Wrapping up the bad news: HIV assembly and release

Abstract

The late Nobel Laureate Sir Peter Medawar once memorably described viruses as 'bad news wrapped in protein'. Virus assembly in HIV is a remarkably well coordinated process in which the virus achieves extracellular budding using primarily intracellular budding machinery and also the unusual phenomenon of export from the cell of an RNA. Recruitment of the ESCRT system by HIV is one of the best documented examples of the comprehensive way in which a virus hijacks a normal cellular process. This review is a summary of our current understanding of the budding process of HIV, from genomic RNA capture through budding and on to viral maturation, but centering on the proteins of the ESCRT pathway and highlighting some recent advances in our understanding of the cellular components involved and the complex interplay between the Gag protein and the genomic RNA.

Figure 1

Diagrammatic overview of the late stages of the HIV life-cycle. (A) After transcription the full length viral RNA is exported from the nucleus to the cytoplasm for Gag (and Gag-Pol) synthesis. Singly spliced RNA is exported to produce the envelope glycoproteins (dark blue). Gag binds to a dimeric genomic RNA via its NC domain to form ribonucleoprotein complex which is trafficked to the membrane where more Gag assembles and budding occurs (black dashed-box and B). During HIV particle assembly or soon after particle release, protease (PR, not shown) cleaves the Gag polyprotein to MA, CA and NC and protein rearrangement occurs to form the mature virion. (B) Close-up view of the HIV budding process. ESCRT-I is recruited to the budding site via interactions between PTAP in p6 of Gag and TSG101 of ESCRT-I (black arrow). The link to ESCRT-III (CHMPs) for budding is via an unknown mechanism but seems to bypass ESCRT-II (black dashed-arrow). Additionally/alternatively, ALIX binds to YPXnL motif also in p6 and NC via V and Bro1 domain, respectively and directs Gag to ESCRT-III via its Bro1 domain for budding (blue arrow). RNA involvement in NC-ALIX binding has been suggested (wavy line), but the identity of the RNA is not clear. HIV has no PPXY motif, but the NEDD4-like ubiquitin ligase family has also been implicated in facilitating HIV joining the ESCRT pathway for budding probably via adaptors on the plasma membrane (NEDD4-2; red arrow) or the ALIX pathway (NEDD4-1). For membrane scission to occur, ESCRT-III components are activated and polymerized to form a dome-shaped structure. VPS4, regulated by LIP5-CHMP5 and CHMP1-ISTI binary complexes (not shown), is recruited to the budding site where it multimerizes to form a dodecamer and disassembles the ESCRT-III filaments for recycling. How membrane scission occurs is unknown.