RESUMEN
We estimated the dynamics of the neutralizing response against XBB sublineages and T cell response in persons with HIV (PWH) with previous AIDS and/or CD4 < 200/mm3 receiving the bivalent original strain/BA.4-5 booster dose in fall 2022. Samples were collected before the shot (Day 0), 15 days, 3, and 6 months after. PWH were stratified by immunization status: hybrid immunity (HI; vaccination plus COVID-19) versus nonhybrid immunity (nHI; vaccination only). Fifteen days after the booster, 16% and 30% of PWH were nonresponders in terms of anti-XBB.1.16 or anti-EG.5.1 nAbs, respectively. Three months after, a significant waning of anti-XBB.1.16, EG.5.1 and -XBB.1 nAbs was observed both in HI and nHI but nAbs in HI were higher than in nHI. Six months after both HI and nHI individuals displayed low mean levels of anti-XBB.1.16 and EG.5.1 nAbs. Regarding T cell response, IFN-γ values were stable over time and similar in HI and nHI. Our data showed that in PWH, during the prevalent circulation of the XBB.1.16, EG.5.1, and other XBB sublineages, a mRNA bivalent vaccine might not confer broad protection against them. With a view to the 2023/2024 vaccination campaign, the use of the monovalent XBB.1.5 mRNA vaccine should be urgently warranted in PWH to provide adequate protection.
Asunto(s)
COVID-19 , Infecciones por VIH , Humanos , COVID-19/prevención & control , Programas de Inmunización , ARN Mensajero , Estaciones del Año , Vacunas de ARNm , Anticuerpos Neutralizantes , Anticuerpos AntiviralesRESUMEN
BACKGROUND: Data on SARS-CoV-2 vaccine immunogenicity in PLWH are currently limited. Aim of the study was to investigate immunogenicity according to current CD4 T-cell count. METHODS: PLWH on ART attending a SARS-CoV-2 vaccination program, were included in a prospective immunogenicity evaluation after receiving BNT162b2 or mRNA-1273. Participants were stratified by current CD4 T-cell count (poor CD4 recovery, PCDR: <200/mm3; intermediate CD4 recovery, ICDR: 200-500/mm3; high CD4 recovery, HCDR: >500/mm3). RBD-binding IgG, SARS-CoV-2 neutralizing antibodies (nAbs) and IFN-γ release were measured. As control group, HIV-negative healthcare workers (HCWs) were used. FINDINGS: Among 166 PLWH, after 1 month from the booster dose, detectable RBD-binding IgG were elicited in 86.7% of PCDR, 100% of ICDR, 98.7% of HCDR, and a neutralizing titre ≥1:10 elicited in 70.0%, 88.2%, and 93.1%, respectively. Compared to HCDR, all immune response parameters were significantly lower in PCDR. After adjusting for confounders, current CD4 T-cell <200/mm3 significantly predicted a poor magnitude of anti-RDB, nAbs and IFN-γ response. As compared with HCWs, PCDR elicited a consistently reduced immunogenicity for all parameters, ICDR only a reduced RBD-binding antibody response, whereas HCDR elicited a comparable immune response for all parameters. CONCLUSION: Humoral and cell-mediated immune response against SARS-CoV-2 were elicited in most of PLWH, albeit significantly poorer in those with CD4 T-cell <200/mm3 versus those with >500 cell/mm3 and HIV-negative controls. A lower RBD-binding antibody response than HCWs was also observed in PLWH with CD4 T-cell 200-500/mm3, whereas immune response elicited in PLWH with a CD4 T-cell >500/mm3 was comparable to HIV-negative population.
Asunto(s)
COVID-19 , Infecciones por VIH , Vacunas Virales , Anticuerpos Antivirales , Vacuna BNT162 , Linfocitos T CD4-Positivos , COVID-19/prevención & control , Vacunas contra la COVID-19 , VIH , Infecciones por VIH/tratamiento farmacológico , Humanos , Inmunidad Celular , Inmunoglobulina G , Recuento de Linfocitos , Estudios Prospectivos , ARN Mensajero , SARS-CoV-2 , VacunaciónRESUMEN
Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD. In particular, very little is known about human immune responses to Ebola virus. Here we evaluate the physiology of the human T cell immune response in EVD patients at the time of admission to the Ebola Treatment Center in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established by the European Mobile Laboratory in the field, we identify an immune signature that is unique in EVD fatalities. Fatal EVD was characterized by a high percentage of CD4(+) and CD8(+) T cells expressing the inhibitory molecules CTLA-4 and PD-1, which correlated with elevated inflammatory markers and high virus load. Conversely, surviving individuals showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation, despite comparable overall T cell activation. Concomitant with virus clearance, survivors mounted a robust Ebola-virus-specific T cell response. Our findings suggest that dysregulation of the T cell response is a key component of EVD pathophysiology.
Asunto(s)
Ebolavirus/inmunología , Fiebre Hemorrágica Ebola/inmunología , Fiebre Hemorrágica Ebola/fisiopatología , Linfocitos T/inmunología , Antígeno CTLA-4/metabolismo , Femenino , Citometría de Flujo , Guinea/epidemiología , Fiebre Hemorrágica Ebola/mortalidad , Humanos , Mediadores de Inflamación/inmunología , Estudios Longitudinales , Activación de Linfocitos , Masculino , Alta del Paciente , Receptor de Muerte Celular Programada 1/metabolismo , Sobrevivientes , Linfocitos T/metabolismo , Carga ViralRESUMEN
Little evidence on coronavirus disease 2019 (COVID-19) in people living with HIV (PLWH) is currently available. We reported clinical and viroimmunological data of all HIV-positive patients admitted to our center with COVID-19 from March 1 to May 12, 2020. Overall, five patients were included: all were virologically-suppressed on antiretroviral therapy and CD4+ count was greater than 350 cell/mm3 in all but two patients. Although all patients had evidence of pneumonia on admission, only one developed respiratory failure. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was never detected from nasopharyngeal swabs in two patients, whereas in the others, viral clearance occurred within a maximum of 43 days. Immunoglobulin G production was elicited in all patients and neutralizing antibodies in all but one patient. Specific-T-cell response developed in all patients but was stronger in those with the more severe presentations. Similarly, the highest level of proinflammatory cytokines was found in the only patient experiencing respiratory failure. Despite a mild presentation, patients with more pronounced immunosuppression showed high degrees of both cytokines production and immune activation. Our study did not find an increased risk and severity of COVID-19 in PLWH. Adaptative cellular immune response to SARS-CoV-2 appeared to correlate to disease severity. The mild clinical picture showed in advanced HIV patients, despite a significant T-cell activation and inflammatory profile, suggests a potential role of HIV-driven immunological dysregulation in avoiding immune-pathogenetic processes. However, other possible explanations, as a protective role of certain antiretroviral drugs, should be considered. Further larger studies are needed to better clarify the impact of HIV infection on COVID-19.
Asunto(s)
Antirretrovirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Infecciones por VIH/tratamiento farmacológico , SARS-CoV-2/efectos de los fármacos , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Recuento de Linfocito CD4 , Coinfección/virología , Citocinas/sangre , Femenino , Inhibidores de Integrasa VIH/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Inmunidad Humoral/inmunología , Masculino , Persona de Mediana Edad , Oxazinas/uso terapéutico , Piperazinas/uso terapéutico , Piridonas/uso terapéutico , ARN Viral/análisis , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Riesgo , Índice de Severidad de la Enfermedad , Tenofovir/uso terapéutico , Personas TransgéneroRESUMEN
Increased production of inflammatory cytokines and myeloid-derived suppressor cells occurs in patients with coronavirus disease 2019. These inversely correlated with perforin-expressing natural killer (NK) and CD3+ T cells. We observed a lower number of perforin-expressing NK cells in intensive care unit (ICU) patients compared with non-ICU patients, suggesting an impairment of the immune cytotoxic arm as a pathogenic mechanism.
Asunto(s)
COVID-19/inmunología , Inflamación/sangre , Células Asesinas Naturales/inmunología , Perforina/inmunología , Linfocitos T Citotóxicos/inmunología , Anciano , COVID-19/sangre , Citocinas/inmunología , Femenino , Humanos , Inflamación/complicaciones , Inflamación/inmunología , Unidades de Cuidados Intensivos/estadística & datos numéricos , Italia , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , SARS-CoV-2RESUMEN
Antiretroviral treatment (ART) of Primary HIV Infection (PHI) has demonstrated virological and immunological benefits. The effect of early ART during PHI on the level of growth factors and chemokines modulating immune cell functions remains to be established. The aim of our work was to analyze the dynamics of 27 cytokines, chemokines and growth/regulation factors in plasma of HIV infected patients treated during PHI. Patients with PHI (nâ¯=â¯43) were enrolled before, 24 and 48â¯weeks after therapy initiation. Quantification of soluble immune mediators was performed in plasma from HIV infected patients and healthy donors (HD, nâ¯=â¯7) by Luminex technology. The cytokines profile was strongly perturbed in primary HIV infected patients when compared to healthy donors (HD). After 48â¯weeks of ART, some of these factors were restored to HD level (IL-2, IL-5, IL-7, IL-9, IL12p70, TNFα) while others persisted higher than HD (IL-6, IL-10, IL-13). Interestingly, a subset of chemokines, such as IL-8, MCP-1, RANTES and CCL27, and growth factors such as HGF, SCF and GM-CSF, increased during ART, reaching values significantly higher than HD after 48â¯weeks. Moreover, the G-CSF and MIP-1ß soluble mediators were persistently altered and showed an inverse correlation with the CD4/CD8 T cell ratio. The increase of chemokines with antiviral activity and of growth factors with hematopoietic and immunomodulatory properties may have beneficial effects. Other studies are mandatory to evaluate the effects of long lasting levels of these factors to clarify their possible role in the context of protection/pathogenesis.
Asunto(s)
Antirretrovirales/uso terapéutico , Quimiocinas/sangre , Citocinas/sangre , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Terapia Antirretroviral Altamente Activa , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Quimiocina CCL2/sangre , Quimiocina CCL27/sangre , Quimiocina CCL5/sangre , Regulación hacia Abajo , Factor Estimulante de Colonias de Granulocitos/sangre , Factor Estimulante de Colonias de Granulocitos y Macrófagos/sangre , Factor de Crecimiento de Hepatocito/sangre , Humanos , Interleucina-10/sangre , Interleucina-12/sangre , Interleucina-13/sangre , Interleucina-2/sangre , Interleucina-5/sangre , Interleucina-7/sangre , Interleucina-8/sangre , Análisis de Componente Principal , Factor de Células Madre/sangre , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Primary and chronic human immunodeficiency virus (HIV) infection alters γδ T-cell features. However, there is no evidence about early combined antiretroviral therapy (cART) and γδ T-cell dynamics. In the present study, HIV-positive individuals were divided into those with early primary infection (EPI) and those with late primary infection (LPI). The analysis of γδ T cells was performed by flow cytometry before and after therapy. Polyfunctional profile was assessed after in vitro peripheral blood mononuclear cell (PBMC) exposure to specific antigens. The results show that primary infection induced an expansion of Vδ1 T cells in LPI. Before treatment, a massive activation of γδ T-cell subsets was observed in both groups of patients, that correlated with disease progression and was significantly reduced after cART introduction. Despite this, CD107A-expressing Vδ1 T cells in both groups were significantly fewer than in healthy donors, but were restored by therapy introduction. Polyfunctional analysis of Vδ1 T cells from HIV-positive individuals revealed a lower frequency of CD107A+ CCL-4+ Vδ1 T-cell subsets than healthy donors that persists after therapy. Functional profile of Vδ2 was similar to that in healthy donors before therapy but, at 6 months, a lower frequency of CD107A, interferon-γ- or tumor necrosis factor-α-producing Vδ2 T cells was observed in the EPI group. Finally, individuals with LPI showed a lower frequency of quadruple-functional Vδ2 T-cell subset. In conclusion, during primary HIV infection, the baseline Vδ1 T-cell activation is correlated with immune reconstitution potential. Moreover, an altered γδ polyfunctional profile occurred, persisting after cART. Further studies are needed to understand whether a longer treatment of primary infection may increase γδ T-cell functionality.
Asunto(s)
Antirretrovirales/administración & dosificación , Infecciones por VIH/inmunología , VIH-1/inmunología , Activación de Linfocitos/efectos de los fármacos , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T/inmunología , Adulto , Quimiocina CCL4/inmunología , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Humanos , Interferón gamma/inmunología , Proteína 1 de la Membrana Asociada a los Lisosomas/inmunología , Masculino , Persona de Mediana Edad , Linfocitos T/patología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
On 31 August, a veterinarian and a farmworker were hospitalised for skin lesions. Both had been exposed to a dead cow on 19 August on a farm near Rome, where eight further cattle died of confirmed anthrax later the same month. At admission, the first case showed a black depressed eschar and another smaller lesion on one hand. The second case presented deep infection of the skin, with involvement of both arms. Anthrax diagnosis was confirmed by detection of B. anthracis DNA in eschar fragments from both patients. T-cell specific immunity was studied by flow cytometry and Elispot assay after stimulation with B. anthracis secretome in blood samples collected from Case 1. Immunoglobulin production was detected by complement fixation assay. In Case 1, specific CD4+ T-cell activation was detected, without antibody production. Specific antibodies were detected only in the second patient with severe cutaneous illness. Both patients recovered. The two human anthrax cases were epidemiologically linked, but anthrax was not suspected at admission in either case. The veterinarian had initially unrecognised professional exposure and the exposed farmworker did initially not report exposure to affected animals. A One Health strategy integrating human and animal investigations was essential to confirm the diagnosis.
Asunto(s)
Carbunco/diagnóstico , Carbunco/epidemiología , Bacillus anthracis/aislamiento & purificación , Agricultores , Exposición Profesional/efectos adversos , Enfermedades Cutáneas Bacterianas/diagnóstico , Enfermedades Cutáneas Bacterianas/epidemiología , Veterinarios , Adulto , Animales , Carbunco/tratamiento farmacológico , Antibacterianos/uso terapéutico , Bovinos , Ecosistema , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Exposición Profesional/prevención & control , Enfermedades Cutáneas Bacterianas/tratamiento farmacológicoRESUMEN
The impact of early antiretroviral therapy (ART) during Primary HIV Infection (PHI) on the hematopoietic progenitor cells (HPCs) homeostasis is not available. This study aimed to characterize HPCs and their relationship with cytokines regulating progenitors function in ART-treated patients with PHI. We enrolled HIV infected patients treated with ART during PHI. Circulating HPCs, Lymphoid-HPCs (L-HPCs) frequency and plasmatic concentrations of IL-7, IL-18 and Stem Cell Factor (SCF) were analysed at baseline and after 6â¯months of therapy. ART introduction during PHI restored the decline of L-HPCs, induced a decrease in the level of pro-inflammatory IL-18 cytokine and a parallel increase of SCF. Moreover, L-HPCs frequency positively correlated with IL-18 at baseline, and with SCF after 6â¯months of therapy, suggesting that different signals impact L-HPCs expansion and maintenance before and after treatment. Finally, the SCF receptor expression on HPCs decreased after early ART initiation. These insights may open new perspectives for the evaluation of cytokine-driven L-HPCs expansion and their impact on the homeostasis of hematopoietic compartment during HIV infection.
Asunto(s)
Infecciones por VIH/sangre , VIH-1 , Células Madre Hematopoyéticas/metabolismo , Interleucina-18/sangre , Factor de Células Madre/sangre , Adulto , Antirretrovirales/administración & dosificación , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Células Madre Hematopoyéticas/patología , Humanos , MasculinoRESUMEN
BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is known to cause major alterations in the cross-talk between hepatic and immune cells thus contributing to the liver disease pathogenesis. Extracellular vesicles have been proved to act as major players in cell-cell communication, and their cargo changes in relation to pathophysiological states. The aim of this study was to evaluate the effects of chronic HCV infection and direct-acting antivirals (DAA) on exosome-delivered microRNAs and on their ability to modulate the innate immune response. METHODS: Exosomes isolated from the plasma of healthy donors and naïve, viremic HCV patients before and after DAA treatment have been compared for their microRNAs cargo by quantitative polymerase chain reaction. Functional assays with peripheral blood cells from healthy donors were performed to assess exosome-mediated immune responses. RESULTS: MicroRNAs associated with HCV-related immunopathogenesis which were found to be enriched in exosomes of HCV viremic patients (in particular, miR-122-5p, miR-222-3p, miR-146a, miR-150-5p, miR-30c, miR-378a-3p and miR-20a-5p) were markedly reduced by DAA therapy. This exosome-microRNA cargo modulation parallels changes in their immunomodulatory properties in ex vivo experiments. Exosomes from HCV patients inhibit NK degranulation activity and this effect correlates with miR-122-5p or miR-222-3p levels. CONCLUSIONS: Enrichment of immunomodulatory microRNAs in exosomes of HCV patients was correlated with their inhibitory activity on innate immune cells function. Direct-acting antivirals (DAA) treatment was observed to revert both microRNA content and functional profiles of systemic exosomes towards those of healthy donors. Exosome-associated microRNAs may provide valuable biomarkers to monitor immune response recovery.
Asunto(s)
Antivirales/farmacología , Exosomas/inmunología , Hepatitis C Crónica/tratamiento farmacológico , MicroARNs/inmunología , Adulto , Anciano , Biomarcadores , Estudios de Casos y Controles , Comunicación Celular , Femenino , Perfilación de la Expresión Génica , Hepacivirus/genética , Humanos , Inmunidad Innata , Masculino , Persona de Mediana EdadRESUMEN
First anti-HCV treatments, that include protease inhibitors in conjunction with IFN-α and Ribavirin, increase the sustained virological response (SVR) up to 80% in patients infected with HCV genotype 1. The effects of triple therapies on dendritic cell (DC) compartment have not been investigated. In this study we evaluated the effect of telaprevir-based triple therapy on DC phenotype and function, and their possible association with treatment outcome. HCV+ patients eligible for telaprevir-based therapy were enrolled, and circulating DC frequency, phenotype, and function were evaluated by flow-cytometry. The antiviral activity of plasmacytoid DC was also tested. In SVR patients, myeloid DC frequency transiently decreased, and returned to baseline level when telaprevir was stopped. Moreover, an up-regulation of CD80 and CD86 on mDC was observed in SVR patients as well as an improvement of IFN-α production by plasmacytoid DC, able to inhibit in vitro HCV replication.
Asunto(s)
Antivirales/uso terapéutico , Células Dendríticas/inmunología , Hepatitis C Crónica/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Anciano , Antígeno B7-1/inmunología , Antígeno B7-2/inmunología , Quimioterapia Combinada , Femenino , Hepatitis C Crónica/inmunología , Humanos , Interferón-alfa/inmunología , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Ribavirina/uso terapéutico , Respuesta Virológica Sostenida , Resultado del Tratamiento , Regulación hacia Arriba , Replicación ViralRESUMEN
West Nile virus (WNV) causes a severe central nervous system infection in humans, primarily in the elderly and immunocompromised subjects. Human γδ T-cells play a critical role in the immune response against viruses, and studies of WNV meningoencephalitis in laboratory mice described a role of γδ T-cells in the protective immune response. Aim of this study was to analyze the cytolytic and non-cytolytic antiviral activity of human Vδ2 T-cells against WNV replication. The anti-WNV activity of soluble factor released by zoledronic acid (ZA)-activated Vδ2 T-cell lines and the cytotoxic capability of Vδ2 T-cell lines against WNV-infected cells were tested in vitro. The activation of Vδ2 T-cell lines was able to inhibit WNV replication through the release of soluble factors. IFN-γ is massively released by activated Vδ2 T-cell lines and is involved in the anti-WNV activity. Moreover, the Vδ2 T-cell lines can efficiently kill WNV-infected cells possibly through perforin-mediated mechanism. Altogether, our results provide insight into the effector functions of human Vδ2 T-cells against WNV. The possibility to target these cells by ZA, a commercially available drug used in humans, could potentially offer a new immunotherapeutic strategy for WNV infection.
Asunto(s)
Subgrupos de Linfocitos T/fisiología , Fiebre del Nilo Occidental/inmunología , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental/inmunología , Animales , Línea Celular , Difosfonatos/farmacología , Humanos , Imidazoles/farmacología , Ratones , Ácido ZoledrónicoAsunto(s)
Antivirales , Coinfección , Infecciones por VIH , Hepatitis C Crónica , Hepatitis C , Antivirales/efectos adversos , Coinfección/tratamiento farmacológico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Linfocitos TRESUMEN
Aim of this work was to investigate a possible correlation between the frequency of JCV-specific T-cells and PML occurrence in HIV-infected subjects and in liver transplant recipients. A significant decrease of JCV-specific T-cells was observed in HIV-PML subjects, highlighting a close relation between JCV-specific T-cell immune impairment and PML occurrence in HIV-subjects. Interestingly, liver-transplant recipients (LTR) showed a low frequency of JCV-specific T-cells, similar to HIV-PML subjects. Nevertheless, none of the enrolled LTR developed PML, suggesting the existence of different immunological mechanisms involved in the maintenance of a protective immune response in LTR.
Asunto(s)
Infecciones por VIH/inmunología , Interferón gamma/inmunología , Virus JC/inmunología , Leucoencefalopatía Multifocal Progresiva/inmunología , Trasplante de Hígado , Linfocitos T/inmunología , Adulto , Anciano , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/cirugía , Infecciones por VIH/virología , VIH-1/genética , VIH-1/inmunología , Humanos , Interferón gamma/genética , Virus JC/genética , Virus JC/aislamiento & purificación , Leucoencefalopatía Multifocal Progresiva/etiología , Leucoencefalopatía Multifocal Progresiva/virología , Masculino , Persona de Mediana Edad , Linfocitos T/virología , Receptores de TrasplantesRESUMEN
BACKGROUND: Antiretroviral therapy has considerably reduced HIV disease progression, but complete eradication of HIV cannot actually be achieved. Moreover, prolonged use of protease inhibitors (PIs) causes profound changes in lipid metabolism with an increased risk of cardiovascular diseases. P-glycoprotein (P-gp) is expressed on many cell types, playing an important role in the efflux of drugs including PIs, limiting their intracellular concentration. Furthermore, several studies showed that P-gp is involved in lipid homeostasis and its activity is regulated by cholesterol. METHODS: THP-1 monocytes were used to study: (i) the influence of low-density lipoprotein (LDL) on P-gp expression and function, assessed by flow cytometry and quantitative real-time PCR analysis and measuring ritonavir and rhodamine-123 dye efflux, respectively; and (ii) the influence of ritonavir on cholesterol mobilization. The intracellular levels of ritonavir or cholesterol were measured by HPLC-UV and filipin staining, respectively. RESULTS: In THP-1 cells, LDL was able to yield an increase in both P-gp expression and activity. THP-1 cells treated with LDL showed a decrease in the intracellular ritonavir concentration in a dose-dependent manner. Notably, ritonavir induced reduced cholesterol mobilization in THP-1 cells, probably due to its inhibitory action on P-gp activity. CONCLUSIONS: Our data indicate a potential interplay between LDL and ritonavir mediated by P-gp. This interaction could influence both therapy effectiveness and cellular lipid metabolism, with important implications in the management of HIV patients treated with boosted PIs.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacocinética , Lipoproteínas LDL/metabolismo , Ritonavir/metabolismo , Ritonavir/farmacocinética , Línea Celular , Cromatografía Líquida de Alta Presión , Citosol/química , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Monocitos , Unión Proteica , Reacción en Cadena en Tiempo Real de la Polimerasa , Espectrofotometría UltravioletaRESUMEN
Hepatitis C virus (HCV) standard of care (SOC) therapy is not effective in a large percentage of patients and its efficacy may be evaluated only after several weeks. The aim of this work was to set up an in vitro liver culture assay able to preemptively predict SOC outcome by using residual liver samples from HCV patients. The in vitro response to SOC was found associated with the in vivo treatment outcome with a concordance of 100%. A wider clinical trial on a larger patient group is necessary to fully evaluate the impact of this procedure on the clinical management of untreated HCV patients.
Asunto(s)
Antivirales/administración & dosificación , Monitoreo de Drogas/métodos , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Hígado/virología , Adulto , Anciano , Biopsia , Femenino , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepacivirus/fisiología , Hepatitis C/virología , Humanos , Técnicas In Vitro , Hígado/efectos de los fármacos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: During HIV infection, effective combined antiretroviral therapy suppresses viral replication and restores the number of circulating CD4+ T cells. However, 15%-30% of treated patients show a discordant response to combined antiretroviral therapy. Myeloid-derived suppressor cells (MDSC) are expanded in HIV+ patients; to better understand the role of MDSC on CD4 T-cell recovery, we evaluated the frequency of MDSC in HIV+ patients under combined antiretroviral therapy and its association with immunologic response. METHODS: We enrolled 60 HIV+ patients, including complete responders (R, n = 44), virologic nonresponders (VNR, n = 5), and immunologic nonresponders (INR, n = 11). The frequency of circulating MDSC and the percentage of activated and naïve CD4 T cells were evaluated by flow cytometry. Plasmatic cytokine levels were analyzed by automated ELISA. RESULTS: As previously observed, polymorphonuclear MDSC (PMN-MDSC) frequency was higher in HIV+ patients compared with healthy donors. Furthermore, PMN-MDSC percentage was higher in INR than R patients, and a significant association between MDSC frequency and immunologic failure was confirmed by a receiver operator characteristic analysis. Accordingly, an inverse correlation was found between the percentages of PMN-MDSC and naïve CD4 T cells. A positive correlation was observed between PMN-MDSC frequency and the percentage of human leucocyte antigen locus DR + CD4 T cells and the plasmatic level of IL-1ß and IL-8. CONCLUSION: Our results show that a high frequency of PMN-MDSC persists in INR, possibly because of immune activation, contributing to CD4 T-cell recovery failure. These findings further highlight the detrimental role of MDSC during HIV infection, suggesting these cells as a possible new therapeutic target.
Asunto(s)
Infecciones por VIH , Células Supresoras de Origen Mieloide , Humanos , Linfocitos T CD4-Positivos , Citocinas , Ensayo de Inmunoadsorción EnzimáticaRESUMEN
OBJECTIVE: To investigate the pharmacokinetics (PK) of tecovirimat in subjects with Mpox. METHODS: This monocentric, prospective, observational study enrolled subjects with Mpox who received standard treatment with oral tecovirimat. Plasma samples for PK assessment were collected at steady state (5-8 days after initiation of antiviral therapy), before and 3, 5, 7 and 12 h after tecovirimat administration. Drug concentrations were determined by validated liquid chromatography coupled with tandem mass spectrometry. PK parameters were calculated using Phoenix 8.1. RESULTS: Overall, 14 male patients hospitalized for severe Mpox with ongoing tecovirimat treatment were enrolled in this study. Six of the 14 patients were living with human immunodeficiency virus (HIV), all of whom were on antiretroviral therapy (ART) and virologically suppressed at the time of hospitalization. Significant differences in tecovirimat PK were observed in subjects without HIV compared with subjects with HIV. In subjects with HIV, the maximum tecovirimat plasma concentration (39%, P≤0.0001), minimum tecovirimat plasma concentration (42%, P=0.0079) and area under the curve from zero to the last measured time-point (40%, P≤0.0001) were significantly lower compared with subjects without HIV, but all concentrations remained above the in-vitro calculated 90% inhibitory concentration. No significant associations were found between demographic/clinical data and tecovirimat PK. All patients recovered completely within 14 (range 6-36) days of treatment initiation. CONCLUSIONS: This study found a significant decrease in plasma exposure of tecovirimat in Mpox patients with HIV on effective ART compared with those without HIV, with no evident impact on clinical outcomes. Although these results need to be confirmed in larger studies, they may provide useful information on the PK of tecovirimat.
Asunto(s)
Infecciones por VIH , Mpox , Humanos , Masculino , Estudios Prospectivos , Infecciones por VIH/tratamiento farmacológico , VIHRESUMEN
A 59-year-old treatment-naive patient with advanced HIV infection presented with a severe and protracted course of mpox (formerly known as monkeypox) that did not respond to the current mpox treatment options. The patient worsened clinically, and developed new mucocutaneous lesions and necrotic evolution of pre-existing ones, along with multiple bilateral lung nodules and the appearance of a tracheal necrotic lesion. Although severe forms of mpox have been observed in people with severe immune system deficiency, including those with advanced HIV presentation, the immunological mechanisms underlying this observation have not yet been fully explained. To our knowledge, this is the first account of a necrotising mpox in a person living with HIV, with viral shedding for more than 11 months and a comprehensive immunological description. Moreover, we documented the virus' persistence by detecting mpox virus DNA from multiple sites and quantified anti-monkeypox virus IgA, IgM, IgG, and neutralising antibodies in serum samples. The severe HIV-driven immune depression and the presence of other co-infections might skew and impair immune responses, thus contributing to the persistence of monkeypox virus infection. Further investigations of immune responses to monkeypox virus infection in people with severe immunosuppression are required to improve management and prevention.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida , Coinfección , Infecciones por VIH , Mpox , Humanos , Persona de Mediana Edad , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , ADN Viral , Monkeypox virusRESUMEN
BACKGROUND: A rapid ART initiation approach can be beneficial in people with advanced HIV disease, in consideration of their high morbidity and mortality. The aim of our study was to evaluate the feasibility, efficacy and safety of rapid ART start with BIC/FTC/TAF in this setting. METHODS: Pilot, single-centre, single-arm, prospective, phase IV clinical trial conducted in a tertiary Italian hospital. Thirty ART-naïve people presenting with advanced HIV-1 diagnosis (defined as the presence of an AIDS-defining event and/or CD4 cell count <200 µL), were enrolled. Main exclusion criteria were active tuberculosis, cryptococcosis and pregnant/breastfeeding women. BIC/FTC/TAF was started within 7 days from HIV diagnosis. The primary endpoint was clinical or virologic failure (VF). Immunological parameters, safety, feasibility, neurocognitive performances and patient-reported outcomes were assessed as well. RESULTS: Over the study period, 40 (34%) of 116 patients diagnosed with HIV infection at INMI Spallanzani had advanced disease, of whom 30 (26%) were enrolled. The proportion of participants with HIV-RNA <50 cp/mL was 9/30 (30%) at week (w) 4, 19/30 (63%) at w12, 24/30 (80%) at w24, 23/30 (77%) at w36 and 27/30 (90%) at w48. Two unconfirmed VF occurred. No ART discontinuation due to toxicity or VF was observed. No ART modification was performed based on the review of genotype and no mutations for the study drugs were detected. Mean CD4 cells count changed by 133 cells/µL at BL to 309 cells/µL at w 48 and 83% of participants had a CD4 > 200 cells/µL at w 48. Two participants developed IRIS and one was diagnosed with disseminated TB and needed an ART switch. INTERPRETATIONS: Our results support the feasibility, efficacy and safety of BIC/FTC/TAF as a rapid ART strategy in patients with advanced HIV disease.