HIV-1 capsid and viral DNA integration

Abstract

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) genome encodes 15 proteins that perform structural, enzymatic, regulatory, and accessory functions. The capsid protein (CA) is the primary structural protein of HIV-1 and plays multiple functions during infection. Early studies predicted that HIV-1 CA mainly protected and delivered the viral genome to the target cell. However, it is now well established that CA plays a critical role after the cellular entry steps of infection. During the early stages, CA promotes reverse transcription of the RNA genome into a DNA copy and the nuclear import/entry step of HIV-1 infection. Emerging evidence also supports the functional role of CA in the post-nuclear entry steps of infection, such as HIV-1 integration. During the late stages of infection, CA coordinates hexameric lattice formation for the assembly of immature virion. CA also regulates theformation of the mature capsid that encases the viral genome and associated factors in the infectious progeny virion. Because of these indispensable roles, HIV-1 CA has emerged as a new and validated target for antiviral drug development. Accordingly, the first CA-targeting drug, lenacapavir (GS-6207), was recently approved to treat certain HIV-1-infected individuals whose viral load cannot be controlled by other antiviral drugs. Still, new and superior CA inhibitors are needed to qualify as part of the front-line antiviral therapy regimens for all infected individuals. The development of such inhibitors requires a clear understanding of CA’s role in HIV-1 infection. In this review, we will describe CA’s role during the early stages of HIV-1 infection, with particular emphasis on post-nuclear entry steps. IMPORTANCE HIV-1 capsid protein (CA)—independently or by recruiting host factors—mediates several key steps of virus replication in the cytoplasm and nucleus of the target cell. Research in the recent years have established that CA is multifunctional and genetically fragile of all the HIV-1 proteins. Accordingly, CA has emerged as a validated and high priority therapeutic target, and the first CA-targeting antiviral drug was recently approved for treating multi-drug resistant HIV-1 infection. However, development of next generation CA inhibitors depends on a better understanding of CA’s known roles, as well as probing of CA’s novel roles, in HIV-1 replication. In this timely review, we present an updated overview of the current state of our understanding of CA’s multifunctional role in HIV-1 replication—with a special emphasis on CA’s newfound post-nuclear roles, highlight the pressing knowledge gaps, and discuss directions for future research.