The Role of Capsid in HIV-1 Nuclear Entry

Abstract

HIV-1 can infect non-dividing cells. The nuclear envelope therefore represents a barrier that HIV-1 must traverse in order to gain access to the host cell chromatin for integration. Hence, nuclear entry is a critical step in the early stages of HIV-1 replication. Following membrane fusion, the viral capsid (CA) lattice, which forms the outer face of the retroviral core, makes numerous interactions with cellular proteins that orchestrate the progress of HIV-1 through the replication cycle. The ability of CA to interact with nuclear pore proteins and other host factors around the nuclear pore determines whether nuclear entry occurs. Uncoating, the process by which the CA lattice opens and/or disassembles, is another critical step that must occur prior to integration. Both early and delayed uncoating have detrimental effects on viral infectivity. How uncoating relates to nuclear entry is currently hotly debated. Recent technological advances have led to intense discussions about the timing, location, and requirements for uncoating and have prompted the field to consider alternative uncoating scenarios that presently focus on uncoating at the nuclear pore and within the nuclear compartment. This review describes recent advances in the study of HIV-1 nuclear entry, outlines the interactions of the retroviral CA protein, and discusses the challenges of investigating HIV-1 uncoating.

Keywords: HIV-1; NPC; capsid; core; nuclear entry; uncoating.

Figure 1

The HIV-1 core and the human NPC. (A) Diagram illustrating how CA assembles to form the fullerene shape of the HIV-1 core, where CA N-terminal domain hexamers are shown in orange and CA N-terminal domain pentamers are shown in green. Core measurements shown in red are taken from [7]. (B) Diagram of the human NPC highlighting relevant features, labelled with dashed lines. Pore measurements shown in red are taken from [35,36]. CNT = channel nucleoporin heterotrimer; FG repeats = phenylalanine-glycine repeats.

Figure 2

Models for HIV-1 uncoating. HIV-1 uncoating has been proposed to occur either early in the cytoplasm, at the NPC or after nuclear entry. The three possibilities are depicted, with host factors involved in uncoating and nuclear entry illustrated. Figure adapted from [57].