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Article ; Online: Role of HIV-1 Tat Protein Interactions with Host Receptors in HIV Infection and Pathogenesis.

Cafaro, Aurelio / Schietroma, Ivan / Sernicola, Leonardo / Belli, Roberto / Campagna, Massimo / Mancini, Flavia / Farcomeni, Stefania / Pavone-Cossut, Maria Rosaria / Borsetti, Alessandra / Monini, Paolo / Ensoli, Barbara

International journal of molecular sciences

2024 Volume 25, Issue 3

Abstract: Each time the virus starts a new round of expression/replication, even under effective antiretroviral therapy (ART), the transactivator of viral transcription Tat is one of the first HIV-1 protein to be produced, as it is strictly required for HIV ... ...

Abstract	Each time the virus starts a new round of expression/replication, even under effective antiretroviral therapy (ART), the transactivator of viral transcription Tat is one of the first HIV-1 protein to be produced, as it is strictly required for HIV replication and spreading. At this stage, most of the Tat protein exits infected cells, accumulates in the extracellular matrix and exerts profound effects on both the virus and neighbor cells, mostly of the innate and adaptive immune systems. Through these effects, extracellular Tat contributes to the acquisition of infection, spreading and progression to AIDS in untreated patients, or to non-AIDS co-morbidities in ART-treated individuals, who experience inflammation and immune activation despite virus suppression. Here, we review the role of extracellular Tat in both the virus life cycle and on cells of the innate and adaptive immune system, and we provide epidemiological and experimental evidence of the importance of targeting Tat to block residual HIV expression and replication. Finally, we briefly review vaccine studies showing that a therapeutic Tat vaccine intensifies ART, while its inclusion in a preventative vaccine may blunt escape from neutralizing antibodies and block early events in HIV acquisition.
MeSH term(s)	Humans ; HIV Infections ; HIV-1/metabolism ; tat Gene Products, Human Immunodeficiency Virus/metabolism ; Antibodies, Neutralizing ; Vaccines/therapeutic use
Chemical Substances	tat Gene Products, Human Immunodeficiency Virus ; Antibodies, Neutralizing ; Vaccines
Language	English
Publishing date	2024-01-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25031704
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The Impact of Human Papilloma Viruses, Matrix Metallo-Proteinases and HIV Protease Inhibitors on the Onset and Progression of Uterine Cervix Epithelial Tumors: A Review of Preclinical and Clinical Studies.

Barillari, Giovanni / Monini, Paolo / Sgadari, Cecilia / Ensoli, Barbara

International journal of molecular sciences

2018 Volume 19, Issue 5

Abstract: Infection of uterine cervix epithelial cells by the Human Papilloma Viruses (HPV) is associated with the development of dysplastic/hyperplastic lesions, termed cervical intraepithelial neoplasia (CIN). CIN lesions may regress, persist or progress to ... ...

Abstract	Infection of uterine cervix epithelial cells by the Human Papilloma Viruses (HPV) is associated with the development of dysplastic/hyperplastic lesions, termed cervical intraepithelial neoplasia (CIN). CIN lesions may regress, persist or progress to invasive cervical carcinoma (CC), a leading cause of death worldwide. CIN is particularly frequent and aggressive in women infected by both HPV and the Human Immunodeficiency Virus (HIV), as compared to the general female population. In these individuals, however, therapeutic regimens employing HIV protease inhibitors (HIV-PI) have reduced CIN incidence and/or clinical progression, shedding light on the mechanism(s) of its development. This article reviews published work concerning: (i) the role of HPV proteins (including HPV-E5, E6 and E7) and of matrix-metalloproteinases (MMPs) in CIN evolution into invasive CC; and (ii) the effect of HIV-PI on events leading to CIN progression such as basement membrane and extracellular matrix invasion by HPV-positive CIN cells and the formation of new blood vessels. Results from the reviewed literature indicate that CIN clinical progression can be monitored by evaluating the expression of MMPs and HPV proteins and they suggest the use of HIV-PI or their derivatives for the block of CIN evolution into CC in both HIV-infected and uninfected women.
MeSH term(s)	Disease Progression ; Epithelial Cells/virology ; Female ; HIV Protease Inhibitors/pharmacology ; HIV Protease Inhibitors/therapeutic use ; Humans ; Matrix Metalloproteinases/metabolism ; Papillomaviridae/physiology ; Uterine Cervical Neoplasms/drug therapy ; Uterine Cervical Neoplasms/virology
Chemical Substances	HIV Protease Inhibitors ; Matrix Metalloproteinases (EC 3.4.24.-)
Language	English
Publishing date	2018-05-09
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms19051418
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Article ; Online: The Impact of Human Papilloma Viruses, Matrix Metallo-Proteinases and HIV Protease Inhibitors on the Onset and Progression of Uterine Cervix Epithelial Tumors

Giovanni Barillari / Paolo Monini / Cecilia Sgadari / Barbara Ensoli

International Journal of Molecular Sciences, Vol 19, Iss 5, p

A Review of Preclinical and Clinical Studies

2018 Volume 1418

Abstract	Infection of uterine cervix epithelial cells by the Human Papilloma Viruses (HPV) is associated with the development of dysplastic/hyperplastic lesions, termed cervical intraepithelial neoplasia (CIN). CIN lesions may regress, persist or progress to invasive cervical carcinoma (CC), a leading cause of death worldwide. CIN is particularly frequent and aggressive in women infected by both HPV and the Human Immunodeficiency Virus (HIV), as compared to the general female population. In these individuals, however, therapeutic regimens employing HIV protease inhibitors (HIV-PI) have reduced CIN incidence and/or clinical progression, shedding light on the mechanism(s) of its development. This article reviews published work concerning: (i) the role of HPV proteins (including HPV-E5, E6 and E7) and of matrix-metalloproteinases (MMPs) in CIN evolution into invasive CC; and (ii) the effect of HIV-PI on events leading to CIN progression such as basement membrane and extracellular matrix invasion by HPV-positive CIN cells and the formation of new blood vessels. Results from the reviewed literature indicate that CIN clinical progression can be monitored by evaluating the expression of MMPs and HPV proteins and they suggest the use of HIV-PI or their derivatives for the block of CIN evolution into CC in both HIV-infected and uninfected women.
Keywords	HPV ; uterine CIN ; uterine cervical carcinoma ; MMP ; HIV-PI ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2018-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: HIV therapeutic vaccines aimed at intensifying combination antiretroviral therapy.

Moretti, Sonia / Cafaro, Aurelio / Tripiciano, Antonella / Picconi, Orietta / Buttò, Stefano / Ensoli, Fabrizio / Sgadari, Cecilia / Monini, Paolo / Ensoli, Barbara

Expert review of vaccines

2020 Volume 19, Issue 1, Page(s) 71–84

Abstract: ... ...

Abstract	Introduction
MeSH term(s)	AIDS Vaccines/administration & dosage ; AIDS Vaccines/immunology ; Animals ; Anti-HIV Agents/administration & dosage ; Anti-HIV Agents/pharmacology ; CD4-Positive T-Lymphocytes/immunology ; Drug Therapy, Combination ; HIV Infections/immunology ; HIV Infections/prevention & control ; HIV Infections/virology ; Humans ; Virus Replication/drug effects
Chemical Substances	AIDS Vaccines ; Anti-HIV Agents
Language	English
Publishing date	2020-01-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2181284-6
ISSN	1744-8395 ; 1476-0584
ISSN (online)	1744-8395
ISSN	1476-0584
DOI	10.1080/14760584.2020.1712199
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Article ; Online: New insights into pathogenesis point to HIV-1 Tat as a key vaccine target.

Ensoli, Barbara / Moretti, Sonia / Borsetti, Alessandra / Maggiorella, Maria Teresa / Buttò, Stefano / Picconi, Orietta / Tripiciano, Antonella / Sgadari, Cecilia / Monini, Paolo / Cafaro, Aurelio

Archives of virology

2021 Volume 166, Issue 11, Page(s) 2955–2974

Abstract: Despite over 30 years of enormous effort and progress in the field, no preventative and/or therapeutic vaccines against human immunodeficiency virus (HIV) are available. Here, we briefly summarize the vaccine strategies and vaccine candidates that in ... ...

Abstract	Despite over 30 years of enormous effort and progress in the field, no preventative and/or therapeutic vaccines against human immunodeficiency virus (HIV) are available. Here, we briefly summarize the vaccine strategies and vaccine candidates that in recent years advanced to efficacy trials with mostly unsatisfactory results. Next, we discuss a novel and somewhat contrarian approach based on biological and epidemiological evidence, which led us to choose the HIV protein Tat for the development of preventive and therapeutic HIV vaccines. Toward this goal, we review here the role of Tat in the virus life cycle as well as experimental and epidemiological evidence supporting its key role in the natural history of HIV infection and comorbidities. We then discuss the preclinical and clinical development of a Tat therapeutic vaccine, which, by improving the functionality and homeostasis of the immune system and by reducing the viral reservoir in virologically suppressed vaccinees, helps to establish key determinants for intensification of combination antiretroviral therapy (cART) and a functional cure. Future developments and potential applications of the Tat therapeutic vaccine are also discussed, as well as the rationale for its use in preventative strategies. We hope this contribution will lead to a reconsideration of the current paradigms for the development of HIV/AIDS vaccines, with a focus on targeting of viral proteins with key roles in HIV pathogenesis.
MeSH term(s)	AIDS Vaccines/immunology ; AIDS Vaccines/pharmacology ; Clinical Trials, Phase I as Topic ; Clinical Trials, Phase II as Topic ; Comorbidity ; HIV Infections/epidemiology ; HIV Infections/transmission ; HIV Infections/virology ; HIV-1/pathogenicity ; HIV-1/physiology ; Humans ; tat Gene Products, Human Immunodeficiency Virus/immunology ; tat Gene Products, Human Immunodeficiency Virus/physiology
Chemical Substances	AIDS Vaccines ; tat Gene Products, Human Immunodeficiency Virus
Language	English
Publishing date	2021-08-14
Publishing country	Austria
Document type	Journal Article ; Review
ZDB-ID	7491-3
ISSN	1432-8798 ; 0304-8608
ISSN (online)	1432-8798
ISSN	0304-8608
DOI	10.1007/s00705-021-05158-z
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Article: Anti-Tat Immunity in HIV-1 Infection: Effects of Naturally Occurring and Vaccine-Induced Antibodies Against Tat on the Course of the Disease.

Cafaro, Aurelio / Tripiciano, Antonella / Picconi, Orietta / Sgadari, Cecilia / Moretti, Sonia / Buttò, Stefano / Monini, Paolo / Ensoli, Barbara

Vaccines

2019 Volume 7, Issue 3

Abstract: HIV-1 Tat is an essential protein in the virus life cycle, which is required for virus gene expression and replication. Most Tat that is produced during infection is released extracellularly and it plays a key role in HIV pathogenesis, including residual ...

Abstract	HIV-1 Tat is an essential protein in the virus life cycle, which is required for virus gene expression and replication. Most Tat that is produced during infection is released extracellularly and it plays a key role in HIV pathogenesis, including residual disease upon combination antiretroviral therapy (cART). Here, we review epidemiological and experimental evidence showing that antibodies against HIV-1 Tat, infrequently occurring in natural infection, play a protective role against disease progression, and that vaccine targeting Tat can intensify cART. In fact, Tat vaccination of subjects on suppressive cART in Italy and South Africa promoted immune restoration, including CD4+ T-cell increase in low immunological responders, and a reduction of proviral DNA even after six years of cART, when both CD4+ T-cell gain and DNA decay have reached a plateau. Of note, DNA decay was predicted by the neutralization of Tat-mediated entry of Env into dendritic cells by anti-Tat antibodies, which were cross-clade binding and neutralizing. Anti-Tat cellular immunity also contributed to the DNA decay. Based on these data, we propose the Tat therapeutic vaccine as a pathogenesis-driven intervention that effectively intensifies cART and it may lead to a functional cure, providing new perspectives and opportunities also for prevention and virus eradication strategies.
Language	English
Publishing date	2019-08-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines7030099
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Article: New insights into pathogenesis point to HIV-1 Tat as a key vaccine target

Ensoli, Barbara / Moretti, Sonia / Borsetti, Alessandra / Maggiorella, Maria Teresa / Buttò, Stefano / Picconi, Orietta / Tripiciano, Antonella / Sgadari, Cecilia / Monini, Paolo / Cafaro, Aurelio

Archives of virology. 2021 Nov., v. 166, no. 11

2021

Abstract	Despite over 30 years of enormous effort and progress in the field, no preventative and/or therapeutic vaccines against human immunodeficiency virus (HIV) are available. Here, we briefly summarize the vaccine strategies and vaccine candidates that in recent years advanced to efficacy trials with mostly unsatisfactory results. Next, we discuss a novel and somewhat contrarian approach based on biological and epidemiological evidence, which led us to choose the HIV protein Tat for the development of preventive and therapeutic HIV vaccines. Toward this goal, we review here the role of Tat in the virus life cycle as well as experimental and epidemiological evidence supporting its key role in the natural history of HIV infection and comorbidities. We then discuss the preclinical and clinical development of a Tat therapeutic vaccine, which, by improving the functionality and homeostasis of the immune system and by reducing the viral reservoir in virologically suppressed vaccinees, helps to establish key determinants for intensification of combination antiretroviral therapy (cART) and a functional cure. Future developments and potential applications of the Tat therapeutic vaccine are also discussed, as well as the rationale for its use in preventative strategies. We hope this contribution will lead to a reconsideration of the current paradigms for the development of HIV/AIDS vaccines, with a focus on targeting of viral proteins with key roles in HIV pathogenesis.
Keywords	HIV infections ; antiretroviral agents ; homeostasis ; immune system ; natural history ; pathogenesis ; therapeutics ; vaccines ; virology ; viruses
Language	English
Dates of publication	2021-11
Size	p. 2955-2974.
Publishing place	Springer Vienna
Document type	Article
Note	Review
ZDB-ID	7491-3
ISSN	1432-8798 ; 0304-8608
ISSN (online)	1432-8798
ISSN	0304-8608
DOI	10.1007/s00705-021-05158-z
Database	NAL-Catalogue (AGRICOLA)

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Article: Challenges in HIV Vaccine Research for Treatment and Prevention.

Ensoli, Barbara / Cafaro, Aurelio / Monini, Paolo / Marcotullio, Simone / Ensoli, Fabrizio

Frontiers in immunology

2014 Volume 5, Page(s) 417

Abstract: Many attempts have been made or are ongoing for HIV prevention and HIV cure. Many successes are in the list, particularly for HIV drugs, recently proposed also for prevention. However, no eradication of infection has been achieved so far with any drug. ... ...

Abstract	Many attempts have been made or are ongoing for HIV prevention and HIV cure. Many successes are in the list, particularly for HIV drugs, recently proposed also for prevention. However, no eradication of infection has been achieved so far with any drug. Further, a residual immune dysregulation associated to chronic immune activation and incomplete restoration of B and T cell subsets, together with HIV DNA persistence in reservoirs, are still unmet needs of the highly active antiretroviral therapy, causing novel "non-AIDS related" diseases that account for a higher risk of death even in virologically suppressed patients. These "ART unmet needs" represent a problem, which is expected to increase by ART roll out. Further, in countries such as South Africa, where six millions of individuals are infected, ART appears unable to contain the epidemics. Regretfully, all the attempts at developing a preventative vaccine have been largely disappointing. However, recent therapeutic immunization strategies have opened new avenues for HIV treatment, which might be exploitable also for preventative vaccine approaches. For example, immunization strategies aimed at targeting key viral products responsible of virus transmission, activation, and maintenance of virus reservoirs may intensify drug efficacy and lead to a functional cure providing new perspectives also for prevention and future virus eradication strategies. However, this approach imposes new challenges to the scientific community, vaccine developers, and regulatory bodies, such as the identification of novel immunological and virological biomarkers to assess efficacy end-points, taking advantage from the natural history of infection and exploiting lessons from former trials. This review will focus first on recent advancement of therapeutic strategies, then on the progresses made in preventative approaches, discussing concepts, and problems for the way ahead for the development of vaccines for HIV treatment and prevention.
Language	English
Publishing date	2014-09-08
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2014.00417
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Article ; Online: HIV-1 Tat Protein Enters Dysfunctional Endothelial Cells via Integrins and Renders Them Permissive to Virus Replication.

Cafaro, Aurelio / Barillari, Giovanni / Moretti, Sonia / Palladino, Clelia / Tripiciano, Antonella / Falchi, Mario / Picconi, Orietta / Pavone Cossut, Maria Rosaria / Campagna, Massimo / Arancio, Angela / Sgadari, Cecilia / Andreini, Claudia / Banci, Lucia / Monini, Paolo / Ensoli, Barbara

International journal of molecular sciences

2020 Volume 22, Issue 1

Abstract: Previous work has shown that the Tat protein of Human Immunodeficiency Virus (HIV)-1 is released by acutely infected cells in a biologically active form and enters dendritic cells upon the binding of its arginine-glycine-aspartic acid (RGD) domain to the ...

Abstract	Previous work has shown that the Tat protein of Human Immunodeficiency Virus (HIV)-1 is released by acutely infected cells in a biologically active form and enters dendritic cells upon the binding of its arginine-glycine-aspartic acid (RGD) domain to the α5β1, αvβ3, and αvβ5 integrins. The up-regulation/activation of these integrins occurs in endothelial cells exposed to inflammatory cytokines that are increased in HIV-infected individuals, leading to endothelial cell dysfunction. Here, we show that inflammatory cytokine-activated endothelial cells selectively bind and rapidly take up nano-micromolar concentrations of Tat, as determined by flow cytometry. Protein oxidation and low temperatures reduce Tat entry, suggesting a conformation- and energy-dependent process. Consistently, Tat entry is competed out by RGD-Tat peptides or integrin natural ligands, and it is blocked by anti-α5β1, -αvβ3, and -αvβ5 antibodies. Moreover, modelling-docking calculations identify a low-energy Tat-αvβ3 integrin complex in which Tat makes contacts with both the αv and β3 chains. It is noteworthy that internalized Tat induces HIV replication in inflammatory cytokine-treated, but not untreated, endothelial cells. Thus, endothelial cell dysfunction driven by inflammatory cytokines renders the vascular system a target of Tat, which makes endothelial cells permissive to HIV replication, adding a further layer of complexity to functionally cure and/or eradicate HIV infection.
MeSH term(s)	Alkynes/pharmacology ; Benzoxazines/pharmacology ; Biomarkers ; Cell Adhesion ; Cell-Penetrating Peptides/metabolism ; Cyclopropanes/pharmacology ; Cytokines/metabolism ; Endothelial Cells/metabolism ; Endothelial Cells/virology ; Fibronectins/metabolism ; HIV Infections/metabolism ; HIV Infections/virology ; HIV-1/drug effects ; HIV-1/physiology ; Host-Pathogen Interactions ; Humans ; Inflammation Mediators/metabolism ; Integrins/chemistry ; Integrins/metabolism ; Models, Molecular ; Oxidation-Reduction ; Protein Binding ; Protein Conformation ; Protein Interaction Domains and Motifs ; Structure-Activity Relationship ; Temperature ; Virus Replication ; Vitronectin/metabolism ; tat Gene Products, Human Immunodeficiency Virus/chemistry ; tat Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	Alkynes ; Benzoxazines ; Biomarkers ; Cell-Penetrating Peptides ; Cyclopropanes ; Cytokines ; Fibronectins ; Inflammation Mediators ; Integrins ; Vitronectin ; tat Gene Products, Human Immunodeficiency Virus ; efavirenz (JE6H2O27P8)
Language	English
Publishing date	2020-12-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22010317
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Article ; Online: HIV-1 Tat Protein Enters Dysfunctional Endothelial Cells via Integrins and Renders Them Permissive to Virus Replication

Aurelio Cafaro / Giovanni Barillari / Sonia Moretti / Clelia Palladino / Antonella Tripiciano / Mario Falchi / Orietta Picconi / Maria Rosaria Pavone Cossut / Massimo Campagna / Angela Arancio / Cecilia Sgadari / Claudia Andreini / Lucia Banci / Paolo Monini / Barbara Ensoli

International Journal of Molecular Sciences, Vol 22, Iss 317, p

2021 Volume 317

Abstract	Previous work has shown that the Tat protein of Human Immunodeficiency Virus (HIV)-1 is released by acutely infected cells in a biologically active form and enters dendritic cells upon the binding of its arginine-glycine-aspartic acid (RGD) domain to the α5β1, αvβ3, and αvβ5 integrins. The up-regulation/activation of these integrins occurs in endothelial cells exposed to inflammatory cytokines that are increased in HIV-infected individuals, leading to endothelial cell dysfunction. Here, we show that inflammatory cytokine-activated endothelial cells selectively bind and rapidly take up nano-micromolar concentrations of Tat, as determined by flow cytometry. Protein oxidation and low temperatures reduce Tat entry, suggesting a conformation- and energy-dependent process. Consistently, Tat entry is competed out by RGD-Tat peptides or integrin natural ligands, and it is blocked by anti-α5β1, -αvβ3, and -αvβ5 antibodies. Moreover, modelling–docking calculations identify a low-energy Tat-αvβ3 integrin complex in which Tat makes contacts with both the αv and β3 chains. It is noteworthy that internalized Tat induces HIV replication in inflammatory cytokine-treated, but not untreated, endothelial cells. Thus, endothelial cell dysfunction driven by inflammatory cytokines renders the vascular system a target of Tat, which makes endothelial cells permissive to HIV replication, adding a further layer of complexity to functionally cure and/or eradicate HIV infection.
Keywords	integrins ; endothelial cells ; inflammatory cytokines ; HIV-1 Tat protein ; cellular uptake ; HIV-1 target cells ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	571 ; 570
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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