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1.
Methods Mol Biol ; 2060: 31-56, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31617171

RESUMEN

Herpes simplex viruses (HSV) types 1 and 2 are ubiquitous. They both cause genital herpes, occasionally severe disease in the immunocompromised, and facilitate much HIV acquisition globally. Despite more than 60 years of research, there is no licensed prophylactic HSV vaccine and some doubt as to whether this can be achieved. Nevertheless, a previous HSV vaccine candidate did have partial success in preventing genital herpes and HSV acquisition and another immunotherapeutic candidate reduced viral shedding and recurrent lesions, inspiring further research. However, the entry pathway of HSV into the anogenital mucosa and the subsequent cascade of immune responses need further elucidation so that these responses could be mimicked or improved by a vaccine, to prevent viral entry and colonization of the neuronal ganglia. For an effective novel vaccine against genital herpes the choice of antigen and adjuvant may be critical. The incorporation of adjuvants of the vaccine candidates in the past, may account for their partial efficacy. It is likely that they can be improved by understanding the mechanisms of immune responses elicited by different adjuvants and comparing these to natural immune responses. Here we review the history of vaccines for HSV, those in development and compare them to successful vaccines for chicken pox or herpes zoster. We also review what is known of the natural immune control of herpes lesions, via interacting innate immunity and CD4 and CD8 T cells and the lessons they provide for development of new, more effective vaccines.

2.
Methods Mol Biol ; 2060: 343-354, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31617189

RESUMEN

Transmission electron microscopy (TEM) provides the resolution necessary to identify both viruses and subcellular components of cells infected with many types of viruses, including herpes simplex virus. Recognized as a powerful tool in both diagnostic and research-based virology laboratories, TEM has made possible the identification of new viruses and has contributed to the elucidation of virus life cycle and virus-host cell interaction.While there are many sample preparation techniques for TEM, conventional processing using chemical fixation and resin embedding remains a useful technique, available in virtually all EM laboratories, for studying virus/cell ultrastructure. In this chapter, we describe the preparation of herpes simplex virus infected primary neurons, grown on plastic coverslips, to allow for sectioning of neurons and axons in their growth plane. This technique allows for TEM examination of cell bodies, axons, growth cones and varicosities, providing powerful insights into virus-cell interaction.

3.
Methods Mol Biol ; 2060: 355-364, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31617190

RESUMEN

Transmission immunoelectron microscopy allows for the ultrastructural detection and localization of herpes simplex virus-1 (HSV-1) particles and viral proteins within the infected cell and their relation to the cell cytoskeleton, cellular proteins, vesicles, membranes, and organelles. For the successful application of immunoelectron microscopy, preservation of cell ultrastructure and of epitope antigenicity is essential during sample preparation. This chapter describes the use of chemical fixation followed by rapid cooling of HSV-1 infected sensory neurons in the presence of sucrose as a cryoprotectant to achieve optimal preservation of cell morphology and the use of freeze substitution and resin polymerization at low temperatures for preservation of protein antigenicity. In order to examine HSV-1 infection in the specialized compartments of the neurons (cell body, axons, and growth cones), neurons cultured on plastic coverslips are flat embedded prior to resin polymerization. Overall, this method allows for the ultrathin sectioning and immunogold labeling of the neurons and their axons in growth plane.

4.
Methods Mol Biol ; 2060: 409-418, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31617194

RESUMEN

Understanding how herpes simplex virus-1 (HSV-1) interacts with different parts of the neuron is fundamental in understanding the mechanisms behind HSV-1 transport during primary and recurrent infections. In this chapter, we describe a unique neuronal culture system that is capable of compartmentalizing neuronal cell bodies from their axons to study the transport of HSV-1 along axons. The ability to separate neuronal cell bodies and axons provides a unique model to investigate the mechanisms used by HSV-1 for viral transport, assembly, and exit from different parts of the neuron.

5.
Vaccine ; 37(43): 6262-6267, 2019 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-31537443

RESUMEN

BACKGROUND: Herpes zoster (HZ) risk appears to vary by sex and geographic ancestry/ethnicity. METHODS: In 2 randomized clinical trials, participants received 2 doses of adjuvanted recombinant zoster vaccine (RZV) or placebo intramuscularly, 2 months apart. In this post-hoc analysis, we investigate efficacy of RZV against HZ and postherpetic neuralgia (PHN) by sex, geographic region, and geographic ancestry/ethnicity in ≥50-year-olds (ZOE-50: NCT01165177) and ≥70-year-olds (pooled data from ZOE-50 and ZOE-70: NCT01165229). RESULTS: Vaccine efficacy against HZ or PHN was similar in women and men. Across geographic regions, efficacy against HZ ranged between 95.7 and 97.2% in ≥50-year-olds, and between 87.3% and 95.1% in ≥70-year-olds; efficacy against PHN ranged between 86.8 and 100% in ≥70-year-olds. Across ancestral/ethnic groups, efficacy ranged between 88.1 and 100% against HZ and between 65.9 and 100% against PHN in ≥70-year-olds. CONCLUSIONS: While the ZOE-50/70 studies were not powered or pre-designed for these post-hoc analyses, RZV appears efficacious against HZ and PHN irrespective of sex, region, or geographic ancestry/ethnicity.

6.
Hum Vaccin Immunother ; : 1-8, 2019 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-31216205

RESUMEN

In two pivotal efficacy studies (ZOE-50; ZOE-70), the adjuvanted recombinant zoster vaccine (RZV) demonstrated >90% efficacy against herpes zoster (HZ). Adults aged ≥50 or ≥70 years (ZOE-50 [NCT01165177]; ZOE-70 [NCT01165229]) were randomized to receive 2 doses of RZV or placebo 2 months apart. Vaccine efficacy and safety were evaluated post-hoc in the pooled (ZOE-50/70) population according to the number and type of selected medical conditions present at enrollment. At enrollment, 82.3% of RZV and 82.7% of placebo recipients reported ≥1 of the 15 selected medical conditions. Efficacy against HZ ranged from 84.5% (95% Confidence Interval [CI]: 46.4-97.1) in participants with respiratory disorders to 97.0% (95%CI: 82.3-99.9) in those with coronary heart disease. Moreover, efficacy remained >90% irrespective of the number of selected medical conditions reported by a participant. As indicated by the similarity of the point estimates, this post-hoc analysis suggests that RZV efficacy remains high in all selected medical conditions, as well as with increasing number of medical conditions. No safety concern was identified by the type or number of medical conditions present at enrollment.

7.
Nat Commun ; 10(1): 2759, 2019 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-31227717

RESUMEN

Langerhans cells (LC) are thought to be the only mononuclear phagocyte population in the epidermis where they detect pathogens. Here, we show that CD11c+ dendritic cells (DCs) are also present. These cells are transcriptionally similar to dermal cDC2 but are more efficient antigen-presenting cells. Compared to LCs, epidermal CD11c+ DCs are enriched in anogenital tissues where they preferentially interact with HIV, express the higher levels of HIV entry receptor CCR5, support the higher levels of HIV uptake and replication and are more efficient at transmitting the virus to CD4 T cells. Importantly, these findings are observed using both a lab-adapted and transmitted/founder strain of HIV. We also describe a CD33low cell population, which is transcriptionally similar to LCs but does not appear to function as antigen-presenting cells or acts as HIV target cells. Our findings reveal that epidermal DCs in anogenital tissues potentially play a key role in sexual transmission of HIV.


Asunto(s)
Células Dendríticas/virología , Células Epidérmicas/virología , Infecciones por VIH/transmisión , VIH-1/inmunología , Presentación de Antígeno/inmunología , Antígeno CD11c/metabolismo , Células Cultivadas , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Epidérmicas/inmunología , Células Epidérmicas/metabolismo , Epidermis/inmunología , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/patogenicidad , Voluntarios Sanos , Humanos , Masculino , Cultivo Primario de Células , Receptores CCR5/metabolismo , Lectina 3 Similar a Ig de Unión al Ácido Siálico/metabolismo , Linfocitos T/inmunología , Internalización del Virus
8.
Front Immunol ; 10: 373, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30894859

RESUMEN

Herpes Simplex Virus (HSV) is a highly prevalent sexually transmitted infection that aside from causing cold sores and genital lesions, causes complications in the immunocompromised and has facilitated a large proportion of HIV acquisition globally. Despite decades of research, there is no prophylactic HSV vaccine ready for use in humans, leaving many questioning whether a prophylactic vaccine is an achievable goal. A previous HSV vaccine trial did have partial success in decreasing acquisition of HSV2-promising evidence that vaccines can prevent acquisition. However, there is still an incomplete understanding of the immune response pathways elicited by HSV after initial mucosal infection and how best to replicate these responses with a vaccine, such that acquisition and colonization of the dorsal root ganglia could be prevented. Another factor to consider in the rational design of an HSV vaccine is adjuvant choice. Understanding the immune responses elicited by different adjuvants and whether lasting humoral and cell-mediated responses are induced is important, especially when studies of past trial vaccines found that a sufficiently protective cell-mediated response was lacking. In this review, we discuss what is known of the immune control involved in initial herpes lesions and reactivation, including the importance of CD4 and CD8 T cells, and the interplay between innate and adaptive immunity in response to primary infection, specifically focusing on the viral relay involved. Additionally, a summary of previous and current vaccine trials, including the components used, immune responses elicited and the feasibility of prophylactic vaccines looking forward, will also be discussed.

9.
Artículo en Inglés | MEDLINE | ID: mdl-30277172

RESUMEN

HSV is an important cause of brain infection. Virus entry is often through breeches in the skin. γδT cells play an immunoprotective role in mice after corneal, genital or footpad (subcutaneous) HSV infection. Here we report that the presence of γδT cells in murine skin is associated with increased severity of herpetic disease, reduced protective cytokine responses and increased viral spread from the skin to the sensory ganglia in the zosteriform model. γδT cell-deficient (TCR δ -/-) mice displayed significantly decreased herpetic lesion severity after flank HSV infection compared to WT C57BL/6 controls at both primary and secondary skin infection sites. Viral titer at the primary skin site was similar to WT mice in γδT cell-deficient mice, but was significantly decreased in the ganglia and secondary skin site. γδT cell-deficient mice showed increased Th1 responses by both T cells and non-T cells at the primary site, and decreased T-cell Th17 responses and immune infiltration at the secondary site. Cytokine responses of epidermal and dermal γδT cells to HSV also differed in WT mice (Th1 in epidermis, and Th17 in the dermis), suggesting a functional dichotomy between these two subsets. Our data suggest that in contrast to other mouse models of HSV infection, skin-resident γδT cells impair the immune response to HSV in skin.

10.
J Infect Dis ; 218(suppl_2): S127-S133, 2018 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-30247592

RESUMEN

Background: Immunization for herpes zoster (HZ) aims to reverse the decline in cell-mediated immunity to varicella zoster virus that occurs with advancing age or immunocompromise. There are 2 vaccines available, one live attenuated (Zoster vaccine, live attenuated [ZVL]) and, recently, a recombinant subunit vaccine (HZ/su). Methods: The literature relevant to the two HZ vaccines was reviewed. Results: ZVL has overall efficacies of 51% and 65% against HZ and postherpetic neuralgia, respectively, with a prominent decline in efficacy with advancing age of the vaccinee. This compares to approximately 90% efficacy against HZ for HZ/su that is minimally affected with advancing age. The efficacy of ZVL against HZ declines over 4 and 8 years, compared with minimal decline so far over 4 years with HZ/su, and immunogenicity that is maintained for 9 years. Local and systemic reactogenicity to HZ/su is much greater than to ZVL. Conclusions: HZ/su establishes an important principle-that a single recombinant viral protein with an effective adjuvant combination can stimulate immunogenicity superior to that of a live attenuated vaccine, and that this can diminish immunosenescence. This provides hope for improvement of other vaccines for aging patients. However, key questions remain unanswered, including the durability of the efficacy of HZ/su, its efficacy as a booster for previous recipients of ZVL, and its efficacy in immunocompromised patients.

11.
J Infect Dis ; 217(11): 1750-1760, 2018 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-29529222

RESUMEN

Background: The herpes zoster subunit vaccine (HZ/su), consisting of varicella-zoster virus glycoprotein E (gE) and AS01B Adjuvant System, was highly efficacious in preventing herpes zoster in the ZOE-50 and ZOE-70 trials. We present immunogenicity results from those trials. Methods: Participants (ZOE-50: ≥50; ZOE-70: ≥70 years of age) received 2 doses of HZ/su or placebo, 2 months apart. Serum anti-gE antibodies and CD4 T cells expressing ≥2 of 4 activation markers assessed (CD42+) after stimulation with gE-peptides were measured in subcohorts for humoral (n = 3293) and cell-mediated (n = 466) immunogenicity. Results: After vaccination, 97.8% of HZ/su and 2.0% of placebo recipients showed a humoral response. Geometric mean anti-gE antibody concentrations increased 39.1-fold and 8.3-fold over baseline in HZ/su recipients at 1 and 36 months post-dose 2, respectively. A gE-specific CD42+ T-cell response was shown in 93.3% of HZ/su and 0% of placebo recipients. Median CD42+ T-cell frequencies increased 24.6-fold (1 month) and 7.9-fold (36 months) over baseline in HZ/su recipients and remained ≥5.6-fold above baseline in all age groups at 36 months. The proportion of CD4 T cells expressing all 4 activation markers increased over time in all age groups. Conclusions: Most HZ/su recipients developed robust immune responses persisting for 3 years following vaccination. Clinical Trials Registration: NCT01165177; NCT01165229.

12.
Viruses ; 10(2)2018 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-29438303

RESUMEN

Actin filaments, microtubules and intermediate filaments form the cytoskeleton of vertebrate cells. Involved in maintaining cell integrity and structure, facilitating cargo and vesicle transport, remodelling surface structures and motility, the cytoskeleton is necessary for the successful life of a cell. Because of the broad range of functions these filaments are involved in, they are common targets for viral pathogens, including the alphaherpesviruses. Human-tropic alphaherpesviruses are prevalent pathogens carried by more than half of the world's population; comprising herpes simplex virus (types 1 and 2) and varicella-zoster virus, these viruses are characterised by their ability to establish latency in sensory neurons. This review will discuss the known mechanisms involved in subversion of and transport via the cytoskeleton during alphaherpesvirus infections, focusing on protein-protein interactions and pathways that have recently been identified. Studies on related alphaherpesviruses whose primary host is not human, along with comparisons to more distantly related beta and gammaherpesviruses, are also presented in this review. The need to decipher as-yet-unknown mechanisms exploited by viruses to hijack cytoskeletal components-to reveal the hidden cytoskeletons in the closet-will also be addressed.


Asunto(s)
Alphaherpesvirinae/fisiología , Citoesqueleto/metabolismo , Infecciones por Herpesviridae/metabolismo , Infecciones por Herpesviridae/virología , Actinas/metabolismo , Animales , Interacciones Huésped-Patógeno , Humanos , Filamentos Intermedios/metabolismo , Microtúbulos/metabolismo , Modelos Biológicos , Miosinas/metabolismo , Unión Proteica , Transporte de Proteínas
13.
Vaccine ; 36(12): 1537-1541, 2018 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-29463421

RESUMEN

BACKGROUND: An adjuvanted herpes zoster (HZ) subunit vaccine, HZ/su, demonstrated high efficacy against HZ and postherpetic neuralgia (PHN) in two randomized, observer-blind, placebo-controlled trials in adults aged ≥50 and ≥70 years (ZOE-50 and ZOE-70, respectively). METHODS: Data from ZOE-50 and ZOE-70 trials were analyzed to evaluate the efficacy of HZ/su against mortality, hospitalizations, and non-PHN complications of HZ including HZ-associated vasculitis, stroke, and disseminated, ophthalmic, neurologic, and visceral diseases. RESULTS: In the pooled ZOE-50/ZOE-70 analysis, 1 of 32 HZ/su recipients (3.1%) and 16 of 477 placebo recipients (3.4%) with a confirmed HZ episode had complications other than PHN. Efficacy against HZ-related complications was 93.7% (95% confidence interval, 59.5-99.9%) in adults aged ≥50 years and 91.6% (43.3-99.8%) in adults ≥70 years. Five HZ-related hospitalizations, all in placebo recipients, and no HZ-related deaths were reported. CONCLUSIONS: HZ/su reduces the risk of HZ-associated complications in older adults (NCT01165177; NCT01165229).


Asunto(s)
Herpes Zóster/epidemiología , Herpes Zóster/etiología , Vacunas/efectos adversos , Anciano , Anciano de 80 o más Años , Ensayos Clínicos Fase III como Asunto , Femenino , Herpes Zóster/diagnóstico , Vacuna contra el Herpes Zóster/administración & dosificación , Vacuna contra el Herpes Zóster/efectos adversos , Vacuna contra el Herpes Zóster/inmunología , Hospitalización , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Neuralgia Posherpética/epidemiología , Neuralgia Posherpética/etiología , Vacunación/efectos adversos , Vacunas/administración & dosificación , Vacunas/inmunología , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/efectos adversos , Vacunas de Subunidad/inmunología
14.
Viruses ; 10(2)2018 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-29473915

RESUMEN

Herpes simplex virus type 1 (HSV-1) is a neuroinvasive human pathogen that has the ability to infect and replicate within epithelial cells and neurons and establish a life-long latent infection in sensory neurons. HSV-1 depends on the host cellular cytoskeleton for entry, replication, and exit. Therefore, HSV-1 has adapted mechanisms to promote its survival by exploiting the microtubule and actin cytoskeletons to direct its active transport, infection, and spread between neurons and epithelial cells during primary and recurrent infections. This review will focus on the currently known mechanisms utilized by HSV-1 to harness the neuronal cytoskeleton, molecular motors, and the secretory and exocytic pathways for efficient virus entry, axonal transport, replication, assembly, and exit from the distinct functional compartments (cell body and axon) of the highly polarized sensory neurons.


Asunto(s)
Citoesqueleto/metabolismo , Herpes Simple/metabolismo , Herpes Simple/virología , Herpesvirus Humano 1/fisiología , Interacciones Huésped-Patógeno , Neuronas/virología , Actinas/metabolismo , Animales , Transporte Axonal , Axones/metabolismo , Axones/virología , Ganglios Espinales/metabolismo , Ganglios Espinales/virología , Humanos , Microtúbulos/metabolismo , Proteínas Motoras Moleculares/metabolismo , Seudópodos/metabolismo , Seudópodos/virología , Ensamble de Virus , Internalización del Virus , Replicación Viral
15.
Curr Med Chem ; 25(19): 2245-2259, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29110589

RESUMEN

The alarming increase of antimicrobial resistance has led to a growing number of studies aiming to develop novel antimicrobial therapeutics. Natural antimicrobial peptides possess a potent and broad-spectrum antimicrobial activity combined with diverse and unique structural motifs, which confer their different mechanisms of action. These peptides are ubiquitous in organisms and are integral to the innate immune system. Recently, identification of antimicrobial peptides from marine crustaceans has become the centre of attention of many researchers. This increasing interest stems from the remarkable diversity in the structural and genetic composition of these peptides compared to terrestrial counterparts. Thus, peptides from marine crustaceans can serve as future templates for novel antimicrobial agents. Here, we provide an overview of various antimicrobial peptides from the marine crustaceans, their antimicrobial activity and structure- activity relationships. We also discuss the potential and challenges of their development as new antimicrobial agents.


Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Secuencia de Aminoácidos , Animales , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Péptidos Catiónicos Antimicrobianos/química , Péptidos Catiónicos Antimicrobianos/aislamiento & purificación , Decápodos (Crustáceos)/química , Descubrimiento de Drogas , Cangrejos Herradura/química , Alineación de Secuencia , Relación Estructura-Actividad
16.
Surv Ophthalmol ; 63(4): 565-578, 2018 Jul - Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29129651

RESUMEN

Herpes simplex keratitis is commonly caused by Herpes simplex virus type 1, which primarily infects eyelids, corneas, or conjunctiva. Herpes simplex virus type 1-through sophisticated interactions with dendritic cells (DCs), a type of antigen-presenting cell)-initiates proinflammatory responses in the cornea. Corneas were once thought to be an immune-privileged region; however, with the recent discovery of DCs that reside in the cornea, this long-held conjecture has been overturned. Therefore, evaluating the clinical, preclinical, and cell-based studies that investigate the roles of DCs in corneas infected with Herpes simplex virus is critical. With in vivo confocal microscopy, animal models, and cell culture experiments, we may further the understanding of the sophisticated interactions of Herpes simplex virus with DCs in the cornea and the molecular mechanism associated with it. It has been shown that specific differentiation of DCs using immunohistochemistry, flow cytometry, and polymerase chain reaction analysis in both human and mice tissues and viral tissue infections are integral to increasing understanding. As for in vivo confocal microscopy, it holds promise as it is the least invasive and a real-time investigation. These tools will facilitate the discovery of various targets to develop new treatments.


Asunto(s)
Córnea/inmunología , Edema Corneal/inmunología , Células Dendríticas/fisiología , Herpesvirus Humano 1/patogenicidad , Queratitis Herpética/inmunología , Animales , Córnea/fisiología , Edema Corneal/fisiopatología , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Inmunohistoquímica , Queratitis Herpética/fisiopatología , Latencia del Virus
17.
Curr Med Chem ; 25(20): 2292-2303, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-28464782

RESUMEN

Hemocyanins are large and versatile glycoproteins performing various immunological and biological functions in many marine invertebrates including arthropods and molluscs. This review discusses the various pharmacological applications of mollusc hemocyanin such as antiviral activity, immunostimulatory and anticancer properties that have been reported in the literature between the years 2000 and 2016. Emphasis is placed on a better mechanistic understanding of hemocyanin as a therapeutic agent. Elucidation of the mechanism of action is essential to improve the clinical efficacy and for a better understanding of some endogenous immunological functions of this complex glycoprotein.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Antineoplásicos/farmacología , Antivirales/farmacología , Hemocianinas/farmacología , Moluscos/química , Neoplasias/tratamiento farmacológico , Virus/efectos de los fármacos , Adyuvantes Inmunológicos/química , Animales , Antineoplásicos/química , Antivirales/química , Hemocianinas/química
18.
J Virol ; 91(20)2017 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-28768867

RESUMEN

Viruses manipulate the complex interferon and interferon-stimulated gene (ISG) system in different ways. We have previously shown that HIV inhibits type I and III interferons in its key target cells but directly stimulates a subset of >20 ISGs in macrophages and dendritic cells, many of which are antiviral. Here, we examine the mechanism of induction of ISGs and show this occurs in two phases. The first phase was transient (0 to 24 h postinfection [hpi]), induced mainly by extracellular vesicles and one of its component proteins, HSP90α, contained within the HIV inoculum. The second, dominant, and persistent phase (>48 hpi) was induced via newly transcribed HIV RNA and sensed via RIGI, as shown by the reduction in ISG expression after the knockdown of the RIGI adaptor, MAVS, by small interfering RNA (siRNA) and the inhibition of both the initiation and elongation of HIV transcription by short hairpin RNA (shRNA) transcriptional silencing. We further define the induction pathway, showing sequential HIV RNA stimulation via Tat, RIGI, MAVS, IRF1, and IRF7, also identified by siRNA knockdown. IRF1 also plays a key role in the first phase. We also show that the ISGs IFIT1 to -3 inhibit HIV production, measured as extracellular infectious virus. All induced antiviral ISGs probably lead to restriction of HIV replication in macrophages, contributing to a persistent, noncytopathic infection, while the inhibition of interferon facilitates spread to adjacent cells. Both may influence the size of macrophage HIV reservoirs in vivo Elucidating the mechanisms of ISG induction may help in devising immunotherapeutic strategies to limit the size of these reservoirs.IMPORTANCE HIV, like other viruses, manipulates the antiviral interferon and interferon-stimulated gene (ISG) system to facilitate its initial infection and establishment of viral reservoirs. HIV specifically inhibits all type I and III interferons in its target cells, including macrophages, dendritic cells, and T cells. It also induces a subset of over 20 ISGs of differing compositions in each cell target. This occurs in two temporal phases in macrophages. Extracellular vesicles contained within the inoculum induce the first, transient phase of ISGs. Newly transcribed HIV RNA induce the second, dominant ISG phase, and here, the full induction pathway is defined. Therefore, HIV nucleic acids, which are potent inducers of interferon and ISGs, are initially concealed, and antiviral ISGs are not fully induced until replication is well established. These antiviral ISGs may contribute to persistent infection in macrophages and to the establishment of viral reservoirs in vivo.


Asunto(s)
Regulación de la Expresión Génica , VIH-1/fisiología , Interferones/metabolismo , Macrófagos/virología , ARN Viral/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Células Dendríticas/virología , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Factor 1 Regulador del Interferón/genética , Factor 1 Regulador del Interferón/metabolismo , Factor 7 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/metabolismo , ARN Interferente Pequeño , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Transducción de Señal
19.
Expert Rev Vaccines ; 16(7): 1-10, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28486850

RESUMEN

INTRODUCTION: Herpes zoster (HZ) causes an often severe and painful rash in older people and may be complicated by prolonged pain (postherpetic neuralgia; PHN) and by dissemination in immune-compromised patients. HZ results from reactivation of latent varicella-zoster virus (VZV) infection, often associated with age-related or other causes of decreased T cell immunity. A live attenuated vaccine boosts this immunity and provides partial protection against HZ, but this decreases with age and declines over 8 years. Areas covered: A new HZ subunit (HZ/su) vaccine combines a key surface VZV glycoprotein (E) with a T cell-boosting adjuvant system (AS01B) and is administered by two intramuscular injections two months apart. Expert commentary: HZ/su showed excellent efficacy of ~90% in immunocompetent adults ≥50 and ≥70 years of age, respectively, in the ZOE-50 and ZOE-70 phase III controlled trials. Efficacy was unaffected by advancing age and persisted for >3 years. Approximately 9.5% of subjects had severe, but transient (1-2 days) injection site pain, swelling or redness. Compliance with both vaccine doses was high (95%). The vaccine will have a major impact on HZ management. Phase I-II trials showed safety and immunogenicity in severely immunocompromised patients. Phase III trial results are expected soon.


Asunto(s)
Vacuna contra el Herpes Zóster/administración & dosificación , Herpes Zóster/prevención & control , Herpesvirus Humano 3/inmunología , Vacunación , Proteínas del Envoltorio Viral/administración & dosificación , Adyuvantes Inmunológicos/administración & dosificación , Anciano , Anciano de 80 o más Años , Herpes Zóster/inmunología , Herpes Zóster/virología , Vacuna contra el Herpes Zóster/efectos adversos , Vacuna contra el Herpes Zóster/inmunología , Herpesvirus Humano 3/patogenicidad , Humanos , Esquemas de Inmunización , Inmunogenicidad Vacunal , Inyecciones Intramusculares , Lípido A/administración & dosificación , Lípido A/análogos & derivados , Lípido A/inmunología , Persona de Mediana Edad , Saponinas/administración & dosificación , Saponinas/inmunología , Factores de Tiempo , Resultado del Tratamiento , Vacunación/efectos adversos , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/inmunología , Proteínas del Envoltorio Viral/efectos adversos , Proteínas del Envoltorio Viral/inmunología
20.
J Leukoc Biol ; 101(6): 1393-1403, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28270408

RESUMEN

Mononuclear phagocytes are present in skin and mucosa and represent one of the first lines of defense against invading pathogens, which they detect via an array of pathogen-binding receptors expressed on their surface. However, their extraction from tissue is difficult, and the isolation technique used has functional consequences on the cells obtained. Here, we compare mononuclear phagocytes isolated from human skin using either enzymatic digestion or spontaneous migration. Cells isolated via enzymatic digestion are in an immature state, and all subsets are easily defined. However, cells isolated by spontaneous migration are in a mature state, and CD141 cross-presenting DCs (cDC1) are more difficult to define. Different pathogen-binding receptors are susceptible to cleavage by blends of collagenase, demonstrating that great care must be taken in choosing the correct enzyme blend to digest tissue if carrying out pathogen-interaction assays. Finally, we have optimized mononuclear phagocyte culture conditions to enhance their survival after liberation from the tissue.


Asunto(s)
Separación Celular/métodos , Enzimas/metabolismo , Monocitos/citología , Fagocitos/citología , Piel/citología , Movimiento Celular , Humanos , Monocitos/inmunología , Monocitos/metabolismo , Fagocitos/inmunología , Fagocitos/metabolismo , Fenotipo , Piel/inmunología , Piel/metabolismo
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