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Evolution toward beta common chain receptor usage links the matrix proteins of HIV-1 and its ancestors to human erythropoietin

Authors :
Arnaldo Caruso
Wuyuan Lu
Antonella Bugatti
Mark Slevin
Alessandro Orro
Pietro Liò
Mario Salmona
Federica Filippini
Alberto Zani
Pietro Mazzuca
Domenico Ribatti
Matteo Uggeri
Robert C. Gallo
Pasqualina D'Ursi
Francesca Caccuri
Source :
Proceedings of the National Academy of Sciences of the United States of America, Proceedings of the National Academy of Sciences of the United States of America 118 (2021). doi:10.1073/pnas.2021366118, info:cnr-pdr/source/autori:Caccuri F.; D'Ursi P.; Uggeri M.; Bugatti A.; Mazzuca P.; Zani A.; Filippini F.; Salmona M.; Ribatti D.; Slevin M.; Orro A.; Lu W.; Lio P.; Gallo R.C.; Caruso A./titolo:Evolution toward beta common chain receptor usage links the matrix proteins of HIV-1 and its ancestors to human erythropoietin/doi:10.1073%2Fpnas.2021366118/rivista:Proceedings of the National Academy of Sciences of the United States of America/anno:2021/pagina_da:/pagina_a:/intervallo_pagine:/volume:118
Publication Year :
2020

Abstract

Significance Immune activation and inflammation are predictors of serious non-AIDS events even in virally suppressed HIV-1−infected individuals. This does not apply to HIV-2−infected patients, who experience a form of attenuated HIV-1 disease. Here, we show that the HIV-1 matrix protein 17 (p17) binds to and activates the common beta chain receptor (βCR). The βCR-activating epitope on p17 is expressed on the matrix protein of HIV-1 ancestors but not on that of HIV-2 and its ancestors. Our finding highlights this epitope as a signature tracing the HIV-1 evolutionary trajectory that may have represented a critical step to enhance the HIV-1 ancestors aggressiveness and early human-to-human transmission. Whether this functional epitope actually marks the pathogenic difference between HIV-1 and HIV-2 needs further investigation.<br />The HIV-1 matrix protein p17 (p17) is a pleiotropic molecule impacting on different cell types. Its interaction with many cellular proteins underlines the importance of the viral protein as a major determinant of human specific adaptation. We previously showed the proangiogenic capability of p17. Here, by integrating functional analysis and receptor binding, we identify a functional epitope that displays molecular mimicry with human erythropoietin (EPO) and promotes angiogenesis through common beta chain receptor (βCR) activation. The functional EPO-like epitope was found to be present in the matrix protein of HIV-1 ancestors SIV originated in chimpanzees (SIVcpz) and gorillas (SIVgor) but not in that of HIV-2 and its ancestor SIVsmm from sooty mangabeys. According to biological data, evolution of the EPO-like epitope showed a clear differentiation between HIV-1/SIVcpz-gor and HIV-2/SIVsmm branches, thus highlighting this epitope on p17 as a divergent signature discriminating HIV-1 and HIV-2 ancestors. P17 is known to enhance HIV-1 replication. Similarly to other βCR ligands, p17 is capable of attracting and activating HIV-1 target cells and promoting a proinflammatory microenvironment. Thus, it is tempting to speculate that acquisition of an epitope on the matrix proteins of HIV-1 ancestors capable of triggering βCR may have represented a critical step to enhance viral aggressiveness and early human-to-human SIVcpz/gor dissemination. The hypothesis that the p17/βCR interaction and βCR abnormal stimulation may also play a role in sustaining chronic activation and inflammation, thus marking the difference between HIV-1 and HIV-2 in term of pathogenicity, needs further investigation.

Details

ISSN :
10916490
Volume :
118
Issue :
2
Database :
OpenAIRE
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Accession number :
edsair.doi.dedup.....cf27c71dfd659103d1b9360fc773f566
Full Text :
https://doi.org/10.1073/pnas.2021366118