In most cell types including natural hosts such as T cells, HIV-1 assembles at the plasma membrane (PM). HIV-1 particle formation is a multi-step process driven by the viral structural protein Gag (Adamson and Freed, 2007
) (). This process includes: 1) targeting of Gag to the PM, 2) Gag binding to membrane, 3) Gag multimerization, 4) encapsidation of viral genomic RNA, 5) incorporation of the viral Env glycoprotein, and 6) budding and release of virus particles. Although the order of some of these steps remains to be determined, regions in Gag involved in each step are well defined. Gag is a multidomain protein consisting of four major domains, matrix (MA), capsid (CA), nucleocapsid (NC), and p6 as well as spacer peptides, SP1 and SP2. MA mediates Gag targeting and binding to the PM and Env incorporation, whereas the CA C-terminal domain (CTD) and NC promote Gag multimerization. The CA-CTD contains a dimerization interface, while NC, an RNA binding domain, is thought to promote higher-order multimerization as scaffolding through NC-RNA-NC binding. NC also contains zinc finger motifs that mediate specific recognition of viral RNA for packaging of the genome. p6 recruits cellular ESCRT complexes that facilitate fission of virions from the PM.
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. (more ...)
Advances in cell biology and biophysics have revealed that the PM is heterogeneous, consisting of multiple microdomains that contain specific sets of lipids and proteins. These microdomains may have various lifetimes, sizes, and dynamics and may coalesce or dissociate from each other, thereby modulating cellular functions. Among them, lipid rafts and tetraspanin-enriched microdomains (TEMs) have been implicated in various aspects of the HIV-1 life cycle. In this review, I will focus on interrelationships between these two specific types of microdomains and HIV-1 assembly. I will also discuss potential roles of these microdomains in two post-assembly events currently under intense scrutiny, i.e., BST-2/tetherin-mediated virion release inhibition and cell-to-cell HIV-1 transmission at virological synapses.