CCL2 mobilizes ALIX to facilitate Gag-p6 mediated HIV-1 virion release

Ajasin, David; Rao, Vasudev R; Wu, Xiaolin; Ramasamy, Santhamani; Pujato, Mario; Ruiz, Arthur P; Fiser, András; Bresnick, Anne R.; Kalpana, Ganjam V.; Prasad, Vinayaka R.

doi:10.7554/elife.35546

Cited by 13 publications

(11 citation statements)

References 68 publications

(82 reference statements)

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“…HIV-1 subtype C virus naturally lacks a YPXL domain [ 71 ], but a PYXE insertion has evolved in treatment-experienced subtype C infected patients [ 72 ]. The effect of these mutations is to enhance the virus replication in the presence of antiretroviral therapy (ART) by allowing engagement with ALIX, which, otherwise, does not occur [ 72 , 73 , 74 ]. Crystallographic studies show both PYXE and YPXL motifs share a similar mode of binding to ALIX [ 75 ].…”

Section: Viral Factors Involved In Entry To the Escrt Pathwaymentioning

confidence: 99%

The Interplay between ESCRT and Viral Factors in the Enveloped Virus Life Cycle

Meng

Lever

2021

Viruses

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Viruses are obligate parasites that rely on host cellular factors to replicate and spread. The endosomal sorting complex required for transport (ESCRT) system, which is classically associated with sorting and downgrading surface proteins, is one of the host machineries hijacked by viruses across diverse families. Knowledge gained from research into ESCRT and viruses has, in turn, greatly advanced our understanding of many other cellular functions in which the ESCRT pathway is involved, e.g., cytokinesis. This review highlights the interplay between the ESCRT pathway and the viral factors of enveloped viruses with a special emphasis on retroviruses.

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Section: Viral Factors Involved In Entry To the Escrt Pathwaymentioning

confidence: 99%

The Interplay between ESCRT and Viral Factors in the Enveloped Virus Life Cycle

Meng

Lever

2021

Viruses

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“…Recent research has suggested an increase in virus production in the presence of CCL2 in HIV-infected macrophages, and this effect is seen to be Gag-mediated via the LYPX motif. This observation is seen to be subtype-specific, where in sharp contrast to HIV-1B, HIV-1C fails to show this response due to the absence of the LYPX motif (55). Thus, the CS-Tat-induced CCL2 production may influence biological functions other than the viral replication of HIV-1C.…”

Section: Discussionmentioning

confidence: 94%

The Signature Amino Acid Residue Serine 31 of HIV-1C Tat Potentiates an Activated Phenotype in Endothelial Cells

Menon

Budhwar²,

Shukla³

et al. 2020

Front. Immunol.

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The natural cysteine to serine variation at position 31 of Tat in HIV-1C disrupts the dicysteine motif attenuating the chemokine function of Tat. We ask if there exists a trade-off in terms of a gain of function for HIV-1C Tat due to this natural variation. We constructed two Tat-expression vectors encoding Tat proteins discordant for the serine 31 residue (CS-Tat vs. CC-Tat), expressed the proteins in Jurkat cells under doxycycline control, and performed the whole transcriptome analysis to compare the early events of Tat-induced host gene expression. Our analysis delineated a significant enrichment of pathways and gene ontologies associated with the angiogenic signaling events in CS-Tat stable cells. Subsequently, we validated and compared angiogenic signaling events induced by CS-vs. CC-Tat using human umbilical vein endothelial cells (HUVEC) and the human cerebral microvascular endothelial cell line (hCMEC/D3). CS-Tat significantly enhanced the production of CCL2 from HUVEC and induced an activated phenotype in endothelial cells conferring on them enhanced migration, invasion, and in vitro morphogenesis potential. The ability of CS-Tat to induce the activated phenotype in endothelial cells could be of significance, especially in the context of HIV-associated cardiovascular and neuronal disorders. The findings from the present study are likely to help appreciate the functional significance of the SAR (signature amino acid residues) influencing the unique biological properties.

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“…The PYKE sequence is most likely the result of a recombination event between HIV-1C that lacks this sequence with HIV-2 that naturally contains the PYKE motif. Insertion of the PYKE motif within HIV-1C Gag enhanced its binding capacity to host cell protein ALIX and correlated with increased viral replication and viral fitness (16, 37). On the one hand, PYKE insertion also increases susceptibility towards GrM cleavage.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic lymphocytes target HIV-1 Gag through granzyme M-mediated cleavage

Saccon

Mikaeloff

Ivern

et al. 2021

Preprint

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HIV-1 leads to progression to immunodeficiency and death of individuals who do not receive successful antiretroviral therapy. Initially, the host its immune response controls the infection, but cannot eliminate the HIV-1 from the host. Cytotoxic lymphocytes are the key effector cells in this response and can mediate crucial antiviral responses through the release of a set of proteases called granzymes towards HIV-1-infected cells. However, little is known about the immunological molecular mechanisms by which granzymes could control HIV-1. Since we noted that HIV-1 subtype C (HIV-1C) Gag with the tetrapeptide insertion PYKE contains a putative granzyme M (GrM) cleavage site (KEPL) that overlaps with the PYKE insertion, we analyzed the proteolytic activity of GrM towards Gag. Immunoblot analysis showed that GrM could cleave Gag proteins from HIV-1B and variants from HIV-1C of which the Gag-PYKE variant was cleaved with extremely high efficiency. The main cleavage site was directly after the insertion after leucine residue 483. GrM-mediated cleavage of Gag was also observed in co-cultures using cytotoxic lymphocytes as effector cells and this cleavage could be inhibited by a GrM inhibitor peptide. Altogether, our data indicate towards a noncytotoxic immunological mechanism by which GrM-positive cytotoxic lymphocytes target the HIV-1 Gag protein within infected cells to potentially control HIV-1 infection. This mechanism could be exploited in new therapeutic strategies to treat HIV-1-infected patients to improve immunological control of the infection.

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CCL2 mobilizes ALIX to facilitate Gag-p6 mediated HIV-1 virion release

Cited by 13 publications

References 68 publications

The Interplay between ESCRT and Viral Factors in the Enveloped Virus Life Cycle

The Interplay between ESCRT and Viral Factors in the Enveloped Virus Life Cycle

The Signature Amino Acid Residue Serine 31 of HIV-1C Tat Potentiates an Activated Phenotype in Endothelial Cells

Cytotoxic lymphocytes target HIV-1 Gag through granzyme M-mediated cleavage

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