HIV-1 uncoating: connection to nuclear entry and regulation by host proteins

Abstract

The RNA genome of human immunodeficiency virus type 1 (HIV-1) is enclosed by a capsid shell that dissociates within the cell in a multistep process known as uncoating, which influences completion of reverse transcription of the viral genome. Double-stranded viral DNA is imported into the nucleus for integration into the host genome, a hallmark of retroviral infection. Reverse transcription, nuclear entry, and integration are coordinated by a capsid uncoating process that is regulated by cellular proteins. Although uncoating is not well understood, recent studies have revealed insights into the process, particularly with respect to nuclear import pathways and protection of the viral genome from DNA sensors. Understanding uncoating will be valuable toward developing novel antiretroviral therapies for HIV-infected individuals.

Keywords: Capsid; HIV-1; Human immunodefiency virus; Nuclear entry; Uncoating; Virus–host interactions.

Figure 1

HIV-1 uncoating is linked to reverse transcription and nuclear import and requires host cell factors. (A) Core opening likely involves multiple steps and utilizes CypA in a cell type-dependent manner to protect the viral DNA genome until nuclear entry, which is facilitated by CA binding of host cell proteins TNPO3, CPSF6, and components of the nuclear pore complex (NUP153 and NUP358). (B) CA mutants, CypA depletion, and CPSF6 depletion induces premature uncoating distal from the nucleus. Exposed viral DNA stimulates an innate immune response via detection of DNA sensors. The resulting IFN response induces expression of MX2, a host factor that prevents viral DNA nuclear entry. (C) Uncoating is accelerated by small molecule inhibitors and nonhuman primate restriction factors, rhTRIM5α and TRIMCyp. Premature uncoating leads to reduced reverse transcription and little nuclear import of viral DNA.