Single molecule fate of HIV-1 envelope reveals late-stage viral lattice incorporation

Buttler, Carmen A.; Pezeshkian, Nairi; Fernandez, Melissa V.; Aaron, Jesse; Norman, Sofya; Freed, Eric O.; Engelenburg, Schuyler B. van

doi:10.1038/s41467-018-04220-w

Cited by 35 publications

(60 citation statements)

References 42 publications

(61 reference statements)

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“…We could also measure that the Gag-Gag interaction mediated by CA-CA dimerization was representing only a third of the Gag attractive energy while the NC-RNA platform represents two third of it [45]. Furthermore, coarse grain modeling predicted recently that the presence of the vRNA lowered the necessary SP1-CA hexameric interaction energy down to 3 kT to achieve correct HIV-1 assembly [61], thus in perfect agreement with our findings in The spatiotemporal aspects of Env incorporation into HIV-1 virions during particle assembly was also studied recently by Buttler et al, [62] using interferometric PALM (iPALM, [63]). They reported that Env was incorporated in preformed Gag lattices to the neck of the assembling virion, as determined by the Env angular distribution on the surface of cell-associated virus.…”

Section: Towards a Real Time Molecular Description Of Hiv Assembly Insupporting

confidence: 91%

Monitoring HIV-1 Assembly in Living Cells: Insight from Dynamic and Single Molecule Microscopy

Inamdar¹,

Floderer²,

Favard³

et al. 2018

Preprint

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HIV-1 assembly is a complex mechanism taking place at the plasma membrane of the host cell. It requires nice spatial and temporal coordination to end up with a full immature virus. Researchers have extensively studied HIV-1 assembly molecular mechanism during the past decades, in order to dissect the respective roles of viral proteins, viral genome and host cell factors. Nevertheless, the time course of the process has been observed in living cells only a decade ago. The very recent revolution of optical microscopy, combining high speed and high spatial resolution now permit to study assemblies and their consequences at the single molecule level within (living) cells. In this review, after a short description of these new approaches, we will show how HIV-1 assembly in cells has been revisited using these advanced super resolution microscopy techniques and how much it could make a bridge in studying assembly from the single molecule to the host cell.

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Section: Towards a Real Time Molecular Description Of Hiv Assembly Insupporting

confidence: 91%

Monitoring HIV-1 Assembly in Living Cells: Insight from Dynamic and Single Molecule Microscopy

Inamdar¹,

Floderer²,

Favard³

et al. 2018

Preprint

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“…Recent evidence suggests a role for recycling in Env incorporation (15)(16)(17) and many studies have explored the role of trafficking motifs in the gp41 CT in promoting the proper spatio-temporal localization of Env during assembly (1,2,18,19), but the role of Env recycling in Env incorporation is not well-defined. Wild-type (WT) HIV-1 has an average of ~10 Env trimers per virion (20) and truncation of the gp41 CT generally results in a 10-fold decrease in Env incorporation in physiologically relevant cell types (which we refer to as being non-permissive to gp41 CT truncation) (21).…”

Section: Introductionmentioning

confidence: 99%

“…The degree of regulation seems to be cell-type and CT dependent. For example, in the non-permissive T-cell line CEM-A, WT Env is localized at the neck of the budding particle while truncation of the gp41 CT results in a more uniform Env distribution around the virus particle (19). In the permissive COS7 fibroblast-like cell line, both WT and CT-truncated Env are evenly distributed around the virus particle.…”

Section: Introductionmentioning

confidence: 99%

“…A functional interaction between the gp41 CT and the matrix (MA) domain of the Gag polyprotein has been postulated to play an important role in capturing Env during viral assembly (23,24). Compelling evidence for the trapping of the gp41 CT by the Gag lattice has been previously demonstrated by various studies showing the clustering of Env trimers at sites of virus assembly (10,12,19,22) and retention of full-length Env, but not CT-truncated Env, in detergent-stripped Gag virus-like particles (25). Further evidence for the trapping of the gp41 CT by the Gag lattice is provided by the ability of single amino acid changes in MA to block WT Env incorporation (26)(27)(28)(29)(30)(31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

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Elucidating the basis for permissivity of the MT-4 T-cell line to replication of an HIV-1 mutant lacking the gp41 cytoplasmic tail

Fernandez

Hoffman

Pezeshkian

et al. 2020

Preprint

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AbstractHIV-1 encodes an envelope glycoprotein (Env) that contains a long cytoplasmic tail (CT) harboring trafficking motifs implicated in Env incorporation into virus particles and viral transmission. In most physiologically relevant cell types, the gp41 CT is required for HIV-1 replication, but in the MT-4 T-cell line the gp41 CT is not required for a spreading infection. To help elucidate the role of the gp41 CT in HIV-1 transmission, in this study we investigated the viral and cellular factors that contribute to the permissivity of MT-4 to gp41 CT truncation. We found that the kinetics of HIV-1 production are faster in MT-4 than in the other T-cell lines tested, but MT-4 express equivalent amounts of HIV-1 proteins on a per-cell basis relative to cells not permissive to CT truncation. MT-4 express higher levels of plasma-membrane-associated Env than non-permissive cells and Env internalization from the plasma membrane is slower compared to another T-cell line, SupT1. Paradoxically, despite the high levels of Env on the surface of MT-4, two-fold less Env is incorporated into virus particles in MT-4 compared to SupT1. Cell-to-cell transmission between co-cultured 293T and MT-4 is higher than in co-cultures of 293T with most other T-cell lines tested, indicating that MT-4 are highly susceptible to this mode of infection. These data help to clarify the long-standing question of how MT-4 cells overcome the requirement for the HIV-1 gp41 CT and support a role for gp41 CT-dependent trafficking in Env incorporation and cell-to-cell transmission in physiologically relevant cell lines.ImportanceThe HIV-1 Env cytoplasmic tail (CT) is required for efficient Env incorporation into nascent particles and viral transmission in primary CD4+ T cells. The MT-4 T-cell line has been reported to support multiple rounds of infection of HIV-1 encoding a gp41 CT truncation. Uncovering the underlying mechanism of MT-4 T-cell line permissivity to gp41 CT truncation would provide key insights into the role of the gp41 CT in HIV-1 transmission. This study reveals that multiple factors contribute to the unique ability of a gp41 CT truncation mutant to spread in cultures of MT-4 cells. The lack of a requirement for the gp41 CT in MT-4 is associated with the combined effects of rapid HIV-1 protein production, high levels of cell-surface Env expression, and increased susceptibility to cell-to-cell transmission compared to non-permissive cells.

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“…Those hexameric structures also have implications for Env incorporation in immature HIV-1 virions [54,55,[57][58][59]. HIV-1 Env incorporation into immature virions is believed to be directed by the long cytoplasmic tail (CT) of gp41 and steric trapping within these MA hexamers of trimers [13,[60][61][62][63][64][65]. This process is highly regulated, considering the low number of Env incorporated into released particles (7-14 trimers) [66].…”

Section: Matrix (Ma P17)mentioning

confidence: 99%

Recent Advances in HIV-1 Gag Inhibitor Design and Development

Dick

Simon

2020

Molecules

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Acquired Immune Deficiency Syndrome (AIDS) treatment with combination antiretroviral therapy (cART) has improved the life quality of many patients since its implementation. However, resistance mutations and the accumulation of severe side effects associated with cART remain enormous challenges that need to be addressed with the continual design and redesign of anti-HIV drugs. In this review, we focus on the importance of the HIV-1 Gag polyprotein as the master coordinator of HIV-1 assembly and maturation and as an emerging drug target. Due to its multiple roles in the HIV-1 life cycle, the individual Gag domains are attractive but also challenging targets for inhibitor design. However, recent encouraging developments in targeting the Gag domains such as the capsid protein with highly potent and potentially long-acting inhibitors, as well as the exploration and successful targeting of challenging HIV-1 proteins such as the matrix protein, have demonstrated the therapeutic viability of this important protein. Such Gag-directed inhibitors have great potential for combating the AIDS pandemic and to be useful tools to dissect HIV-1 biology.

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Single molecule fate of HIV-1 envelope reveals late-stage viral lattice incorporation

Cited by 35 publications

References 42 publications

Monitoring HIV-1 Assembly in Living Cells: Insight from Dynamic and Single Molecule Microscopy

Monitoring HIV-1 Assembly in Living Cells: Insight from Dynamic and Single Molecule Microscopy

Elucidating the basis for permissivity of the MT-4 T-cell line to replication of an HIV-1 mutant lacking the gp41 cytoplasmic tail

Recent Advances in HIV-1 Gag Inhibitor Design and Development

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