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1.
Vaccine ; 41(20): 3171-3177, 2023 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-37088603

RESUMEN

The widespread outbreak of the monkeypox virus (MPXV) recognized in 2022 poses new challenges for public healthcare systems worldwide. With more than 86,000 people infected, there is concern that MPXV may become endemic outside of its original geographical area leading to repeated human spillover infections or continue to be spread person-to-person. Fortunately, classical public health measures (e.g., isolation, contact tracing and quarantine) and vaccination have blunted the spread of the virus, but cases are continuing to be reported in 28 countries in March 2023. We describe here the vaccines and drugs available for the prevention and treatment of MPXV infections. However, although their efficacy against monkeypox (mpox) has been established in animal models, little is known about their efficacy in the current outbreak setting. The continuing opportunity for transmission raises concerns about the potential for evolution of the virus and for expansion beyond the current risk groups. The priorities for action are clear: 1) more data on the efficacy of vaccines and drugs in infected humans must be gathered; 2) global collaborations are necessary to ensure that government authorities work with the private sector in developed and low and middle income countries (LMICs) to provide the availability of treatments and vaccines, especially in historically endemic/enzootic areas; 3) diagnostic and surveillance capacity must be increased to identify areas and populations where the virus is present and may seed resurgence; 4) those at high risk of severe outcomes (e.g., immunocompromised, untreated HIV, pregnant women, and inflammatory skin conditions) must be informed of the risk of infection and be protected from community transmission of MPXV; 5) engagement with the hardest hit communities in a non-stigmatizing way is needed to increase the understanding and acceptance of public health measures; and 6) repositories of monkeypox clinical samples, including blood, fluids, tissues and lesion material must be established for researchers. This MPXV outbreak is a warning that pandemic preparedness plans need additional coordination and resources. We must prepare for continuing transmission, resurgence, and repeated spillovers of MPXV.


Asunto(s)
Vacunas , Embarazo , Animales , Humanos , Femenino , /prevención & control , Virus de la Viruela de los Monos , Vacunación , Brotes de Enfermedades/prevención & control
2.
J Transl Med ; 20(1): 39, 2022 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-35073923

RESUMEN

BACKGROUND: The chemokine receptor CCR5 is the major coreceptor for HIV-1 cell entry. We previously observed that not all CCR5 mAbs reduce HIV-1 infection, suggesting that only some CCR5 populations are permissive for HIV-1 entry. This study aims to better understand the relevant conformational states of the cellular coreceptor, CCR5, involved in HIV entry. We hypothesized that CCR5 assumes multiple configurations during normal cycling on the plasma membrane, but only particular forms facilitate HIV-1 infection. METHODS: To this end, we quantified different CCR5 populations using six CCR5 monoclonal antibodies (mAbs) with different epitope specificities and visualized them with super-resolution microscopy. We quantified each surface CCR5 population before and after HIV-1 infection. RESULTS: Based on CCR5 conformational changes, down-modulation, and trafficking rates (internalization and recycling kinetics), we were able to distinguish among heterogeneous CCR5 populations and thus which populations might best be targeted to inhibit HIV-1 entry. We assume that a decreased surface presence of a particular CCR5 subpopulation following infection means that it has been internalized due to HIV-1 entry, and that it therefore represents a highly relevant target for future antiviral therapy strategies. Strikingly, this was most true for antibody CTC8, which targets the N-terminal region of CCR5 and blocks viral entry more efficiently than it blocks chemokine binding. CONCLUSIONS: Defining the virus-host interactions responsible for HIV-1 transmission, including specific coreceptor populations capable of establishing de novo infections, is essential for the development of an HIV-1 vaccine. This study hopefully will facilitate further development of inhibitors to block CCR5 usage by HIV-1, as well as inform future HIV-1 vaccine design.


Asunto(s)
Infecciones por VIH , VIH-1 , Humanos , Receptores CCR5 , Internalización del Virus
3.
Pharmaceutics ; 13(11)2021 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-34834213

RESUMEN

Combined antiretroviral therapy (cART) is treatment with a combination of several antiretroviral drugs that block multiple stages in the virus replication cycle. An estimated 60% of the 38 million HIV-1 patients globally receive some form of cART. The benefits of cART for controlling HIV-1 replication, transmission, and infection rates have led to its universal recommendation. Implementation has caused a substantial reduction in morbidity and mortality of persons living with HIV-1/AIDS (PLWHA). More specifically, standard cART has provided controlled, undetectable levels of viremia, high treatment efficacy, reduction in pill burden, and an improved lifestyle in HIV-1 patients overall. However, HIV-1 patients living with AIDS (HPLA) generally show high viral loads upon cART interruption. Latently infected resting CD4+ T cells remain a major barrier to curing infected patients on long-term cART. There is a critical need for more effective compounds and therapies that not only potently reactivate latently infected cells, but also lead to the death of these reactivated cells. Efforts are ongoing to better control ongoing viral propagation, including the identification of appropriate animal models that best mimic HIV-1 pathogenesis, before proceeding with clinical trials. Limited toxicity profiles, improved drug penetration to certain tissues, and extended-release formulations are needed to cover gaps in existing HIV-1 treatment options. This review will cover past, current, and new cART strategies recently approved or in ongoing development.

4.
J Transl Med ; 19(1): 453, 2021 10 30.
Artículo en Inglés | MEDLINE | ID: mdl-34717655

RESUMEN

HIV-1 reservoirs persist in the presence of combined antiretroviral therapy (cART). However, cART has transformed HIV-1 infection into a chronic disease marked by control of HIV-1 viral load and mortality reduction. Major challenges remain, including viral resistance upon termination of cART and persistence and identification of tissue distribution of HIV-1 reservoirs. Thus, appropriate animal models that best mimic HIV-1 pathogenesis are important, and the current study complements our previously published validation of the CD34+ hematopoietic humanized mouse model for this purpose. Here we analyze viral suppression using the recently developed combination of antiretrovirals that include Tenofovir Disoproxil (TDF), Emtricitabine (FTC), and Dolutegravir (DTG), a choice based on recent clinical outcomes showing its improved antiretroviral potency, CD4+ T cell preservation, tolerability, and prevention of viral drug resistance compared to that of previous regimens. We used quantitative Airyscan-based super resolution confocal microscopy of selected mouse tissues. Our data allowed us to identify specific solid tissue reservoirs of human T cells expressing the HIV-1 core protein p24. In particular, lymph node, brain, spleen, and liver were visualized as reservoirs for residual infected cells. Marked reduction of viral replication was evident. Considering that detection and visualization of cryptic sites of HIV-1 infection in tissues are clearly crucial steps towards HIV-1 eradication, appropriate animal models with pseudo-human immune systems are needed. In fact, current studies with humans and non-human primates have limited sample availability at multiple stages of infection and cannot easily analyze the effects of differently administered combined antiretroviral treatments on multiple tissues. That is easier to manage when working with humanized mouse models, although we realize the limitations due to low human cell recovery and thus the number of cells available for thorough and comprehensive analyses. Nonetheless, our data further confirm that the CD34+ humanized mouse model is a potentially useful pre-clinical model to study and improve current anti-HIV-1 therapies.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Animales , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Ratones , Oxazinas , Piperazinas , Piridonas , Tenofovir/farmacología , Tenofovir/uso terapéutico , Carga Viral
5.
Int J Mol Sci ; 22(8)2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33918708

RESUMEN

Several species of mycoplasmas, including Mycoplasma fermentans, are associated with certain human cancers. We previously isolated and characterized in our laboratory a strain of human mycoplasma M. fermentans subtype incognitus (MF-I1) able to induce lymphoma in a Severe Combined Immuno-Deficient (SCID) mouse model, and we demonstrated that its chaperone protein, DnaK, binds and reduces functions of human poly-ADP ribose polymerase-1 (PARP1) and ubiquitin carboxyl-terminal hydrolase protein-10 (USP10), which are required for efficient DNA repair and proper p53 activities, respectively. We also showed that other bacteria associated with human cancers (including Mycoplasmapneumoniae, Helicobacterpylori, Fusobacteriumnucleatum, Chlamydiathrachomatis, and Chlamydia pneumoniae) have closely related DnaK proteins, indicating a potential common mechanism of cellular transformation. Here, we quantify dnaK mRNA copy number by RT-qPCR analysis in different cellular compartments following intracellular MF-I1 infection of HCT116 human colon carcinoma cells. DnaK protein expression in infected cells was also detected and quantified by Western blot. The amount of viable intracellular mycoplasma reached a steady state after an initial phase of growth and was mostly localized in the cytoplasm of the invaded cells, while we detected a logarithmically increased number of viable extracellular bacteria. Our data indicate that, after invasion, MF-I1 is able to establish a chronic intracellular infection. Extracellular replication was more efficient while MF-I1 cultured in cell-free axenic medium showed a markedly reduced growth rate. We also identified modifications of important regulatory regions and heterogeneous lengths of dnaK mRNA transcripts isolated from intracellular and extracellular MF-I1. Both characteristics were less evident in dnaK mRNA transcripts isolated from MF-I1 grown in cell-free axenic media. Taken together, our data indicate that MF-I1, after establishing a chronic infection in eukaryotic cells, accumulates different forms of dnaK with efficient RNA turnover.


Asunto(s)
Proteínas Bacterianas/genética , Regulación Bacteriana de la Expresión Génica , Proteínas HSP70 de Choque Térmico/genética , Mycoplasma fermentans/genética , Células Cultivadas , Células HCT116 , Humanos , Mutación , Infecciones por Mycoplasma/microbiología
6.
AIDS Res Hum Retroviruses ; 36(10): 835-841, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32623916

RESUMEN

The efficacy of combined antiretroviral therapy (cART) against HIV-1 is evidenced by reduction of plasma viremia, disease progression, viral transmission, and mortality. However, major challenges still remain in HIV-1 management, especially the emergence of resistant strains and the persistence of viral reservoirs, apparent after cART treatment interruption. Efforts are ongoing to explore the most effective means to intensify cART and successfully control residual viral replication. We anticipate that the reduction by cART of HIV-1 reservoirs could be further enhanced by combining cART with entry inhibitors and drugs that silence CCR5 expression. CCR5-targeting drugs are attractive option because of their low side effects when combined with other antiretroviral drugs. The concept that their inclusion would be effective has been supported by the reduction in two long terminal repeat unintegrated circular DNA, a marker for new infections, when CCR5-targeting drugs are added to standard antiretroviral treatment. This study is, in part, an extension of our previous study demonstrating greater preservation of human CD4+ T-cells and CD4+/CD8+ cell ratios in HIV-infected CD34+ NSG mice when CCR5-targeting drugs were included with standard cART. In this study, we treated HIV-1-infected cell cultures with cART or cART plus CCR5-targeting drugs (maraviroc and rapamycin). We found that treatment intensification with CCR5-targeting drugs led to a significant reduction of HIV-1 replication in peripheral blood ononuclear cells (PBMCs), as judged by measured viral DNA copies and p24 levels. Our data provide proof of principle for the benefit of adding CCR5-targeting drugs to traditional, standard cART to further lower viremia and subsequently reduce viral reservoirs in clinical settings, while potentially lowering side effects by reducing cART concentrations.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Preparaciones Farmacéuticas , Animales , Fármacos Anti-VIH/uso terapéutico , Relación CD4-CD8 , Infecciones por VIH/tratamiento farmacológico , Humanos , Maraviroc , Ratones , Receptores CCR5 , Carga Viral
7.
J AIDS HIV Treat ; 2(1): 23-29, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32457941

RESUMEN

Despite decades of intensive basic and clinical research efforts, there is still no successful vaccine candidate against human immunodeficiency virus (HIV-1). Standard combined antiretroviral therapy (cART) has been successfully developed and has given remarkable results suppressing HIV-1 infection and transmission. However, cART cannot fully clear the virus from the infected patients. A cure for HIV-1 is highly desirable to stop both the spread of the virus in humans and disease progression in HIV-1 patients. A safe and effective cure strategy for HIV-1 infection will require appropriate animal models that properly mimic HIV-1 infection and advance HIV-1 cure research. Animal models have been a crucial tool in the drug discovery process for investigation of HIV-1 disease mainly in preclinical evaluations of antiretroviral drugs and vaccines. An ideal animal model should recapitulate the main aspects of human-specific HIV-1 infection and pathogenesis with their associated immune responses, while permitting invasive antiretroviral studies. The best humanized mouse models would allow a thorough evaluation of antiretroviral strategies that are aimed towards reducing the establishment and size of the HIV-1 reservoirs. In this review, we evaluate multiple humanized mouse models while presenting their strengths and limitations for HIV-1 research. These humanized mouse models have been tailored in recent decades and heavily employed to address specific quintessential and remaining questions of HIV-1 persistence, pathogenesis and ultimately, eradication.

8.
J AIDS HIV Treat ; 1(1): 1-5, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31414081
9.
AIDS Res Hum Retroviruses ; 35(8): 718-728, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31099257

RESUMEN

Significant progress has been made in the diagnostics and treatment of AIDS since the discovery of the human immunodeficiency virus type 1 (HIV-1) in 1983. The remarkable effectiveness of combined antiretroviral therapy (cART) is evidenced by mortality reduction, control of peripheral blood viral load, and in a nearly normal quality of HIV patients' lives. Remaining obstacles in treatment and cure are drug toxicities and side effects, viral resistance, persistence of HIV-1 reservoirs on termination of cART treatment, the cost of lifelong antiretroviral therapy, and the stigma associated with taking antiretroviral drugs. As determined by plasma viral RNA and peripheral blood mononuclear cells (PBMC) proviral DNA, we show improved suppression of productive HIV infection in human CD34+ hematopoietic stem cell-engrafted NOD (nonobese diabetic)-SCID (severe combined immunodeficiency)-il2rg-/- (NSG) mice by combined treatment with cART and CCR5 targeting drugs, compared with cART alone, as well as an increased preservation of human CD4+ T cells (defined as CD45+ CD3+ CD4+ cells) and CD4+/CD8+ cell ratios in infected mice. The data also suggest a possible reduction in viral reservoirs. Our data confirm that this animal model is suitable for detection of productive HIV infection, replication, and establishment of viral reservoirs. The data also provide proof of principle for the utility of combining CCR5 targeting drugs, maraviroc and rapamycin, with traditional cART to improve control of viremia and reduce viral reservoirs. This study thus serves as a model for future HIV-1 studies that could lead to the clinical development of new generations of antiretroviral drugs.


Asunto(s)
Fármacos Anti-VIH/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Trasplante de Células Madre Hematopoyéticas , Receptores CCR5/efectos de los fármacos , Animales , Antígenos CD34/metabolismo , Relación CD4-CD8 , Linfocitos T CD4-Positivos/inmunología , Modelos Animales de Enfermedad , Células Madre Hematopoyéticas/virología , Humanos , Subunidad gamma Común de Receptores de Interleucina/genética , Maraviroc/farmacología , Ratones , Ratones Noqueados , Ratones SCID , Sirolimus/farmacología , Carga Viral/efectos de los fármacos , Viremia/tratamiento farmacológico
10.
AIDS Res Hum Retroviruses ; 32(2): 178-86, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26059995

RESUMEN

We have previously shown that FLSC, a chimeric protein containing HIV-1BAL gp120 and the D1 and D2 domains of human CD4, blocks the binding and entry of HIV-1 into target cells by occluding CCR5, the major HIV-1 coreceptor. In an effort to improve the antiviral potential of FLSC, we fused it with the hinge-CH2-CH3 region of human IgG1. The IgG moiety should increase both the affinity and stability in vivo of FLSC, due to the resultant bivalency and an extended serum half-life, thereby increasing its antiviral potency. We previously showed that (FLSC) IgG1 indeed had greater antiviral activity against T cell infections. Here we extend these results to macrophages, for which (FLSC) IgG1 has a more potent antiviral activity than FLSC alone, due in part to its higher binding affinity for CCR5. We also test both compounds in a relevant humanized mouse model and show that, as anticipated, the IgG1 moiety confers a greatly extended half-life. These data, taken together with previous results, suggest potential clinical utility for (FLSC) IgG1 and support further developmental work toward eventual clinical trials.


Asunto(s)
Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5/farmacología , Antígenos CD4/farmacología , Proteína gp120 de Envoltorio del VIH/farmacología , Fragmentos Fc de Inmunoglobulinas/farmacología , Inmunoglobulina G/farmacología , Macrófagos/efectos de los fármacos , Animales , Línea Celular Tumoral , Células HEK293 , VIH-1/efectos de los fármacos , Células HeLa , Humanos , Macrófagos/virología , Ratones , Ratones Noqueados , Ratones SCID , Microscopía Confocal , Receptores CCR5/metabolismo
12.
J Infect Dis ; 208(12): 2085-94, 2013 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-23922365

RESUMEN

BACKGROUND: Targeting host-cell pathways to increase the potency of nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs) is an important strategy for clinical investigation. Resveratrol is a natural product that inhibits cellular ribonucleotide reductase, prolonging the S phase of the cell cycle and preferentially lowering dATP levels. METHODS: We performed in vitro evaluation of resveratrol on the antiviral activity of adenosine analog tenofovir (TFV) against sensitive and drug-resistant human immunodeficiency virus type 1 (HIV-1), from subtypes B and C, in primary cells. RESULTS: Resveratrol enhanced the antiviral activity of TFV by up to 10-fold and restored susceptibility of TFV-resistant viruses. Resveratrol prevented wild-type HIV-1 from developing phenotypic resistance to TFV. Notably, resveratrol enhanced TFV activity against sensitive and resistant HIV-1 from both subtypes B and C. CONCLUSIONS: Prolonged wide-scale use of thymidine analogs in the setting of viral failure has limited the efficacy of second-line NRTI-based regimens in Africa. Moreover, the extensive use of ddI and d4T has led to high frequencies of the K65R mutation, further compromising TFV efficacy. In light of increasing resistance to commonly used NRTIs in global HIV treatment programs, targeting nucleoside biosynthesis with resveratrol, or derivatives with improved bioavailabilities, is a potential strategy to maintain, enhance, and restore susceptibility of commonly used NRTIs.


Asunto(s)
Adenina/análogos & derivados , VIH-1/metabolismo , Organofosfonatos/farmacología , Purinas/biosíntesis , Inhibidores de la Transcriptasa Inversa/farmacología , Estilbenos/farmacología , Adenina/farmacología , Células Cultivadas , Farmacorresistencia Viral , Sinergismo Farmacológico , VIH-1/efectos de los fármacos , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Purinas/metabolismo , Receptores CCR5 , Resveratrol , Tenofovir , Replicación Viral/efectos de los fármacos
13.
Retrovirology ; 10: 92, 2013 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-23985023

RESUMEN

BACKGROUND: Human Immunodeficiency Virus Type I (HIV-1) infection is associated with a high incidence of B-cell lymphomas. The role of HIV in these lymphomas is unclear and currently there are no valid in vivo models for better understanding HIV-related lymphomagenesis. Transgenic (Tg) 26 mice have a 7.4-kb pNL4-3 HIV-1 provirus lacking a 3.1-kb sequence encompassing parts of the gag-pol region. Approximately 15% of these HIV Tg mice spontaneously develop lymphoma with hallmark pre-diagnostic markers including skin lesions, diffuse lymphadenopathy and an increase in pro-inflammatory serum cytokines. Here we describe the phenotypic and molecular characteristics of the B cell leukemia/lymphoma in the Tg mice. RESULTS: The transformed B cell population consists of CD19+pre-BCR+CD127+CD43+CD93+ precursor B cells. The tumor cells are clonal and characterized by an increased expression of several cellular oncogenes. Expression of B cell-stimulatory cytokines IL-1ß, IL-6, IL-10, IL-12p40, IL-13 and TNFα and HIV proteins p17, gp120 and nef were elevated in the Tg mice with lymphoma. CONCLUSIONS: Increased expression of HIV proteins and the B-cell stimulatory factors is consistent with the interpretation that one or more of these factors play a role in lymphoma development. The lymphomas share many similarities with those occurring in HIV/AIDS+ patients and may provide a valuable model for understanding AIDS-related lymphomagenesis and elucidating the role played by HIV-1.


Asunto(s)
VIH-1/genética , Linfoma de Células B/patología , Linfoma de Células B/virología , Ratones Transgénicos , Provirus/genética , Animales , Antígenos CD/análisis , Linfocitos B/química , Linfocitos B/virología , Citocinas/biosíntesis , ADN Viral/química , ADN Viral/genética , Expresión Génica , Proteínas del Virus de la Inmunodeficiencia Humana/biosíntesis , Inmunofenotipificación , Ratones , Datos de Secuencia Molecular , Análisis de Secuencia de ADN
14.
Stem Cells Dev ; 22(1): 148-57, 2013 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-22734943

RESUMEN

Over the past 10 years, a great deal has been learned about the fundamental biology and therapeutic application of bone marrow-derived human mesenchymal stem cells (MSCs). Intravenous administration of these cells is the preferred route for therapeutic delivery of MSCs. Vascular endothelial cells (ECs) are the first cell type that MSCs encounter following IV administration. However, little is known about the biological consequences of interactions between MSCs and ECs, and if any therapeutic benefit results from this interaction. We show that MSCs exert potent stabilizing effects on ECs using an in vitro coculture system. Such effects include decreased EC proliferation and the reduction of EC vascular network formation in matrigel. Interestingly, these effects appear to require EC-MSC contact and result in enhanced colocalization of VE-Cadherin and ß-catenin at the cell membrane. Disruption of the VE-Cadherin/ß-catenin interaction abrogates the observed effects. As a functional in vivo correlate, we show that intravenously administered MSCs strongly inhibit angiogenesis in a matrigel plug assay. Taken together, these results identify a novel mechanism of action of MSCs that involves a contact-dependent EC interaction. These findings are relevant to intravenous use of MSCs and provide insight into further optimizing therapeutic strategies involving MSCs.


Asunto(s)
Antígenos CD/metabolismo , Cadherinas/metabolismo , Proliferación Celular , Células Endoteliales de la Vena Umbilical Humana/fisiología , Células Madre Mesenquimatosas/fisiología , Neovascularización Fisiológica , beta Catenina/metabolismo , Uniones Adherentes/metabolismo , Animales , Comunicación Celular , Técnicas de Cocultivo , Colágeno , Combinación de Medicamentos , Puntos de Control de la Fase G1 del Ciclo Celular , Humanos , Laminina , Masculino , Trasplante de Células Madre Mesenquimatosas , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Proteoglicanos , Vía de Señalización Wnt , Proteína Wnt3A/metabolismo
15.
AIDS ; 25(9): 1232-5, 2011 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-21505306

RESUMEN

CCR5 blockers inhibit CCR5-tropic (R5) HIV-1, including strains resistant to other antiretrovirals. We demonstrate that the CCR5 antibody HGS004 and the CCR5 antagonist maraviroc have potent antiviral synergy against R5 HIV-1, translating into dose reductions of more than 10-fold for maraviroc and more than 150-fold for HGS004. These data, together with the high barrier of resistance to HGS004, suggest that combinations of maraviroc and HGS004 could provide effective preventive and therapeutic strategies against R5 HIV-1.


Asunto(s)
Antagonistas de los Receptores CCR5 , Ciclohexanos/inmunología , Farmacorresistencia Viral/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Receptores CCR5/inmunología , Triazoles/inmunología , Ciclohexanos/antagonistas & inhibidores , Farmacorresistencia Viral/inmunología , Quimioterapia Combinada , Infecciones por VIH/inmunología , VIH-1/inmunología , Humanos , Maraviroc , Triazoles/antagonistas & inhibidores
16.
Virology ; 411(1): 32-40, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21232779

RESUMEN

R5 HIV-1 strains resistant to the CCR5 antagonist Maraviroc (MVC) can use drug-bound CCR5. We demonstrate that MVC-resistant HIV-1 exhibits delayed kinetics of coreceptor engagement and fusion during drug-bound versus free CCR5 infection of cell lines. Antibodies directed against the second extracellular loop (ECL2) of CCR5 had greater antiviral activity against MVC-bound compared to MVC-free CCR5 infection. However, in PBMCs, only ECL2 CCR5 antibodies HGS004 and HGS101, but not 2D7, inhibited infection by MVC resistant HIV-1 more potently with MVC-bound than with free CCR5. In addition, HGS004 and HGS101, but not 2D7, restored the antiviral activity of MVC against resistant virus in PBMCs. In flow cytometric studies, CCR5 binding by the HGS mAbs, but not by 2D7, was increased when PBMCs were treated with MVC, suggesting MVC increases exposure of the relevant epitope. Thus, HGS004 and HGS101 have antiviral mechanisms distinct from 2D7 and could help overcome MVC resistance.


Asunto(s)
Fármacos Anti-VIH/farmacología , Anticuerpos/inmunología , Ciclohexanos/farmacología , Farmacorresistencia Viral , VIH-1/fisiología , Receptores CCR5/inmunología , Triazoles/farmacología , Internalización del Virus , Antagonistas de los Receptores CCR5 , Células Cultivadas , VIH-1/efectos de los fármacos , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/virología , Maraviroc , Pruebas de Sensibilidad Microbiana
17.
Stem Cells Dev ; 20(1): 89-101, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20446815

RESUMEN

The barrier formed by endothelial cells (ECs) plays an important role in tissue homeostasis by restricting passage of circulating molecules and inflammatory cells. Disruption of the endothelial barrier in pathologic conditions often leads to uncontrolled inflammation and tissue damage. An important component of this barrier is adherens junctions, which restrict paracellular permeability. The transmembrane protein vascular endothelial (VE)-cadherin and its cytoplasmic binding partner ß-catenin are major components of functional adherens junctions. We show that mesenchymal stem cells (MSCs) significantly reduce endothelial permeability in cocultured human umbilical vascular endothelial cells (HUVECs) and following exposure to vascular endothelial growth factor, a potent barrier permeability-enhancing agent. When grown in cocultures with HUVECs, MSCs increased VE-cadherin levels and enhanced recruitment of both VE-cadherin and ß-catenin to the plasma membrane. Enhanced membrane localization of ß-catenin was associated with a decrease in ß-catenin-driven gene transcription. Disruption of the VE-cadherin/ß-catenin interaction by overexpressing a truncated VE-cadherin lacking the ß-catenin interacting domain blocked the permeability-stabilizing effect of MSCs. Interestingly, a conditioned medium from HUVEC-MSC cocultures, but not from HUVEC or MSC cells cultured alone, significantly reduced endothelial permeability. In addition, intravenous administration of MSCs to brain-injured rodents reduced injury-induced enhanced blood-brain barrier permeability. Similar to the effect on in vitro cultures, this stabilizing effect on blood-brain barrier function was associated with increased expression of VE-cadherin. Taken together, these results identify a putative mechanism by which MSCs can modulate vascular EC permeability. Further, our results suggest that the mediator(s) of these vascular protective effects is a secreted factor(s) released as a result of direct MSC-EC interaction.


Asunto(s)
Antígenos CD/metabolismo , Cadherinas/metabolismo , Permeabilidad Capilar , Endotelio Vascular/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Transducción de Señal , beta Catenina/metabolismo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/patología , Lesiones Encefálicas/patología , Lesiones Encefálicas/terapia , Permeabilidad Capilar/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Técnicas de Cocultivo , Medios de Cultivo Condicionados/farmacología , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Endotelio Vascular/efectos de los fármacos , Humanos , Inyecciones Intravenosas , Masculino , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Unión Proteica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Venas Umbilicales/citología
18.
Cancer Biomark ; 9(1-6): 341-74, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-22112484

RESUMEN

In the past several decades, great progress has been made in our understanding of normal hematopoiesis and its malignant transformation. This article provides a comprehensive and up-to-date review of pathogenesis of leukemia and lymphoma, with an emphasis on early molecular events. Current concepts of normal hematopoiesis and its key regulatory processes are summarized. Various environmental and infectious factors that play a causative role in hematopoietic malignancies are described. In particular, several causative viruses, i.e. HTLV1, HHV8 and EBV, are discussed in depth. Numerous genetic abnormalities have been identified in leukemia and lymphoma, including chromosomal translocations, gene deletions, amplifications, and point mutations. Synopses are included for the most frequently encountered aberrations, and their relation to normal and malignant hematopoiesis, disease classification and prognosis. Major molecular mechanisms and signal transduction pathways involved in the leukemogenesis are depicted; these include blockage of differentiation, self-sustainable proliferation, abnormal cell cycle progression and impaired apoptosis. Also included are the recently discovered microRNAs, and their potential role in the pathogenesis of leukemia and lymphoma. Future directions in leukemia and lymphoma research are presented, including several modern molecular technologies and their importance in developing new biomarkers for early detection of leukemia and lymphoma.


Asunto(s)
Leucemia/etiología , Linfoma/etiología , Animales , Biomarcadores de Tumor/genética , Ambiente , Regulación Neoplásica de la Expresión Génica , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Leucemia/diagnóstico , Leucemia/genética , Leucemia/patología , Linfoma/diagnóstico , Linfoma/genética , Linfoma/patología , Estadificación de Neoplasias , Transducción de Señal
19.
J Virol ; 82(11): 5460-71, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18353949

RESUMEN

Human immunodeficiency virus (HIV) type 1 infection requires functional interactions of the viral surface (gp120) glycoprotein with cell surface CD4 and a chemokine coreceptor (usually CCR5 or CXCR4) and of the viral transmembrane (gp41) glycoprotein with the target cell membrane. Extensive genetic variability, generally in gp120 and the gp41 ectodomain, can result in altered coreceptor use, fusion kinetics, and neutralization sensitivity. Here we describe an R5 HIV variant that, in contrast to its parental virus, infects T-cell lines expressing low levels of cell surface CCR5. This correlated with an ability to infect cells in the absence of CD4, increased sensitivity to a neutralizing antibody recognizing the coreceptor binding site of gp120, and increased resistance to the fusion inhibitor T-20. Surprisingly, these properties were determined by alterations in gp41, including the cytoplasmic tail, a region not previously shown to influence coreceptor use. These data indicate that HIV infection of cells with limiting levels of cell surface CCR5 can be facilitated by gp41 sequences that are not exposed on the envelope ectodomain yet induce allosteric changes in gp120 that facilitate exposure of the CCR5 binding site.


Asunto(s)
Antígenos CD4/metabolismo , Proteína gp41 de Envoltorio del VIH/metabolismo , Receptores CCR5/metabolismo , Secuencia de Aminoácidos , Animales , Antígenos CD4/genética , Línea Celular , Chlorocebus aethiops , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/metabolismo , Proteína gp41 de Envoltorio del VIH/química , Proteína gp41 de Envoltorio del VIH/genética , VIH-1/genética , VIH-1/metabolismo , Humanos , Datos de Secuencia Molecular , Receptores CCR5/genética , Sensibilidad y Especificidad , Alineación de Secuencia , Linfocitos T/metabolismo , Virión/genética , Virión/metabolismo
20.
AIDS Res Hum Retroviruses ; 23(1): 33-42, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17263630

RESUMEN

A potential strategy to combat the worldwide AIDS epidemic is to develop a vaginal microbicide that prevents the sexual transmission of HIV-1. One approach for preventing vaginal HIV transmission is to block the viral coreceptor CCR5 with naturally occurring chemokine ligands. In this study, we used a cynomolgus macaque model to evaluate whether a variant of the CCR5 ligand RANTES (-2 RANTES), tested alone or in a nonphospholipid liposome carrier (Novasomes 7474), blocks vaginal challenge with a CCR5-tropic simian/human immunodeficiency virus (SHIV(162P3)). When tested in vitro, the synthetic chemokine potently inhibited SHIV(162P3) infection of cynomolgus macaque peripheral blood mononuclear cells (PBMC). Colposcopic examinations of treated animals and histological examination of cervicovaginal biopsies showed minimal signs of tissue inflammation following vaginal application of Novasomes 7474, -2 RANTES formulated in Novasomes 7474, or -2 RANTES alone. Following vaginal challenge with SHIV(162P3), complete protection was observed in four of six animals treated vaginally with -2 RANTES (0.13 mM) formulated in Novasomes 7474. However, the same proportion of animals was protected by treatment with Novasomes 7474 carrier alone. Two of five animals treated with 0.5 mM -2 RANTES in PBS were protected from infection. Further, all animals were infected when treated with lower chemokine concentrations. These findings indicate that natural CCR5 ligands may have limited efficacy in stringent nonhuman primate models for vaginal infection. In comparison, liposomal agents such as Novasomes 7474 provide comparatively robust protection against vaginal transmission.


Asunto(s)
Fármacos Anti-VIH/farmacología , Antiinfecciosos Locales/farmacología , Quimiocina CCL5/farmacología , VIH-1/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Administración Intravaginal , Animales , Fármacos Anti-VIH/administración & dosificación , Antiinfecciosos Locales/toxicidad , Colposcopía , Modelos Animales de Enfermedad , Estudios de Evaluación como Asunto , Femenino , Liposomas , Macaca mulatta , ARN Viral/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Factores de Tiempo , Vagina/efectos de los fármacos , Carga Viral
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