Relationships between plasma membrane microdomains and HIV-1 assembly

Abstract

Advances in cell biology and biophysics revealed that cellular membranes consist of multiple microdomains with specific sets of components such as lipid rafts and TEMs (tetraspanin-enriched microdomains). An increasing number of enveloped viruses have been shown to utilize these microdomains during their assembly. Among them, association of HIV-1 (HIV type 1) and other retroviruses with lipid rafts and TEMs within the PM (plasma membrane) is well documented. In this review, I describe our current knowledge on interrelationships between PM microdomain organization and the HIV-1 particle assembly process. Microdomain association during virus particle assembly may also modulate subsequent virus spread. Potential roles played by microdomains will be discussed with regard to two post-assembly events, i.e., inhibition of virus release by a raft-associated protein BST-2/tetherin and cell-to-cell HIV-1 transmission at virological synapses.

Fig. 1

HIV-1 Gag and virus particle assembly. A. Structural and functional domains are shown. MA, matrix; CA, capsid; NC, nucleocapsid; SP, spacer peptide. N-terminal myristylation is shown as (m−). B. A general outline of virus assembly process is shown. For clarity, RNA molecules associated with NC are not depicted.

Fig. 2

Association of Gag with lipid raft microdomains. NMR studies suggest that binding of PI(4,5)P₂ to the MA highly basic region induces exposure of the N-terminal myristate moiety as well as sequestration of the highly unsaturated 2’-acyl chain of PI(4,5)P₂ (A). Two exposed saturated acyl chains, i.e., the N-terminal myristate and the 1’ acyl chain of PI(4,5)P₂, are postulated to promote partitioning of the Gag molecule to a raft domain, which may become stabilized or coalesce with other rafts upon Gag multimerization (B). Multiple saturated acyl chains associated with a Gag cluster may also induce formation of a stable raft-like domain (C). Possibilities shown in B and C are not mutually exclusive.

Fig. 3

Structure and function of BST-2/tetherin. A. Key structural features and a possible mode of microdomain partitioning are shown. Cysteine residues that form disulfide bonds in BST-2/tetherin dimers are depicted. Glycosylation sites are not shown. B. Proposed modes for BST-2/tetherin-mediated physical linkage between virions and the plasma membrane are illustrated.

Fig. 4

Virological synapse and potential involvement of uropods in its formation. A. Key features of the virological synapse formed between a virus-producing T cell and a target T cell are shown. Major components of the virological synapse are listed. B. Accumulation of assembling and assembled viruses to uropods enriched in cell adhesion molecules may facilitate formation of virological synapses upon contact of uropods with a new target cell. Alternatively, virus-laden platforms may be formed at uropods and laterally move over the plasma membrane to cell-cell contacts at other area of virus-producing cells.