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The Life-Cycle of the HIV-1 Gag – RNA Complex

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ABSTRACT

Human immunodeficiency virus type 1 (HIV-1) replication is a highly regulated process requiring the recruitment of viral and cellular components to the plasma membrane for assembly into infectious particles. This review highlights the recent process of understanding the selection of the genomic RNA (gRNA) by the viral Pr55Gag precursor polyprotein, and the processes leading to its incorporation into viral particles.

No MeSH data available.


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Human immunodeficiency virus type 1 (HIV-1) genome and Gag organization. (A) The Pr55Gag protein. Major functions of the different domains are indicated; (B) The HIV-1 5′ untranslated region (UTR) contains the major packaging region SL1–SL4. The major Gag binding domain comprises nucleotides 227–237 in the NL43 strain [68]; (C) A region overlapping the Gag-Pol frameshift signal and (D) the Rev response element (RRE), might also be implicated in packaging. ZF: zinc finger; MA: matrix; CA: capsid; NC: nucleocapsid; p1: spacer domain SP2; p2: spacer domain SP1; TAR: Tat responsive element; Poly-A: polyadenylation signal, U5: unique 5′ region, PBS: primer binding site; SL: stem loop; DIS: dimerization initiation site; SD: splice donor; U3: unique 3′ region; R: repeat region; PR: protease; RT: reverse transcriptase; int: integrase; vif: viral infectivity factor; vpu: viral protein U; vpr: viral protein R; gp: glycoprotein; nef: negative factor.
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viruses-08-00248-f002: Human immunodeficiency virus type 1 (HIV-1) genome and Gag organization. (A) The Pr55Gag protein. Major functions of the different domains are indicated; (B) The HIV-1 5′ untranslated region (UTR) contains the major packaging region SL1–SL4. The major Gag binding domain comprises nucleotides 227–237 in the NL43 strain [68]; (C) A region overlapping the Gag-Pol frameshift signal and (D) the Rev response element (RRE), might also be implicated in packaging. ZF: zinc finger; MA: matrix; CA: capsid; NC: nucleocapsid; p1: spacer domain SP2; p2: spacer domain SP1; TAR: Tat responsive element; Poly-A: polyadenylation signal, U5: unique 5′ region, PBS: primer binding site; SL: stem loop; DIS: dimerization initiation site; SD: splice donor; U3: unique 3′ region; R: repeat region; PR: protease; RT: reverse transcriptase; int: integrase; vif: viral infectivity factor; vpu: viral protein U; vpr: viral protein R; gp: glycoprotein; nef: negative factor.

Mentions: The specific binding of Gag to the gRNA directs its encapsidation into nascent virus particles. Gag is a polyprotein with four structural domains MA, CA, NC and p6 and two short spacer peptides, SP1 (p2) and SP2 (p1) (Figure 2A). The C-terminal domain of CA contains the protein dimerization interface, whereas the MA domain binds plasma membrane lipids. Membrane binding is directed by a bipartite signal: the myristoyl group at its N-terminus, which facilitates hydrophobic interactions with membranes, and the highly basic region (HBR) at the MA surface, which mediates electrostatic interactions with cellular lipids like phosphatidylinositol-4,5-bisphosphate (PIP2) [42,43,53]. MA also interacts with nucleic acids [54,55], and this is now thought to regulate the interaction between Gag and cellular membranes [4,55,56,57]. The NC domain specifically interacts with the gRNA through its two CCHC-type zinc finger motifs [7,58,59]. However, in vitro assays demonstrate that Gag has a higher affinity for the gRNA than the NC domain alone, strongly suggesting that other domains contribute to the Gag-gRNA interaction [13,17,60,61,62]. NC binding to RNA promotes the multimerization of Gag during virus assembly [7], and assembly in vitro can be initiated by a variety of nucleic acids, including short DNA oligonucleotides [58]. Remarkably, NC of HIV-1 Gag can be functionally replaced with a leucine zipper protein-protein interaction domain elegantly demonstrating that RNA per se is not needed for viral assembly, but serves only to promote Gag-Gag multimerization [63,64,65,66,67].


The Life-Cycle of the HIV-1 Gag – RNA Complex
Human immunodeficiency virus type 1 (HIV-1) genome and Gag organization. (A) The Pr55Gag protein. Major functions of the different domains are indicated; (B) The HIV-1 5′ untranslated region (UTR) contains the major packaging region SL1–SL4. The major Gag binding domain comprises nucleotides 227–237 in the NL43 strain [68]; (C) A region overlapping the Gag-Pol frameshift signal and (D) the Rev response element (RRE), might also be implicated in packaging. ZF: zinc finger; MA: matrix; CA: capsid; NC: nucleocapsid; p1: spacer domain SP2; p2: spacer domain SP1; TAR: Tat responsive element; Poly-A: polyadenylation signal, U5: unique 5′ region, PBS: primer binding site; SL: stem loop; DIS: dimerization initiation site; SD: splice donor; U3: unique 3′ region; R: repeat region; PR: protease; RT: reverse transcriptase; int: integrase; vif: viral infectivity factor; vpu: viral protein U; vpr: viral protein R; gp: glycoprotein; nef: negative factor.
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viruses-08-00248-f002: Human immunodeficiency virus type 1 (HIV-1) genome and Gag organization. (A) The Pr55Gag protein. Major functions of the different domains are indicated; (B) The HIV-1 5′ untranslated region (UTR) contains the major packaging region SL1–SL4. The major Gag binding domain comprises nucleotides 227–237 in the NL43 strain [68]; (C) A region overlapping the Gag-Pol frameshift signal and (D) the Rev response element (RRE), might also be implicated in packaging. ZF: zinc finger; MA: matrix; CA: capsid; NC: nucleocapsid; p1: spacer domain SP2; p2: spacer domain SP1; TAR: Tat responsive element; Poly-A: polyadenylation signal, U5: unique 5′ region, PBS: primer binding site; SL: stem loop; DIS: dimerization initiation site; SD: splice donor; U3: unique 3′ region; R: repeat region; PR: protease; RT: reverse transcriptase; int: integrase; vif: viral infectivity factor; vpu: viral protein U; vpr: viral protein R; gp: glycoprotein; nef: negative factor.
Mentions: The specific binding of Gag to the gRNA directs its encapsidation into nascent virus particles. Gag is a polyprotein with four structural domains MA, CA, NC and p6 and two short spacer peptides, SP1 (p2) and SP2 (p1) (Figure 2A). The C-terminal domain of CA contains the protein dimerization interface, whereas the MA domain binds plasma membrane lipids. Membrane binding is directed by a bipartite signal: the myristoyl group at its N-terminus, which facilitates hydrophobic interactions with membranes, and the highly basic region (HBR) at the MA surface, which mediates electrostatic interactions with cellular lipids like phosphatidylinositol-4,5-bisphosphate (PIP2) [42,43,53]. MA also interacts with nucleic acids [54,55], and this is now thought to regulate the interaction between Gag and cellular membranes [4,55,56,57]. The NC domain specifically interacts with the gRNA through its two CCHC-type zinc finger motifs [7,58,59]. However, in vitro assays demonstrate that Gag has a higher affinity for the gRNA than the NC domain alone, strongly suggesting that other domains contribute to the Gag-gRNA interaction [13,17,60,61,62]. NC binding to RNA promotes the multimerization of Gag during virus assembly [7], and assembly in vitro can be initiated by a variety of nucleic acids, including short DNA oligonucleotides [58]. Remarkably, NC of HIV-1 Gag can be functionally replaced with a leucine zipper protein-protein interaction domain elegantly demonstrating that RNA per se is not needed for viral assembly, but serves only to promote Gag-Gag multimerization [63,64,65,66,67].

View Article: PubMed Central - PubMed

ABSTRACT

Human immunodeficiency virus type 1 (HIV-1) replication is a highly regulated process requiring the recruitment of viral and cellular components to the plasma membrane for assembly into infectious particles. This review highlights the recent process of understanding the selection of the genomic RNA (gRNA) by the viral Pr55Gag precursor polyprotein, and the processes leading to its incorporation into viral particles.

No MeSH data available.


Related in: MedlinePlus