A Highly Conserved Residue in the C-Terminal Helix of HIV-1 Matrix Is Required for Envelope Incorporation into Virus Particles

Brandano, Laura A; Stevenson, Mario

doi:10.1128/jvi.06047-11

Cited by 30 publications

(38 citation statements)

References 70 publications

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“…Mutations have been identified in MA that prevent the incorporation of Env into particles (22)(23)(24)(25)(26). The majority of these mutations map to the tips of the MA trimer (27), a region of the protein that lies around the central aperture of the hexamer of trimers.…”

Section: Significancementioning

confidence: 99%

Biochemical evidence of a role for matrix trimerization in HIV-1 envelope glycoprotein incorporation

Tedbury

Novikova

Ablan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

122

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The matrix (MA) domain of HIV Gag has important functions in directing the trafficking of Gag to sites of assembly and mediating the incorporation of the envelope glycoprotein (Env) into assembling particles. HIV-1 MA has been shown to form trimers in vitro; however, neither the presence nor the role of MA trimers has been documented in HIV-1 virions. We developed a cross-linking strategy to reveal MA trimers in virions of replication-competent HIV-1. By mutagenesis of trimer interface residues, we demonstrated a correlation between loss of MA trimerization and loss of Env incorporation. Additionally, we found that truncating the long cytoplasmic tail of Env restores incorporation of Env into MA trimer-defective particles, thus rescuing infectivity. We therefore propose a model whereby MA trimerization is required to form a lattice capable of accommodating the long cytoplasmic tail of HIV-1 Env; in the absence of MA trimerization, Env is sterically excluded from the assembling particle. These findings establish MA trimerization as an obligatory step in the assembly of infectious HIV-1 virions. As such, the MA trimer interface may represent a novel drug target for the development of antiretrovirals.HIV | retrovirus | matrix | envelope | trimerization

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Section: Significancementioning

confidence: 99%

Biochemical evidence of a role for matrix trimerization in HIV-1 envelope glycoprotein incorporation

Tedbury

Novikova

Ablan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

122

View full text Add to dashboard Cite

show abstract

“…Env incorporation is thought to be an active process. It is blocked by distinct mutations and deletions in the membrane binding matrix (MA) domain of Gag or by small truncations in the long cytoplasmic tail (CT) of Env (20)(21)(22)(23)(24)(25)(26)(27); reviewed in reference 28). Interestingly, while these studies strongly suggest that direct or indirect interactions between Env and Gag mediate Env incorporation into viral particles, deletion of the whole cytoplasmic tail of Env (⌬CT) can overcome many of the incorporation defects imposed by mutations in MA, at least in some cell types (23,24,29,30).…”

mentioning

confidence: 99%

Clustering and Mobility of HIV-1 Env at Viral Assembly Sites Predict Its Propensity To Induce Cell-Cell Fusion

Roy

Chan

Lambelé

et al. 2013

J Virol

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HIV-1 Env mediates virus attachment to and fusion with target cell membranes, and yet, while Env is still situated at the plasma membrane of the producer cell and before its incorporation into newly formed particles, Env already interacts with the viral receptor CD4 on target cells, thus enabling the formation of transient cell contacts that facilitate the transmission of viral particles. During this first encounter with the receptor, Env must not induce membrane fusion, as this would prevent the producer cell and the target cell from separating upon virus transmission, but how Env's fusion activity is controlled remains unclear. To gain a better understanding of the Env regulation that precedes viral transmission, we examined the nanoscale organization of Env at the surface of producer cells. Utilizing superresolution microscopy (stochastic optical reconstruction microscopy [STORM]) and fluorescence recovery after photobleaching (FRAP), we quantitatively assessed the clustering and dynamics of Env upon its arrival at the plasma membrane. We found that Gag assembly induced the aggregation of small Env clusters into larger domains and that these domains were completely immobile. Truncation of the cytoplasmic tail (CT) of Env abrogated Gag's ability to induce Env clustering and restored Env mobility at assembly sites, both of which correlated with increased Env-induced fusion of infected and uninfected cells. Hence, while Env trapping by Gag secures Env incorporation into viral particles, Env clustering and its sequestration at assembly sites likely also leads to the repression of its fusion function, and thus, by preventing the formation of syncytia, Gag helps to secure efficient transfer of viral particles to target cells.

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“…Regarding the interaction domains, the basic and C-terminal domains of HIV-1 matrix Gag physically interact with the GP41CT (72, 75,83). Mutagenesis analyses suggest that the matrix substitution L49D destabilizes the GP120-GP41 interaction, but this impairment can be rescued by a Y710S substitution at the GP41CT (84).…”

Section: (Iii) Matrixmentioning

confidence: 99%

“…Regarding the interaction domains, data from mutagenesis analyses suggest that amino acid substitutions (e.g., E16K, K29E, K31E, and E99V) in matrix Gag can impair Env packaging (74,75,292,298). Substitutions at serine positions (S9, S67, S72, and S77) in HIV-1 matrix Gag dramatically reduce the phosphorylation of matrix Gag and inhibit the binding of matrix Gag to lipid rafts, thereby causing an impairment of Env packaging (299).…”

Section: Lymphocytes (292) (Iii) Given That Gag and Env Proteins Arementioning

confidence: 99%

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HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Clercq

2016

Microbiol Mol Biol Rev

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SUMMARYThe HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.

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A Highly Conserved Residue in the C-Terminal Helix of HIV-1 Matrix Is Required for Envelope Incorporation into Virus Particles

Cited by 30 publications

References 70 publications

Biochemical evidence of a role for matrix trimerization in HIV-1 envelope glycoprotein incorporation

Biochemical evidence of a role for matrix trimerization in HIV-1 envelope glycoprotein incorporation

Clustering and Mobility of HIV-1 Env at Viral Assembly Sites Predict Its Propensity To Induce Cell-Cell Fusion

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

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