In a mature, infectious HIV-1 virion, the viral genome is housed within a conical capsid core made up of the viral capsid (CA) protein. During infection, the CA protein interacts with several cellular factors to enable efficient HIV-1 genome replication, timely core disassembly, nuclear import and the integration of the viral genome into the genome of the target cell.
Several models of capsid core uncoating have been proposed, including immediate uncoating, cytoplasmic uncoating and uncoating at nuclear pores. The first model suggests that the HIV-1 capsid core dissociates almost immediately on viral entry; the second is a model of gradual uncoating as the virus travels through the cytoplasm until it reaches the nucleus; and the final model suggests that an intact capsid core reaches the nuclear pore complexes (NPCs). These models may not be mutually exclusive and could depend on the type of cell infected and its status of activation.
Both viral and cellular factors are important for regulating viral uncoating. For example, the activity of viral integrase has been shown to affect the stability of the viral capsid core. The stability of the capsid core is also influenced by interactions between CA and the host protein cyclophilin A and microtubule motor proteins, such as dynein and kinesin-1.
The viral capsid also influences nuclear import via interactions with host proteins, such as cleavage and polyadenylation specificity factor 6 (CPSF6), transportin 3 (TNPO3) and proteins that are part of NPCs.
Understanding the viral uncoating process and the role of CA during infection will enable the design of new therapeutic strategies against HIV-1, including the development of compounds that affect the stability of the capsid core.
In a mature, infectious HIV-1 virion, the viral genome is housed within a conical capsid core made from the viral capsid (CA) protein. The CA protein and the structure into which it assembles facilitate virtually every step of infection through a series of interactions with multiple host cell factors. This Review describes our understanding of the interactions between the viral capsid core and several cellular factors that enable efficient HIV-1 genome replication, timely core disassembly, nuclear import and the integration of the viral genome into the genome of the target cell. We then discuss how elucidating these interactions can reveal new targets for therapeutic interactions against HIV-1.
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The authors thank O. Pornillos and J. Luban for discussions.
The authors declare no competing financial interests.
A genus of retroviruses. Genus members include HIV-1 and related primate immunodeficiency viruses. Lentiviruses are distinguished by the expression of specific regulatory proteins and the ability to infect non-dividing cells.
- Antiretroviral therapy
Treatment using a combination of pharmacological inhibitors of viral enzymes (including reverse transcriptase, protease and, more recently, integrase), which together potently suppress viral replication, reduce viral load and prevent the development of acquired immune deficiency syndrome (AIDS) in patients with HIV.
An enzyme that breaks down proteins into smaller substrates. All retroviruses express an aspartyl protease, which cleaves immature polyproteins incorporated into virions, including Gag and less-abundant Gag–Pro and Gag–Pro–Pol polyproteins. This protease is a critical target of antiretroviral therapy, as polyprotein cleavage is absolutely necessary for viral infectivity.
- Fullerene cone
A closed conical structure primarily made of linked hexagonal rings. The term 'fullerene' was originally used to describe hollow carbon structures that adopt spherical or elliptical shapes. This shape is also adopted by the hexamers and pentamers of capsid protein that form the viral core of HIV.
- Reverse transcriptase
An enzyme that generates cDNA from RNA. All retroviruses express a reverse transcriptase enzyme, a DNA polymerase that copies the viral genomic RNA in the process of reverse transcription. During this process, reverse transcriptase uses both RNA and DNA templates to generate a linear, double-stranded DNA genome. This enzyme is a critical target of antiretroviral therapy.
An enzyme that catalyses the integration of DNA segments with longer DNA chains. All retroviruses express an integrase enzyme, which is responsible for inserting the double-stranded DNA genome generated by reverse transcriptase into the host-cell DNA.
- Cyclic GMP–AMP synthase
(cGAS). An intrinsic sensor of cytosolic DNA that, when activated, initiates the expression of interferon-dependent genes associated with the antiviral state.
- Three-prime repair exonuclease 1
(TREX1). A cytosolic exonuclease that degrades HIV-1 DNA accumulated in target cells. Despite this seemingly antiviral function, TREX1-mediated degradation of viral DNA products correlates with an inhibition of innate immune sensors leading to type I interferon activation.
- Reverse transcription complex
(RTC). The term used for viral ribonucleoprotein after it has entered the target cell and begun reverse transcription of its RNA genome. As reverse transcription is thought to initiate rapidly after fusion, we use this term to generically describe the infectious viral complex following fusion.
- Simple retroviruses
Basic retroviruses, such as murine leukaemia virus, that contain only the genes gag (which encodes viral structural proteins, such as matrix and capsid), pro (which encodes the viral protease), pol (which encodes the reverse transcriptase and integrase proteins) and env (which encodes the viral protein envelope).
- Nuclear pore complexes
(NPCs). Large (∼50 mDa) multiprotein assemblies that govern transport across the nuclear envelope. NPCs are made up of approximately 30 different proteins, termed nucleoporins.
- Restriction factors
Proteins with antiviral activity when expressed in cells. Generally, such antiviral proteins exhibit signs of positive selective pressure and viruses show clear evidence of adaptation designed to mitigate the antiviral activity.
- Antiviral state
A generalized description of the state induced following induction of interferon-stimulated genes, which collectively act to reduce infection by a broad range of viruses.
- Pre-integration complex
(PIC). Following the completion of reverse transcription, integrase-mediated endonuclease priming of the 5′- and 3′-ends of the genome generates a replicative intermediate capable of integrating into target DNA. We use the term PIC when the ability to integrate into surrogate DNA has been demonstrated in specific studies.
A microtubule motor protein in cells that couples ATP hydrolysis with mechanical movement of cellular cargos. Dynein transports cargos towards the minus end of the microtubule, which is typically at the microtubule-organizing centre adjacent to the nucleus.
A component of the cytoskeleton that is formed from polymerized tubulin. It provides the framework necessary for dynein and kinesin motors to transport numerous cargos, including viruses, that are otherwise too large to diffuse through the protein-dense cytoplasm.
A motor protein that couples ATP hydrolysis with mechanical movement of cargos, in a manner similar to dynein. However, unlike dynein, there are many types of kinesins, and these motors typically traffic cargos towards the plus ends of microtubules, away from the nucleus.
- Two-long-terminal-repeat circles
(2-LTR circles). Loops of genome and LTRs. The completely reverse-transcribed HIV-1 genome is flanked on either side by LTRs, which ultimately define the genomic boundaries of the provirus following successful integration. At a low frequency, the cellular non-homologous end joining (NHEJ) repair pathway joins the LTRs, resulting in 2-LTR circles. As the NHEJ pathway is active only in the nucleus, the presence of 2-LTR circles is used as a surrogate for nuclear entry of the pre-integration complex.
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Campbell, E., Hope, T. HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat Rev Microbiol 13, 471–483 (2015). https://doi.org/10.1038/nrmicro3503
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