A model for cofactor use during HIV-1 reverse transcription and nuclear entry

Abstract

Lentiviruses have evolved to infect and replicate in a variety of cell types in vivo whilst avoiding the powerful inhibitory activities of restriction factors or cell autonomous innate immune responses. In this review we offer our opinions on how HIV-1 uses a series of host proteins as cofactors for infection. We present a model that may explain how the capsid protein has a fundamental role in the early part of the viral lifecycle by utilising cyclophilin A (CypA), cleavage and polyadenylation specificity factor-6 (CPSF6), Nup358 and TNPO3 to orchestrate a coordinated process of DNA synthesis, capsid uncoating and integration targeting that evades innate responses and promotes integration into preferred areas of chromatin.

Figure 1

A hypothetical model of cofactor mediated HIV-1 nuclear entry and integration targeting. Shortly after entry into the cytoplasm CypA and CPSF6 are recruited to the viral core. These interactions suppress premature reverse transcription by a mechanism that remains unclear. CPSF6 recruitment allows HIV-1 to utilise the cofactors used by CPSF6 itself for nuclear entry, including TNPO3. At the NPC CA recruits the cyclophilin domain of Nup358. CPSF6 nuclear entry releases the virus enabling DNA synthesis. Nup358 use allows docking or tethering of the reverse transcription complex to the NPC, where appropriately orchestrated uncoating can expose the viral pre-integration complex for interaction with transport factors including TNPO3. In the absence of CypA or CPSF6 interaction, reverse transcription drives cytoplasmic uncoating, leading to Nup358 and TNPO3 independence and retargeted integration. We envisage a complex process of carefully orchestrated simultaneous reverse transcription, uncoating and integration events that have evolved to allow evasion of innate immune sensors. The use of proteins with a role in active transcription such as CPSF6, with its role in RNA 3′ end processing, allows HIV-1 to target transcriptionally active chromatin.