Abstract
The host immunophilin cyclophilin A (CypA) binds to the capsid protein (CA) of HIV-1 and regulates its infectivity. Depending on the target cell type, CypA can either promote or inhibit HIV-1 infection. The ability of CypA to promote HIV-1 infection has been extensively studied and linked to several steps in early replication including uncoating, reverse transcription and nuclear import. By contrast, the mechanism by which CypA inhibits infection is less well understood. We investigated the mechanism by which CypA potentiates restriction of HIV-1 by the tripartite motif-containing protein 5 (TRIM5α). Depletion of TRIM5α in the African green monkey cell line Vero, resulted in a loss of inhibition of infection by CypA, demonstrating that inhibition by CypA is mediated by TRIM5α. Complementary genetic and biochemical assays failed to demonstrate an ability of CypA to promote binding of TRIM5α to the viral capsid. TRIM5α inhibits HIV-1 reverse transcription in a proteasome-dependent manner; however, we observed that inhibition of proteasome activity did not reduce the ability of CypA to inhibit infection, suggesting that CypA acts at a step after reverse transcription. Accordingly, we observed a CypA-dependent reduction in the accumulation of nuclear HIV-1 DNA, indicating that CypA specifically promotes TRIM5α inhibition of HIV-1 nuclear import. We also observed that the ability of CypA to inhibit HIV-1 infection is abolished by amino acid substitutions within the conserved CPSF6-binding surface in CA. Our results indicate that CypA inhibits HIV-1 infection in Vero cells not by promoting TRIM5α binding to the capsid but by blocking nuclear import of the HIV-1 preintegration complex.
Highlights
In the early stages of human immunodeficiency virus type I (HIV-1) infection, a subviral complex comprised of the capsid (CA) protein shell, the viral genome, and accessory proteins, known as the core, undergoes a controlled disassembly process termed uncoating [1,2,3,4]
To confirm the previously reported ability of cyclophilin A (CypA) to potentiate TRIM5α restriction in old world monkey cells, we examined the effect of inhibiting CypA-CA interactions in Vero cells [20,21,36,44]
CypA depletion increased infectivity of P90A HIV-1 to a much less extent than wild type HIV-1 (Fig 1C). These results indicate that binding of CypA to the incoming viral capsid inhibits HIV-1 infection of Vero cells by a mechanism that depends on expression of TRIM5α
Summary
In the early stages of human immunodeficiency virus type I (HIV-1) infection, a subviral complex comprised of the capsid (CA) protein shell, the viral genome, and accessory proteins, known as the core, undergoes a controlled disassembly process termed uncoating [1,2,3,4]. HIV1 uncoating is influenced by the sequence of HIV-1 CA, and facilitates reverse transcription of viral RNA and particle entry into the nucleus, where the virus gains access to host chromatin [4,5,6]. The role of CA during infection is typically considered in terms of this structural. Cyclophilin A and TRIM5 restriction of HIV-1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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