Revisiting HIV-1 uncoating

Abstract

HIV uncoating is defined as the loss of viral capsid that occurs within the cytoplasm of infected cells before entry of the viral genome into the nucleus. It is an obligatory step of HIV-1 early infection and accompanies the transition between reverse transcription complexes (RTCs), in which reverse transcription occurs, and pre-integration complexes (PICs), which are competent to integrate into the host genome. The study of the nature and timing of HIV-1 uncoating has been paved with difficulties, particularly as a result of the vulnerability of the capsid assembly to experimental manipulation. Nevertheless, recent studies of capsid structure, retroviral restriction and mechanisms of nuclear import, as well as the recent expansion of technical advances in genome-wide studies and cell imagery approaches, have substantially changed our understanding of HIV uncoating. Although early work suggested that uncoating occurs immediately following viral entry in the cell, thus attributing a trivial role for the capsid in infected cells, recent data suggest that uncoating occurs several hours later and that capsid has an all-important role in the cell that it infects: for transport towards the nucleus, reverse transcription and nuclear import. Knowing that uncoating occurs at a later stage suggests that the viral capsid interacts extensively with the cytoskeleton and other cytoplasmic components during its transport to the nucleus, which leads to a considerable reassessment of our efforts to identify potential therapeutic targets for HIV therapy. This review discusses our current understanding of HIV uncoating, the functional interplay between infectivity and timely uncoating, as well as exposing the appropriate methods to study uncoating and addressing the many questions that remain unanswered.

Superresolution imaging of HIV in infected cells with FlAsH-PALM

“…Although biochemical analyses of intracellular HIV initially concluded that capsids were lost immediately postfusion (39,40), EM data revealed intact HIV capsids at or near nuclear pores (33) indicating that capsid uncoating does not necessarily precede viral trafficking to the NE. This is further supported by studies showing that premature uncoating upon retroviral restriction leads to abortive infection (41)(42)(43), and mutations in capsid proteins influence the requirement for nuclear pore components (35,(44)(45)(46). Recent work suggests that the trigger for uncoating is linked to the reverse transcription process (33,36).…”

“…ing does not occur randomly in the cytoplasm and is critical for infection; but, the exact timing and location of uncoating has been debated (35)(36)(37)(38). Although biochemical analyses of intracellular HIV initially concluded that capsids were lost immediately postfusion (39,40), EM data revealed intact HIV capsids at or near nuclear pores (33) indicating that capsid uncoating does not necessarily precede viral trafficking to the NE.…”

Polymeric Anti‐HIV Therapeutics

“…[14] The viral and cell surface membrane fusion leads to the release of the virus contents, including the viral capsid which uncoats to release the two copies of RNA, the reverse transcriptase and integrase, via a mechanism that is still poorly understood. [21] The viral RNA is reverse transcribed into double stranded DNA, [22] which is then transported to the cell nucleus as a preintegration complex [23,24] and integrated into the cell genome, catalyzed by the viral integrase. [8] Integration of the viral double stranded DNA in the host genome DNA subsequently leads to the production of mRNA transcripts that are spliced into small pieces that encode the proteins Tat and Rev, which facilitate the export of the unspliced mRNA into the cytoplasm.…”

Molecular Crosstalk between HIV-1 Integration and Host Proteins – Implications for Therapeutics

“…After penetrating the cell membrane, the HIV-1 core particle, which contains genomic RNA and the proteins needed to establish an infection, is first released into the cytoplasm where it then undergoes the uncoating process. Although this uncoating is defined as the loss of HIV-1 capsid (CA) protein after the entry step, the nature and timing of the uncoating process is poorly understood (Arhel, 2010). The formation of the reverse transcription complex (RTC), in which reverse transcription from viral RNA to DNA takes place, accompanies the uncoating of infecting virion core (Warrilow et al, 2009;Arhel, 2010).…”

“…Although this uncoating is defined as the loss of HIV-1 capsid (CA) protein after the entry step, the nature and timing of the uncoating process is poorly understood (Arhel, 2010). The formation of the reverse transcription complex (RTC), in which reverse transcription from viral RNA to DNA takes place, accompanies the uncoating of infecting virion core (Warrilow et al, 2009;Arhel, 2010). Currently, little is known about the components of the RTC, although several studies have shown that matrix (MA), Vpr, RT, and IN are contained in the HIV-1 RTC (Fassati & Goff, 2001;McDonald et al, 2002;Iordanskiy et al, 2006).…”