The central domain of the matrix protein of HIV-1: influence on protein structure and virus infectivity

ABSTRACT We have previously demonstrated by Gag polyprotein budding assays that the Gag p9 protein of equine infectious anemia virus (EIAV) utilizes a unique YPDL motif as a late assembly domain (L domain) to facilitate release of the budding virus particle from the host cell plasma membrane (B. A. Puffer, L. J. Parent, J. W. Wills, and R. C. Montelaro, J. Virol. 71:6541-6546, 1997). To characterize in more detail the role of the YPDL L domain in the EIAV life cycle, we have examined the replication properties of a series of EIAV proviral mutants in which the parental YPDL L domain was replaced by a human immunodeficiency virus type 1 (HIV-1) PTAP or Rous sarcoma virus (RSV) PPPY L domain in the p9 protein or by proviruses in which the parental YPDL or HIV-1 PTAP L domain was inserted in the viral matrix protein. The replication properties of these L-domain variants were examined with respect to Gag protein expression and processing, virus particle production, and virus infectivity. The data from these experiments indicate that (i) the YPDL L domain of p9 is required for replication competence (assembly and infectivity) in equine cell cultures, including the natural target equine macrophages; (ii) all of the functions of the YPDL L domain in the EIAV life cycle can be replaced by replacement of the parental YPDL sequence in p9 with the PTAP L-domain segment of HIV-1 p6 or the PPPY L domain of RSV p2b; and (iii) the assembly, but not infectivity, functions of the EIAV proviral YPDL substitution mutants can be partially rescued by inclusions of YPDL and PTAP L-domain sequences in the C-terminal region of the EIAV MA protein. Taken together, these data demonstrate that the EIAV YPDL L domain mediates distinct functions in viral budding and infectivity and that the HIV-1 PTAP and RSV PPPY L domains can effectively facilitate these dual replication functions in the context of the p9 protein. In light of the fact that YPDL, PTAP, and PPPY domains evidently have distinct characteristic binding specificities, these observations may indicate different portals into common cellular processes that mediate EIAV budding and infectivity, respectively.

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Matrix and Envelope Coevolution Revealed in a Patient Monitored since Primary Infection with Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.01213-09 ◽

2009 ◽

Vol 83 (19) ◽

pp. 9875-9889 ◽

Cited By ~ 10

Author(s):

Elodie Beaumont ◽

Daniela Vendrame ◽

Bernard Verrier ◽

Emmanuelle Roch ◽

François Biron ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Amino Acid ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Matrix Protein ◽

Immunodeficiency Virus ◽

The Matrix ◽

Hiv 1

ABSTRACT Lentiviruses, including human immunodeficiency virus type 1 (HIV-1), typically encode envelope glycoproteins (Env) with long cytoplasmic tails (CTs). The strong conservation of CT length in primary isolates of HIV-1 suggests that this factor plays a key role in viral replication and persistence in infected patients. However, we report here the emergence and dominance of a primary HIV-1 variant carrying a natural 20-amino-acid truncation of the CT in vivo. We demonstrated that this truncation was deleterious for viral replication in cell culture. We then identified a compensatory amino acid substitution in the matrix protein that reversed the negative effects of CT truncation. The loss or rescue of infectivity depended on the level of Env incorporation into virus particles. Interestingly, we found that a virus mutant with defective Env incorporation was able to spread by cell-to-cell transfer. The effects on viral infectivity of compensation between the CT and the matrix protein have been suggested by in vitro studies based on T-cell laboratory-adapted virus mutants, but we provide here the first demonstration of the natural occurrence of similar mechanisms in an infected patient. Our findings provide insight into the potential of HIV-1 to evolve in vivo and its ability to overcome major structural alterations.

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HIV-1 p17 Matrix Protein Interacts with Heparan Sulfate Side Chain of CD44v3, Syndecan-2, and Syndecan-4 Proteoglycans Expressed on Human Activated CD4+ T Cells Affecting Tumor Necrosis Factor α and Interleukin 2 Production

Journal of Biological Chemistry ◽

10.1074/jbc.m110.191270 ◽

2011 ◽

Vol 286 (22) ◽

pp. 19541-19548 ◽

Cited By ~ 17

Author(s):

Maria A. De Francesco ◽

Manuela Baronio ◽

Claudio Poiesi

Keyword(s):

T Cells ◽

Heparan Sulfate ◽

Matrix Protein ◽

Interleukin 2 ◽

Fluorescence Analysis ◽

Heparin Binding ◽

The Matrix ◽

C And N ◽

Factor Α ◽

Hiv 1

HIV-1 p17 contains C- and N-terminal sequences with positively charged residues and a consensus cluster for heparin binding. We have previously demonstrated by affinity chromatography that HIV-1 p17 binds strongly to heparin-agarose at physiological pH and to human activated CD4+ T cells. In this study we demonstrated that the viral protein binds to heparan sulfate side chains of syndecan-2, syndecan-4, and CD44v3 purified from HeLa cells and that these heparan sulfate proteoglycans (HSPGs) co-localize with HIV-1 p17 on activated human CD4+ T cells by confocal fluorescence analysis. Moreover, we observed a stimulatory or inhibitory activity when CD4+ T cells were activated with mitogens together with nanomolar or micromolar concentrations of the matrix protein.

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HEED, the Product of the Human Homolog of the MurineeedGene, Binds to the Matrix Protein of HIV-1

Journal of Biological Chemistry ◽

10.1074/jbc.274.3.1635 ◽

1999 ◽

Vol 274 (3) ◽

pp. 1635-1645 ◽

Cited By ~ 27

Author(s):

Régis Peytavi ◽

Saw See Hong ◽

Bernard Gay ◽

Arnaud Dupuy d’Angeac ◽

Luc Selig ◽

...

Keyword(s):

Matrix Protein ◽

Human Homolog ◽

The Matrix ◽

Hiv 1

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Redundant Roles for Nucleocapsid and Matrix RNA-Binding Sequences in Human Immunodeficiency Virus Type 1 Assembly

Journal of Virology ◽

10.1128/jvi.79.22.13839-13847.2005 ◽

2005 ◽

Vol 79 (22) ◽

pp. 13839-13847 ◽

Cited By ~ 68

Author(s):

David E. Ott ◽

Lori V. Coren ◽

Tracy D. Gagliardi

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Matrix Protein ◽

Particle Production ◽

Rna Binding ◽

Immunodeficiency Virus ◽

The Matrix ◽

Hiv 1

ABSTRACT RNA appears to be required for the assembly of retroviruses. This is likely due to binding of RNA by multiple Gags, which in turn organizes and stabilizes the Gag-Gag interactions that form the virion. While the nucleocapsid (NC) domain is the most conspicuous RNA-binding region of the human immunodeficiency virus type 1 (HIV-1) Gag polyprotein, we have previously shown that NC is not strictly required for efficient particle production. To determine if an RNA requirement for HIV-1 assembly exists, we analyzed virions produced by an NC deletion mutant for the presence of RNA. The results revealed that virions without NC still contained significant amounts of RNA. Since these packaged RNAs are probably incorporated by other RNA-binding sequences in Gag, an RNA-binding site in the matrix protein (MA) of Gag was mutated. While this mutation did not interfere with HIV-1 replication, a construct with both MA and NC mutations (MX/NX) failed to produce particles. The MX/NX mutant was rescued in trans by coassembly with several forms of Gag: wild-type Gag, either of the single-mutant Gags, or Gag truncations that contain MA or NC sequences. Addition of basic sequences to the MX/NX mutant partially restored particle production, consistent with a requirement for Gag-RNA binding in addition to Gag-Gag interactions. Together, these results support an RNA-binding requirement for Gag assembly, which relies on binding of RNA by MA or NC sequences to condense, organize, and stabilize the HIV-1 Gag-Gag interactions that form the virion.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2021366118 ◽

2020 ◽

Vol 118 (2) ◽

pp. e2021366118

Author(s):

Francesca Caccuri ◽

Pasqualina D’Ursi ◽

Matteo Uggeri ◽

Antonella Bugatti ◽

Pietro Mazzuca ◽

...

Keyword(s):

Matrix Protein ◽

Molecular Mimicry ◽

Cell Types ◽

Biological Data ◽

Matrix Proteins ◽

Target Cells ◽

Human Erythropoietin ◽

The Matrix ◽

The Difference ◽

Hiv 1

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.

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Inhibition of Early and Late Events of the HIV-1 Replication Cycle by Cytoplasmic Fab Intrabodies against the Matrix Protein, p17

Molecular Medicine ◽

10.1007/bf03401802 ◽

1997 ◽

Vol 3 (2) ◽

pp. 96-110 ◽

Cited By ~ 35

Author(s):

Reuven Levin ◽

Abner M. Mhashilkar ◽

Tatyana Dorfman ◽

Anatoly Bukovsky ◽

Christy Zani ◽

...

Keyword(s):

Matrix Protein ◽

Replication Cycle ◽

The Matrix ◽

Hiv 1

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Encapsulating Quantum Dots within HIV-1 Virions through Site-Specific Decoration of the Matrix Protein Enables Single Virus Tracking in Live Primary Macrophages

Nano Letters ◽

10.1021/acs.nanolett.8b02800 ◽

2018 ◽

Vol 18 (12) ◽

pp. 7457-7468 ◽

Cited By ~ 5

Author(s):

Qin Li ◽

Wen Yin ◽

Wei Li ◽

Zhiping Zhang ◽

Xiaowei Zhang ◽

...

Keyword(s):

Quantum Dots ◽

Matrix Protein ◽

Site Specific ◽

The Matrix ◽

Single Virus Tracking ◽

Hiv 1

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Analysis of the Viral Elements Required in the Nuclear Import of HIV-1 DNA

Journal of Virology ◽

10.1128/jvi.01952-09 ◽

2009 ◽

Vol 84 (2) ◽

pp. 729-739 ◽

Cited By ~ 48

Author(s):

Lise Rivière ◽

Jean-Luc Darlix ◽

Andrea Cimarelli

Keyword(s):

Nuclear Import ◽

Matrix Protein ◽

Active Phase ◽

Cell Types ◽

Target Cells ◽

Nuclear Pore ◽

Viral Dna ◽

The Matrix ◽

Central Polypurine Tract ◽

Hiv 1

ABSTRACT HIV-1 possesses an exquisite ability to infect cells independently from their cycling status by undergoing an active phase of nuclear import through the nuclear pore. This property has been ascribed to the presence of karyophilic elements present in viral nucleoprotein complexes, such as the matrix protein (MA); Vpr; the integrase (IN); and a cis-acting structure present in the newly synthesized DNA, the DNA flap. However, their role in nuclear import remains controversial at best. In the present study, we carried out a comprehensive analysis of the role of these elements in nuclear import in a comparison between several primary cell types, including stimulated lymphocytes, macrophages, and dendritic cells. We show that despite the fact that none of these elements is absolutely required for nuclear import, disruption of the central polypurine tract-central termination sequence (cPPT-CTS) clearly affects the kinetics of viral DNA entry into the nucleus. This effect is independent of the cell cycle status of the target cells and is observed in cycling as well as in nondividing primary cells, suggesting that nuclear import of viral DNA may occur similarly under both conditions. Nonetheless, this study indicates that other components are utilized along with the cPPT-CTS for an efficient entry of viral DNA into the nucleus.

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Structure of Equine Infectious Anemia Virus Matrix Protein

Journal of Virology ◽

10.1128/jvi.76.4.1876-1883.2002 ◽

2002 ◽

Vol 76 (4) ◽

pp. 1876-1883 ◽

Cited By ~ 28

Author(s):

Hideki Hatanaka ◽

Oleg Iourin ◽

Zihe Rao ◽

Elizabeth Fry ◽

Alan Kingsman ◽

...

Keyword(s):

Matrix Protein ◽

Equine Infectious Anemia Virus ◽

Sequence Similarity ◽

Membrane Binding ◽

Host Cells ◽

Immunodeficiency Virus ◽

The Matrix ◽

Equine Infectious Anemia ◽

Anemia Virus ◽

Hiv 1

ABSTRACT The Gag polyprotein is key to the budding of retroviruses from host cells and is cleaved upon virion maturation, the N-terminal membrane-binding domain forming the matrix protein (MA). The 2.8-Å resolution crystal structure of MA of equine infectious anemia virus (EIAV), a lentivirus, reveals that, despite showing no sequence similarity, more than half of the molecule can be superimposed on the MAs of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV). However, unlike the structures formed by HIV-1 and SIV MAs, the oligomerization state observed is not trimeric. We discuss the potential of this molecule for membrane binding in the light of conformational differences between EIAV MA and HIV or SIV MA.

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