that the recruitment of specific host proteins to the HIV-1 capsid is necessary for preventing premature DNA synthesis and stimulation of innate DNA receptors. Myeloid cells stimulated with a capsid mutant (P90A) with impaired CypA interaction, produced cGAMP through a mechanism dependent on the reverse transcriptase. This result shows that the HIV-1 genome is recognized by cGAS in cases with non-intact capsids. Hence HIV-1 has evolved a defense against cytosolic detectors, relying on the cloaking of a replication intermediate by the host factors CPSF6 and CypA.