The roles of lipids and nucleic acids in HIV-1 assembly.

Ayna Alfadhli,Eric Barklis

doi:10.3389/fmicb.2014.00253

Abstract

During HIV-1 assembly, precursor Gag (PrGag) proteins are delivered to plasma membrane (PM) assembly sites, where they are triggered to oligomerize and bud from cells as immature virus particles. The delivery and triggering processes are coordinated by the PrGag matrix (MA) and nucleocapsid (NC) domains. Targeting of PrGag proteins to membranes enriched in cholesterol and phosphatidylinositol-4,5-bisphosphate (PI[4,5]P2) is mediated by the MA domain, which also has been shown to bind both RNA and DNA. Evidence suggests that the nucleic-acid-binding function of MA serves to inhibit PrGag binding to inappropriate intracellular membranes, prior to delivery to the PM. At the PM, MA domains putatively trade RNA ligands for PI(4,5)P2 ligands, fostering high-affinity membrane binding. Triggering of oligomerization, budding, and virus particle release results when NC domains on adjacent PrGag proteins bind to viral RNA, leading to capsid (CA) domain oligomerization. This process leads to the assembly of immature virus shells in which hexamers of membrane-bound MA trimers appear to organize above interlinked CA hexamers. Here, we review the functions of retroviral MA proteins, with an emphasis on the nucleic-acid-binding capability of the HIV-1 MA protein, and its effects on membrane binding.

Highlights

FUNCTIONS OF RETROVIRAL MA PROTEINS Retroviruses such as the human immunodeficiency virus (HIV) are membrane-enveloped viruses that bud from the plasma membranes of infected host cells (Coffin et al, 1997; Swanstrom and Wills, 1997; Freed, 1998; Goff, 2001)
In vitro studies have shown direct binding between MA and the cytoplasmic tail (CT) Env in several biochemical experiments for both HIV-1 and Simian immunodeficiency virus (SIV; Cosson, 1996; Wyma et al, 2000; Manrique et al, 2008). Consistent with these observations, structural studies have shown that HIV-1 MA proteins assemble lattices on phosphatidylinositol-(4,5)-bisphosphate (PI[4,5]P2) membranes in which residues implicated in CT binding point toward lattice holes (Yu et al, 1992; Dorfman et al, 1994; Freed and Martin, 1996; Ono et al, 1997; Murakami and Freed, 2000; Davis et al, 2006; Bhatia et al, 2007; Alfadhli et al, 2009a; Checkley et al, 2011; Tedbury et al, 2013)
While the NC domains of retroviral precursor Gag (PrGag) proteins are essential for viral RNA encapsidation, experiments have shown that MA proteins may possess binding functions and can substitute for the HIV-1 NC protein assembly function (Ott et al, 2005). [deletion of the NC domain dramatically reduces the assembly of murine leukemia virus (MLV) particles (Muriaux et al, 2004)]

Summary

Introduction

FUNCTIONS OF RETROVIRAL MA PROTEINS Retroviruses such as the human immunodeficiency virus (HIV) are membrane-enveloped viruses that bud from the plasma membranes of infected host cells (Coffin et al, 1997; Swanstrom and Wills, 1997; Freed, 1998; Goff, 2001). The assembly process of retroviruses appears to be triggered by the association of PrGag proteins with viral RNA (vRNA) at the plasma membrane (Rein, 1994; Spearman et al, 1994; Muriaux et al, 2001; Jouvenet et al, 2006, 2008; Ott et al, 2009).

Results

Conclusion