Structural and mechanistic bases for a potent HIV-1 capsid inhibitor

Bester, S.M.; Wei, Guochao; Zhao, Haiyan; Adu‐Ampratwum, Daniel; Iqbal, Naseer; Courouble, Valentine V; Francis, Ashwanth C.; Annamalai, Arun S.; Singh, Parmit K.; Shkriabai, Nikoloz; Blerkom, Peter Van; Morrison, James H.; Poeschla, Eric M.; Engelman, Alan; Melikyan, Gregory B.; Griffin, Patrick R.; Fuchs, James R.; Asturias, Francisco J.; Kvaratskhelia, Mamuka

doi:10.1126/science.abb4808

Cited by 158 publications

(161 citation statements)

References 57 publications

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“…10f ). Recent reports 34 , 35 have demonstrated that an experimental long-acting HIV-1 CA inhibitor, GS-6207 (Lenacapavir, Gilead Sciences), targets the same hydrophobic cavity. Therefore, future studies are warranted to elucidate how GS-6207 affects Sec24C interactions with incoming HIV-1 cores in the cytoplasm of infected cells.…”

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confidence: 99%

Sec24C is an HIV-1 host dependency factor crucial for virus replication

et al. 2021

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Sec24C is an HIV-1 host dependency factor crucial for virus replication

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“…Nup153 and CPSF6 bind to a conserved hydrophobic binding pocket in the CA NTD, involving α-helices 3 and 4 [ 45 , 46 , 47 , 117 ]. This pocket also binds the antiretroviral small molecules PF74 [ 46 , 119 ], BI-2 [ 46 ], and GS-6207 [ 120 , 121 ]. The CA mutations N74D and A77V disrupt this binding pocket and are widely used to study the function of these host factors.…”

Section: Host Factors That Interact With Hiv-1 Ca Around the Nuclear Pore Complexmentioning

confidence: 99%

The Role of Capsid in HIV-1 Nuclear Entry

Guedán

Caroe

Barr

et al. 2021

Viruses

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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.

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“…This is not good news for the virus, and this viral weakness selects the viral capsid as an exceptional target for a new class of drugs. A recent compound, called Lenacapavir, interferes with the binding of Nup153 and CPSF6 to in vitro assembled cores, stabilizing them [ 140 ]. Thus, Lenacapavir is a first-in-class HIV-1 capsid inhibitor with potent antiviral activity against both wild-type virus and resistant mutants to current antiretroviral agents.…”

Section: Hivmentioning

confidence: 99%

The Viral Capsid: A Master Key to Access the Host Nucleus

Blanco-Rodriguez

Nunzio

2021

Viruses

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Viruses are pathogens that have evolved to hijack the cellular machinery to replicate themselves and spread to new cells. During the course of evolution, viruses developed different strategies to overcome the cellular defenses and create new progeny. Among them, some RNA and many DNA viruses require access to the nucleus to replicate their genome. In non-dividing cells, viruses can only access the nucleus through the nuclear pore complex (NPC). Therefore, viruses have developed strategies to usurp the nuclear transport machinery and gain access to the nucleus. The majority of these viruses use the capsid to manipulate the nuclear import machinery. However, the particular tactics employed by each virus to reach the host chromatin compartment are very different. Nevertheless, they all require some degree of capsid remodeling. Recent notions on the interplay between the viral capsid and cellular factors shine new light on the quest for the nuclear entry step and for the fate of these viruses. In this review, we describe the main components and function of nuclear transport machinery. Next, we discuss selected examples of RNA and DNA viruses (HBV, HSV, adenovirus, and HIV) that remodel their capsid as part of their strategies to access the nucleus and to replicate.

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Structural and mechanistic bases for a potent HIV-1 capsid inhibitor

Cited by 158 publications

References 57 publications

Sec24C is an HIV-1 host dependency factor crucial for virus replication

Sec24C is an HIV-1 host dependency factor crucial for virus replication

The Role of Capsid in HIV-1 Nuclear Entry

The Viral Capsid: A Master Key to Access the Host Nucleus

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