HIV-1 Assembly at the Plasma Membrane: Gag Trafficking and Localization

Abstract

Virus particle formation of HIV-1 is a multi-step process driven by a viral structural protein Gag. This process takes place at the plasma membrane in most cell types. However, the pathway that directs Gag to the plasma membrane has recently come under intense scrutiny because of its importance in production of progeny virions as well as virus transmission at cell-cell contacts. This review highlights recent advances in our current understanding of mechanisms that traffic and localize Gag to the plasma membrane. In addition, findings on Gag association with specific plasma membrane domains are discussed in light of potential roles in cell-to-cell transmission.

Figure 1

Organization of Gag domains and steps in HIV-1 particle production. A) The major Gag domains, MA, CA, NC, and p6, as well as the spacer peptides SP1 and SP2 are shown. N-terminal myristate moiety is shown as (m-). Positions of functional domains are also indicated. Upon virus release, the viral protease cleaves Pr55^Gag and gives rise to individual mature Gag proteins from four major domains of Pr55^Gag. B) Major steps of virus particle assembly and release are shown.

Figure 2

Potential involvement of endosomal trafficking pathways in Gag targeting. A) The major organelles and routes in endosomal trafficking pathways are shown. EE/SE, early endosome/sorting endosome; LE/MVB, late endosome/multivesicular body; RE, recycling endosome; TGN, trans-Golgi network. B) Potential Gag trafficking routes. Gag may be either directly targeted to the PM (pathway 1) or transported to the PM through endosomal trafficking routes (pathway 2). Along the latter pathway, Gag may form virus particles inside the endosomal lumen and later get released extracellularly by fusion of endosomes with the PM (pathway 3). However, the interpretation of Gag localization data is complicated because virus particles accumulated in endosomes may have been formed at the PM and internalized before being released to the extracellular space (pathway 4).

Figure 3

Schematic representation of plasma membrane domains involved in HIV-1 assembly. TEM, tetraspanin-enriched microdomain; ELD, endosome-like domain; VCC, virus-containing compartment. Markers for each domain are listed. See text for more detail.