Maturation of HIV-1

doi:10.1126/science.abj9075

GSTDTAP > 气候变化

DOI	10.1126/science.abj9075
	Maturation of HIV-1
	Yuta Hikichi; Eric O. Freed
	2021-08-06
发表期刊	Science
出版年	2021
英文摘要	HIV-1 particle assembly is driven by the Gag polyprotein precursor, which contains several structural and functional domains that engage in protein-protein, protein-lipid, and protein-RNA interactions during virion assembly. Concomitant with virus release from an infected cell, the viral protease cleaves the Gag precursor to liberate the mature Gag proteins, triggering a morphological transformation of the virus particle, called maturation. The matrix (MA) domain plays key roles in directing Gag to the plasma membrane of the host cell and in the incorporation of the viral envelope glycoprotein (Env) complex into the assembling particle. On page 700 of this issue, Qu et al. ([ 1 ][1]) report the cryo–electron tomography (cryo-ET) structure of MA in both immature and mature particles. The results provide important insights into HIV-1 assembly and maturation and the role that MA plays in these processes. These findings may suggest new antiviral strategies that target MA. The Gag polyprotein precursor contains MA, capsid (CA), nucleocapsid (NC), and p6 domains ([ 2 ][2], [ 3 ][3]). The NC domain is flanked by two spacer peptides, SP1 and SP2. The structure of the intact HIV-1 Gag precursor has been challenging to determine because of its large size and flexibility. However, structures are available for individual mature Gag proteins and for some domains of the Gag precursor—notably, CA. As an isolated protein, MA folds into a highly globular structure ([ 4 ][4], [ 5 ][5]). A myristic acid moiety covalently linked to the amino terminus of MA anchors Gag in the lipid bilayer of the virion, and a highly basic region of MA interacts electrostatically with the acidic headgroup of the host cell plasma membrane lipid, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] ([ 6 ][6], [ 7 ][7]). The interaction between the MA domain of Gag and PI(4,5)P2 targets Gag to the inner leaflet of the plasma membrane, where HIV-1 assembly takes place. The structural changes that take place within Gag and Env in the newly released virus particle during the maturation step are essential for entry into and productive infection of new cells. HIV-1 MA was shown to crystallize as a trimer ([ 5 ][5]) and assemble into a hexameric lattice of trimers on an artificial PI(4,5)P2–containing membrane monolayer ([ 8 ][8]). Although CA forms a hexagonal lattice in both the immature particle and the mature CA core, the orientation and intersubunit interactions of CA differ in these two contexts ([ 9 ][9]). In contrast to CA, the arrangement of MA in HIV-1 virions has until now been largely refractory to high-resolution structural analysis because of the curved and flexible nature of the viral membrane. Defining the structure of the MA lattice in virions is key to understanding how MA functions in Gag targeting, Env incorporation, and viral infection. To address this key gap in our knowledge of HIV-1 structure, Qu et al. demonstrate that MA assembles into hexamers of trimers in both immature and mature virions, with the trimeric structure similar to that of the previously reported crystallized MA trimer ([ 5 ][5]) (see the figure). However, the arrangement of MA in the immature and mature lattice is very different, demonstrating that the MA lattice, like the CA lattice ([ 9 ][9]), undergoes a rearrangement on particle maturation. A hole in the MA lattice is located at the center of the hexamer of trimers. This hole, which has been hypothesized to be a docking site for the cytoplasmic tail of the viral transmembrane Env glycoprotein gp41, is lined with basic residues in the immature particle but neutral residues in the mature virion. MA mutations that impair Env incorporation are not exposed to the central holes of the immature MA lattice but rather, in some cases, are located at trimer interfaces, which is consistent with a role for MA trimerization in Env incorporation ([ 10 ][10], [ 11 ][11]). ![Figure][12] Maturation of the matrix lattice The membrane-bound HIV-1 matrix (MA) domain assembles into a hexamer of trimers in both immature and mature virions. The arrangement and intertrimer interactions of the MA lattice differ in immature and mature particles. The central gap in the MA lattice is hypothesized to interact with the envelope glycoprotein (Env, comprising gp41 and gp120) cytoplasmic tail (double-headed arrows). At the bottom is shown the electrostatic surface potentials. GRAPHIC: C. BICKEL/ SCIENCE The results of Qu et al. also indicate changes in MA-lipid interaction. Specifically, in the immature particle, both acyl chains of PI(4,5)P2 are embedded in the membrane bilayer, whereas in the mature particle, a density consistent with an acyl chain, possibly derived from PI(4,5) P2, is embedded into a proposed acyl chain binding groove in MA ([ 7 ][7]). This study demonstrates that particle maturation changes both the protein-protein and protein-lipid interaction properties of MA, presumably priming the virion for the subsequent infection process, possibly by changing the dynamic properties of the viral membrane. Because gp41 could not be resolved in the current analysis, it is unclear how the gp41 cytoplasmic tail is accommodated by the MA lattice, a key step in Env incorporation during particle assembly. Moreover, it is unknown how the conformational changes in MA that accompany particle maturation affect the structure and dynamics of Env. Previous studies have shown that Env in immature virions is fusion-incompetent and that cleavage events downstream of SP1 can activate fusogenicity, enabling the virus to enter target cells ([ 12 ][13], [ 13 ][14]). Qu et al. likewise show that cleavage of Gag downstream of SP1 is sufficient to trigger structural rearrangement of the MA lattice. The suppression of fusion observed in immature particles requires the gp41 cytoplasmic tail ([ 12 ][13], [ 13 ][14]). Env trimers cluster in a maturation-dependent fashion on HIV-1 particles, and again, this clustering is dependent on the gp41 cytoplasmic tail ([ 14 ][15]). Together, these findings suggest that structural rearrangement of the MA lattice during maturation may activate Env fusogenicity by changing the conformation, mobility, and/or clustering of Env trimers, allowing virus entry. Because it has been reported that virus maturation affects the stiffness of HIV-1 particles ([ 15 ][16]), what role do the structural rearrangements of MA, and the resulting extrusion of lipid acyl chains from the viral membrane, play in this shift in rigidity? Further understanding HIV-1 assembly and maturation, as provided by the study of Qu et al. , will potentially reveal new therapeutic targets for controlling this pathogen. 1. [↵][17]1. K. Qu et al ., Science 373, 700 (2021). [OpenUrl][18][Abstract/FREE Full Text][19] 2. [↵][20]1. E. O. Freed , Nat. Rev. Microbiol. 13, 484 (2015). [OpenUrl][21][CrossRef][22][PubMed][23] 3. [↵][24]1. W. I. Sundquist, 2. H.-G. Kräusslich , Cold Spring Harb. Perspect. Med. 2, a006924 (2012). [OpenUrl][25][Abstract/FREE Full Text][26] 4. [↵][27]1. M. A. Massiah et al ., J. Mol. Biol. 244, 198 (1994). [OpenUrl][28][CrossRef][29][PubMed][30][Web of Science][31] 5. [↵][32]1. C. P. Hill, 2. D. Worthylake, 3. D. P. Bancroft, 4. A. M. Christensen, 5. W. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/335567
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Yuta Hikichi,Eric O. Freed. Maturation of HIV-1[J]. Science,2021.
APA	Yuta Hikichi,&Eric O. Freed.(2021).Maturation of HIV-1.Science.
MLA	Yuta Hikichi,et al."Maturation of HIV-1".Science (2021).