1. DExD/H-box helicases in HIV-1 replication and their inhibition.
- Author
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Heaton, Steven M., Gorry, Paul R., and Borg, Natalie A.
- Subjects
- *
HELICASES , *HIV , *RNA viruses , *DNA helicases , *ANTIRETROVIRAL agents , *RETROVIRUSES , *GUANOSINE triphosphate - Abstract
Antiretroviral therapy (ART) reduces human immunodeficiency virus type 1 (HIV-1) infection, but selection of treatment-refractory variants remains a major challenge. HIV-1 encodes 16 canonical proteins, a small number of which are the singular targets of nearly all antiretrovirals developed to date. Cellular factors are increasingly being explored, which may present more therapeutic targets, more effectively target certain aspects of the viral replication cycle, and/or limit viral escape. Unlike most other positive-sense RNA viruses that encode at least one helicase, retroviruses are limited to the host repertoire. Accordingly, HIV-1 subverts DEAD-box helicase 3X (DDX3X) and numerous other cellular helicases of the Asp-Glu-x-Asp/His (DExD/H)-box family to service multiple aspects of its replication cycle. Here we review DDX3X and other DExD/H-box helicases in HIV-1 replication and their inhibition. Most positive-sense RNA viruses encode at least one helicase, but retroviruses evolved to usurp helicase functionality from the host. Targeting such dependencies has increasingly featured in novel host-oriented antiviral and antiretroviral strategies. Numerous methods for targeting host helicase DDX3X have been developed in recent years, some with anti-HIV-1 activity. With appropriate modification, these may also be amenable to other individual or clades of related DDX/DHX helicases also implicated in HIV-1 replication. The exportin-1-dependent nuclear export mechanism of DDX3X was recently revised to require both a nuclear export signal and Ran–GTP. Further studies investigating the subcellular trafficking mechanisms of DDX3X in the context of HIV-1 infection may reveal new ways to therapeutically target HIV-1. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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