The Protein Network of HIV Budding

Abstract

HIV release requires TSG101, a cellular factor that sorts proteins into vesicles that bud into multivesicular bodies (MVB). To test whether other proteins involved in MVB biogenesis (the class E proteins) also participate in HIV release, we identified 22 candidate human class E proteins. These proteins were connected into a coherent network by 43 different protein-protein interactions, with AIP1 playing a key role in linking complexes that act early (TSG101/ESCRT-I) and late (CHMP4/ESCRT-III) in the pathway. AIP1 also binds the HIV-1 p6(Gag) and EIAV p9(Gag) proteins, indicating that it can function directly in virus budding. Human class E proteins were found in HIV-1 particles, and dominant-negative mutants of late-acting human class E proteins arrested HIV-1 budding through plasmal and endosomal membranes. These studies define a protein network required for human MVB biogenesis and indicate that the entire network participates in the release of HIV and probably many other viruses.

Macrophages and HIV-1: dangerous liaisons

“…Gag drives HIV-1 budding through the Gag p6 late domain (L domain). L domain binds the tumour susceptibility gene 101 (TSG101), hijacking the host's MVB vesicle formation machinery, and recruits proteins of the ESCRT (endosomal sorting complexes required for transport) family, which regulate MVB biogenesis and cellular vacuolar protein sorting pathways (Pornillos et al, 2003;Strack et al, 2003;von Schwedler et al, 2003). The release of HIV-1 also seems to differ in T cells and in macrophages.…”

Gene therapy progress and prospects: Novel gene therapy approaches for AIDS

“…Overexpression of the N terminus of Tsg101 strongly inhibited virus production by affecting budding. 59 Expression of the mutant Vps4 ATPase was shown to block HIV-1 formation 60 and disrupted the interaction between AIP1 and CHMP proteins (ESCRT-III), 61,62 all parts of the MVB machinery. It is possible to envision small molecules or peptides targeted against the p6-Tsg101 interaction or similar pathways.…”

VPS37 Isoforms Differentially Modulate the Ternary Complex Formation of ALIX, ALG-2, and ESCRT-I

“…9,10) The PSAP sequence within the ALIX C-terminal PRR binds TSG101. 9,11) Weak interaction between ALIX and TSG101 is enhanced by Ca 2þ . 12) ALG-2 is a 22-kDa Ca 2þ -binding protein with five serial EF-hands repeats.…”