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1.
Sci Rep ; 11(1): 4954, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33654181

RESUMEN

The prophylactic vaccines available to protect against infections by HPV are well tolerated and highly immunogenic. People with HIV have a higher risk of developing HPV infection and HPV-associated cancers due to a lower immune response, and due to viral interactions. We performed a systematic review of RCTs to assess HPV vaccines efficacy and safety on HIV-infected people compared to placebo or no intervention in terms of seroconversion, infections, neoplasms, adverse events, CD4+ T-cell count and HIV viral load. The vaccine-group showed a seroconversion rate close to 100% for each vaccine and a significantly higher level of antibodies against HPV vaccine types, as compared to the placebo group (MD = 4333.3, 95% CI 2701.4; 5965.1 GMT EL.U./ml for HPV type 16 and MD = 1408.8, 95% CI 414.8; 2394.7 GMT EL.U./ml for HPV type 18). There were also no differences in terms of severe adverse events (RR = 0.6, 95% CI 0.2; 1.6) and no severe adverse events (RR = 0.6, 95% CI 0.9; 1.2) between vaccine and placebo groups. Secondary outcomes, such as CD4 + T-cell count and HIV viral load, did not differ between groups (MD = 14.8, 95% CI - 35.1; 64.6 cells/µl and MD = 0.0, 95% CI - 0.3; 0.3 log10 RNA copies/ml, respectively). Information on the remaining outcomes was scarce and that did not allow us to combine the data. The results support the use of the HPV vaccine in HIV-infected patients and highlight the need of further RCTs assessing the effectiveness of the HPV vaccine on infections and neoplasms.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/inmunología , Seguridad del Paciente , Adolescente , Adulto , Anticuerpos Antivirales , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/virología , Femenino , Humanos , Masculino , Infecciones por Papillomavirus/virología , Vacunas contra Papillomavirus/efectos adversos , Salud Pública , Ensayos Clínicos Controlados Aleatorios como Asunto , Riesgo , Resultado del Tratamiento , Carga Viral , Esparcimiento de Virus , Adulto Joven
2.
Front Immunol ; 12: 636768, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33777028

RESUMEN

Understanding the causes of the diverse outcome of COVID-19 pandemic in different geographical locations is important for the worldwide vaccine implementation and pandemic control responses. We analyzed 42 unexposed healthy donors and 28 mild COVID-19 subjects up to 5 months from the recovery for SARS-CoV-2 specific immunological memory. Using HLA class II predicted peptide megapools, we identified SARS-CoV-2 cross-reactive CD4+ T cells in around 66% of the unexposed individuals. Moreover, we found detectable immune memory in mild COVID-19 patients several months after recovery in the crucial arms of protective adaptive immunity; CD4+ T cells and B cells, with a minimal contribution from CD8+ T cells. Interestingly, the persistent immune memory in COVID-19 patients is predominantly targeted towards the Spike glycoprotein of the SARS-CoV-2. This study provides the evidence of both high magnitude pre-existing and persistent immune memory in Indian population. By providing the knowledge on cellular immune responses to SARS-CoV-2, our work has implication for the development and implementation of vaccines against COVID-19.


Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Linfocitos B/virología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , /diagnóstico , Estudios de Casos y Controles , Femenino , Humanos , Inmunidad Celular , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto Joven
3.
Viruses ; 13(2)2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33557210

RESUMEN

HIV-1 infection elicits a complex dynamic of the expression various host genes. High throughput sequencing added an expressive amount of information regarding HIV-1 infections and pathogenesis. RNA sequencing (RNA-Seq) is currently the tool of choice to investigate gene expression in a several range of experimental setting. This study aims at performing a meta-analysis of RNA-Seq expression profiles in samples of HIV-1 infected CD4+ T cells compared to uninfected cells to assess consistently differentially expressed genes in the context of HIV-1 infection. We selected two studies (22 samples: 15 experimentally infected and 7 mock-infected). We found 208 differentially expressed genes in infected cells when compared to uninfected/mock-infected cells. This result had moderate overlap when compared to previous studies of HIV-1 infection transcriptomics, but we identified 64 genes already known to interact with HIV-1 according to the HIV-1 Human Interaction Database. A gene ontology (GO) analysis revealed enrichment of several pathways involved in immune response, cell adhesion, cell migration, inflammation, apoptosis, Wnt, Notch and ERK/MAPK signaling.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Infecciones por VIH/virología , VIH-1/fisiología , Transcriptoma , Linfocitos T CD4-Positivos/virología , Perfilación de la Expresión Génica , Ontología de Genes , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Interacciones Huésped-Patógeno , Humanos
4.
Science ; 371(6535)2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33542150

RESUMEN

HIV-1 has high mutation rates and exists as mutant swarms within the host. Rapid evolution of HIV-1 allows the virus to outpace the host immune system, leading to viral persistence. Approaches to targeting immutable components are needed to clear HIV-1 infection. Here, we report that the caspase recruitment domain-containing protein 8 (CARD8) inflammasome senses HIV-1 protease activity. HIV-1 can evade CARD8 sensing because its protease remains inactive in infected cells before viral budding. Premature intracellular activation of the viral protease triggered CARD8 inflammasome-mediated pyroptosis of HIV-1-infected cells. This strategy led to the clearance of latent HIV-1 in patient CD4+ T cells after viral reactivation. Thus, our study identifies CARD8 as an inflammasome sensor of HIV-1, which holds promise as a strategy for the clearance of persistent HIV-1 infection.


Asunto(s)
Proteínas Adaptadoras de Señalización CARD/metabolismo , Infecciones por VIH/virología , Proteasa del VIH/metabolismo , VIH-1/fisiología , Inflamasomas/metabolismo , Proteínas de Neoplasias/metabolismo , Piroptosis , Alquinos/farmacología , Fármacos Anti-VIH/farmacología , Benzoxazinas/farmacología , Proteínas Adaptadoras de Señalización CARD/química , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD4-Positivos/virología , Caspasa 1/metabolismo , Ciclopropanos/farmacología , Activación Enzimática , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Humanos , Macrófagos/fisiología , Macrófagos/virología , Proteínas de Neoplasias/química , Inhibidores de la Transcriptasa Inversa/farmacología , Rilpivirina/farmacología , Células THP-1 , Latencia del Virus
5.
Nat Commun ; 12(1): 165, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420062

RESUMEN

The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a scalable method for intact HIV-1 reservoir quantification. This droplet digital PCR-based assay simultaneously targets two HIV-1 regions to distinguish genomically intact proviruses against a large background of defective ones, and its application has yielded insights into HIV-1 persistence. Reports of assay failures however, attributed to HIV-1 polymorphism, have recently emerged. Here, we describe a diverse North American cohort of people with HIV-1 subtype B, where the IPDA yielded a failure rate of 28% due to viral polymorphism. We further demonstrate that within-host HIV-1 diversity can lead the IPDA to underestimate intact reservoir size, and provide examples of how this phenomenon could lead to erroneous interpretation of clinical trial data. While the IPDA represents a major methodological advance, HIV-1 diversity should be addressed before its widespread adoption as a principal readout in HIV-1 remission trials.


Asunto(s)
Biodiversidad , ADN Viral/análisis , VIH-1/genética , Provirus/genética , Secuencia de Bases , Linfocitos T CD4-Positivos/virología , ADN Viral/genética , Infecciones por VIH/virología , Humanos , Filogenia , Reacción en Cadena de la Polimerasa/métodos
6.
J Diabetes Res ; 2021: 9526701, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33490288

RESUMEN

The induction of inflammation and cytokine storm was proposed to play a critical role in COVID-19. This study is aimed at investigating the relationship between glucose metabolism and the inflammatory state of inpatients with COVID-19. 71 inpatients with COVID-19 were classified into nondiabetes mellitus (NDM) group, impaired fasting glucose (IFG) group, and diabetes mellitus (DM) group. The average hospitalization days were significantly shorter in DM patients when compared with patients in the IFG group and NDM group. CD4+ T cell percentage was higher while CD8+ T cells percentage was lower in the DM group than those in the NDM group. The serum levels of IL-6, IL-2, IL-10, and INF-γ in the DM group were upregulated when compared with those in the NDM group. The serum levels of TNF-α, IL-4, IL-2, IL-10, and INF-γ were significantly higher in the DM group than those in the IFG group. A significant difference was observed in CD4+ T cell, CD4+/CD8+ ratio percentage, IL-6, and IL-10 between the NDM group and DM group with adjusted BMI. In conclusion, COVID-19 patients with elevated glucose levels have promoted cytokine profiles and immune response.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Diabetes Mellitus Tipo 2/inmunología , Mediadores de Inflamación/inmunología , /inmunología , Adulto , Anciano , Biomarcadores/sangre , Glucemia/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , /epidemiología , Citocinas/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Interacciones Huésped-Patógeno , Humanos , Mediadores de Inflamación/sangre , Tiempo de Internación , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Tiempo
7.
J Exp Med ; 218(4)2021 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-33464307

RESUMEN

Virus-specific T cells play essential roles in protection against multiple virus infections, including SARS-CoV and MERS-CoV. While SARS-CoV-2-specific T cells have been identified in COVID-19 patients, their role in the protection of SARS-CoV-2-infected mice is not established. Here, using mice sensitized for infection with SARS-CoV-2 by transduction with an adenovirus expressing the human receptor (Ad5-hACE2), we identified SARS-CoV-2-specific T cell epitopes recognized by CD4+ and CD8+ T cells in BALB/c and C57BL/6 mice. Virus-specific T cells were polyfunctional and were able to lyse target cells in vivo. Further, type I interferon pathway was proved to be critical for generating optimal antiviral T cell responses after SARS-CoV-2 infection. T cell vaccination alone partially protected SARS-CoV-2-infected mice from severe disease. In addition, the results demonstrated cross-reactive T cell responses between SARS-CoV and SARS-CoV-2, but not MERS-CoV, in mice. Understanding the role of the T cell response will guide immunopathogenesis studies of COVID-19 and vaccine design and validation.


Asunto(s)
/inmunología , Epítopos de Linfocito T/inmunología , Interacciones Huésped-Patógeno/fisiología , Linfocitos T/inmunología , Linfocitos T/virología , /genética , Animales , Anticuerpos Neutralizantes/sangre , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/virología , Chlorocebus aethiops , Reacciones Cruzadas , Mapeo Epitopo , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Virus del SRAS/inmunología , /patogenicidad , Células Vero
8.
Methods Mol Biol ; 2157: 239-249, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32820408

RESUMEN

Fluorescence in situ hybridization (FISH) is a powerful, broadly used microscopy-based technique that leverages fluorescently labeled nucleic acid probes to detect parts of the genome inside metaphase or interphase cell nuclei. In recent years, different methodologies developed to visualize genome topology and spatial relationships between genes have gained much attention as instruments to decode the relationship between chromatin structure and function. In addition to chromosome conformation capture-based techniques, highly multiplexed forms of FISH combined with high-throughput and super-resolution microscopy are used to map and spatially define contact frequencies between different genomic regions. All these approaches have strongly contributed to our knowledge of how the human genome is packed in the cell nucleus.In this chapter, we describe detailed step-by-step protocols for 3D immuno-DNA FISH detection of genes and Human immunodeficiency virus 1 (HIV-1) provirus in primary CD4+ T cells from healthy donors, or cells infected in vitro with the virus. Our multicolor 3D-FISH technique allows, by using up to three fluorophores, visualization of spatial positioning of loci inside a 3D cell nucleus.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Núcleo Celular/metabolismo , VIH-1/aislamiento & purificación , Hibridación Fluorescente in Situ/métodos , Linfocitos T CD4-Positivos/virología , Cromosomas Humanos/metabolismo , Humanos
9.
Nat Commun ; 11(1): 5542, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33139735

RESUMEN

The HIV-1 reservoir is the major hurdle to curing HIV-1. However, the impact of the viral genome on the HIV-1 reservoir, i.e. its heritability, remains unknown. We investigate the heritability of the HIV-1 reservoir size and its long-term decay by analyzing the distribution of those traits on viral phylogenies from both partial-pol and viral near full-length genome sequences. We use a unique nationwide cohort of 610 well-characterized HIV-1 subtype-B infected individuals on suppressive ART for a median of 5.4 years. We find that a moderate but significant fraction of the HIV-1 reservoir size 1.5 years after the initiation of ART is explained by genetic factors. At the same time, we find more tentative evidence for the heritability of the long-term HIV-1 reservoir decay. Our findings indicate that viral genetic factors contribute to the HIV-1 reservoir size and hence the infecting HIV-1 strain may affect individual patients' hurdle towards a cure.


Asunto(s)
Antirretrovirales/farmacología , VIH-1/efectos de los fármacos , VIH-1/genética , Adulto , Linfocitos T CD4-Positivos/virología , Estudios de Cohortes , ADN Viral/genética , Femenino , Genoma Viral , Infecciones por VIH/virología , Humanos , Masculino , Factores de Tiempo , Carga Viral
10.
Nat Rev Immunol ; 20(11): 709-713, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33024281

RESUMEN

Immunity is a multifaceted phenomenon. For T cell-mediated memory responses to SARS-CoV-2, it is relevant to consider their impact both on COVID-19 disease severity and on viral spread in a population. Here, we reflect on the immunological and epidemiological aspects and implications of pre-existing cross-reactive immune memory to SARS-CoV-2, which largely originates from previous exposure to circulating common cold coronaviruses. We propose four immunological scenarios for the impact of cross-reactive CD4+ memory T cells on COVID-19 severity and viral transmission. For each scenario, we discuss its implications for the dynamics of herd immunity and on projections of the global impact of SARS-CoV-2 on the human population, and assess its plausibility. In sum, we argue that key potential impacts of cross-reactive T cell memory are already incorporated into epidemiological models based on data of transmission dynamics, particularly with regard to their implications for herd immunity. The implications of immunological processes on other aspects of SARS-CoV-2 epidemiology are worthy of future study.


Asunto(s)
Anticuerpos Antivirales/biosíntesis , Betacoronavirus/inmunología , Infecciones por Coronaviridae/prevención & control , Infecciones por Coronavirus/prevención & control , Pandemias/prevención & control , Neumonía Viral/prevención & control , Vacunas Virales/inmunología , Inmunidad Adaptativa/efectos de los fármacos , Betacoronavirus/efectos de los fármacos , Betacoronavirus/patogenicidad , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Coronaviridae/efectos de los fármacos , Coronaviridae/inmunología , Infecciones por Coronaviridae/epidemiología , Infecciones por Coronaviridae/inmunología , Infecciones por Coronaviridae/virología , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Reacciones Cruzadas , Humanos , Inmunidad Colectiva/efectos de los fármacos , Memoria Inmunológica , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Neumonía Viral/virología , Rhinovirus/efectos de los fármacos , Rhinovirus/inmunología , Vacunas Virales/administración & dosificación , Vacunas Virales/biosíntesis
11.
Nat Commun ; 11(1): 5412, 2020 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-33110078

RESUMEN

Viral rebound following antiretroviral therapy (ART) discontinuation in HIV-1-infected individuals is believed to originate from a small pool of CD4+ T cells harboring replication-competent provirus. However, the origin and nature of the rebound virus has remained unclear. Recent studies have suggested that rebound virus does not originate directly from individual latent proviruses but rather from recombination events involving multiple proviruses. Here we evaluate the origin of rebound virus in 16 ART-suppressed, chronically SIV-infected rhesus monkeys following ART discontinuation. We sequence viral RNA and viral DNA in these animals prior to ART initiation, during ART suppression, and following viral rebound, and we compare rebound viral RNA after ART discontinuation with near full-length viral DNA from peripheral blood and lymph node mononuclear cells (PBMC and LNMC) during ART suppression. Sequences of initial rebound viruses closely match viral DNA sequences in PBMC and LNMC during ART suppression. Recombinant viruses are rare in the initial rebound virus populations but arise quickly within 2-4 weeks after viral rebound. These data suggest that intact proviral DNA in PBMC and LNMC during ART suppression is likely the direct origin of viral rebound in chronically SIV-infected rhesus monkeys following ART discontinuation.


Asunto(s)
Antirretrovirales/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios/fisiología , Animales , Linfocitos T CD4-Positivos/virología , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/fisiología , Humanos , Macaca mulatta , Masculino , Pacientes Desistentes del Tratamiento , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/genética , Carga Viral/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacos
12.
BMC Infect Dis ; 20(1): 756, 2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-33059622

RESUMEN

BACKGROUND: Infection with the Human Immunodeficiency Virus (HIV) dramatically increases the risk of developing active tuberculosis (TB). Several studies have indicated that co-infection with TB increases the risk of HIV progression and death. Sub-Saharan Africa bears the brunt of these dual epidemics, with about 2.4 million HIV-infected people living with TB. The main objective of our study was to assess whether the pre-HAART CD4+ T-lymphocyte counts and percentages could serve as biomarkers for post-HAART treatment immune-recovery in HIV-positive children with and without TB co-infection. METHODS: The data analyzed in this retrospective study were collected from a cohort of 305 HIV-infected children being treated with HAART. A Lehmann family of ROC curves were used to assess the diagnostic performance of pre- HAART treatment CD4+ T-lymphocyte count and percentage as biomarkers for post-HAART immune recovery. The Kaplan-Meier estimator was used to compare differences in post-HAART recovery times between patients with and without TB co-infection. RESULTS: We found that the diagnostic performance of both pre-HARRT treatment CD4+ T-lymphocyte count and percentage was comparable and achieved accuracies as high as 74%. Furthermore, the predictive capability of pre-HAART CD4+ T-lymphocyte count and percentage were slightly better in TB-negative patients. Our analyses also indicate that TB-negative patients have a shorter recovery time compared to the TB-positive patients. CONCLUSIONS: Pre-HAART CD4+ T-lymphocyte count and percentage are stronger predictors of immune recovery in TB-negative pediatric patients, suggesting that TB co-infection complicates the treatment of HIV in this cohort. These findings suggest that the detection and treatment of TB is essential for the effectiveness of HAART in HIV-infected pediatric patients.


Asunto(s)
Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Coinfección , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Tuberculosis/complicaciones , Infecciones Oportunistas Relacionadas con el SIDA , Biomarcadores/análisis , Linfocitos T CD4-Positivos/virología , Niño , Preescolar , Femenino , Ghana , Infecciones por VIH/microbiología , Infecciones por VIH/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Curva ROC , Estudios Retrospectivos , Resultado del Tratamiento , Tuberculosis/virología
13.
PLoS Pathog ; 16(9): e1008834, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32956422

RESUMEN

Despite the widespread use of anti-retroviral therapy, human immunodeficiency virus (HIV) still persists in an infected cell reservoir that harbors transcriptionally silent yet replication-competent proviruses. While significant progress has been made in understanding how the HIV reservoir is established, transcription repression mechanisms that are enforced on the integrated viral promoter have not been fully revealed. In this study, we performed a whole-genome CRISPR knockout screen in HIV infected T cells to identify host genes that potentially promote HIV latency. Of several top candidates, the KRAB-containing zinc finger protein, ZNF304, was identified as the top hit. ZNF304 silences HIV gene transcription through associating with TRIM28 and recruiting to the viral promoter heterochromatin-inducing methyltransferases, including the polycomb repression complex (PRC) and SETB1. Depletion of ZNF304 expression reduced levels of H3K9me3, H3K27me3 and H2AK119ub repressive histone marks on the HIV promoter as well as SETB1 and TRIM28, ultimately enhancing HIV gene transcription. Significantly, ZNF304 also promoted HIV latency, as its depletion delayed the entry of HIV infected cells into latency. In primary CD4+ cells, ectopic expression of ZNF304 silenced viral transcription. We conclude that by associating with TRIM28 and recruiting host transcriptional repressive complexes, SETB1 and PRC, to the HIV promoter, ZNF304 silences HIV gene transcription and promotes viral latency.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Regulación Viral de la Expresión Génica , Silenciador del Gen , VIH-1/fisiología , Proteínas Represoras , Factores de Transcripción , Transcripción Genética , Latencia del Virus , Linfocitos T CD4-Positivos/virología , Sistemas CRISPR-Cas , Técnicas de Inactivación de Genes , Estudio de Asociación del Genoma Completo , Humanos , Células Jurkat , Regiones Promotoras Genéticas , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína 28 que Contiene Motivos Tripartito/genética , Proteína 28 que Contiene Motivos Tripartito/metabolismo
14.
PLoS Comput Biol ; 16(9): e1007470, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32941445

RESUMEN

Human T-lymphotropic virus type-1 (HTLV-1) persists within hosts via infectious spread (de novo infection) and mitotic spread (infected cell proliferation), creating a population structure of multiple clones (infected cell populations with identical genomic proviral integration sites). The relative contributions of infectious and mitotic spread to HTLV-1 persistence are unknown, and will determine the efficacy of different approaches to treatment. The prevailing view is that infectious spread is negligible in HTLV-1 persistence beyond early infection. However, in light of recent high-throughput data on the abundance of HTLV-1 clones, and recent estimates of HTLV-1 clonal diversity that are substantially higher than previously thought (typically between 104 and 105 HTLV-1+ T cell clones in the body of an asymptomatic carrier or patient with HTLV-1-associated myelopathy/tropical spastic paraparesis), ongoing infectious spread during chronic infection remains possible. We estimate the ratio of infectious to mitotic spread using a hybrid model of deterministic and stochastic processes, fitted to previously published HTLV-1 clonal diversity estimates. We investigate the robustness of our estimates using three alternative estimators. We find that, contrary to previous belief, infectious spread persists during chronic infection, even after HTLV-1 proviral load has reached its set point, and we estimate that between 100 and 200 new HTLV-1 clones are created and killed every day. We find broad agreement between all estimators. The risk of HTLV-1-associated malignancy and inflammatory disease is strongly correlated with proviral load, which in turn is correlated with the number of HTLV-1-infected clones, which are created by de novo infection. Our results therefore imply that suppression of de novo infection may reduce the risk of malignant transformation.


Asunto(s)
Infecciones por HTLV-I , Interacciones Huésped-Patógeno , Virus Linfotrópico T Tipo 1 Humano , Linfocitos T CD4-Positivos/virología , Infecciones por HTLV-I/fisiopatología , Infecciones por HTLV-I/virología , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/fisiología , Virus Linfotrópico T Tipo 1 Humano/clasificación , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/patogenicidad , Humanos , Mitosis/genética , Mitosis/fisiología , Modelos Biológicos , Provirus/genética , Provirus/patogenicidad , Carga Viral/genética , Integración Viral/genética
15.
PLoS Pathog ; 16(9): e1008853, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32886726

RESUMEN

HIV-1 transmission is associated with a severe bottleneck in which a limited number of variants from a pool of genetically diverse quasispecies establishes infection. The IAVI protocol C cohort of discordant couples, female sex workers, other heterosexuals and men who have sex with men (MSM) present varying risks of HIV infection, diverse HIV-1 subtypes and represent a unique opportunity to characterize transmitted/founder viruses (TF) where disease outcome is known. To identify the TF, the HIV-1 repertoire of 38 MSM participants' samples was sequenced close to transmission (median 21 days post infection, IQR 18-41) and assessment of multivariant infection done. Patient derived gag genes were cloned into an NL4.3 provirus to generate chimeric viruses which were characterized for replicative capacity (RC). Finally, an evaluation of how the TF virus predicted disease progression and modified the immune response at both acute and chronic HIV-1 infection was done. There was higher prevalence of multivariant infection compared with previously described heterosexual cohorts. A link was identified between multivariant infection and replicative capacity conferred by gag, whereby TF gag tended to be of lower replicative capacity in multivariant infection (p = 0.02) suggesting an overall lowering of fitness requirements during infection with multiple variants. Notwithstanding, multivariant infection was associated with rapid CD4+ T cell decline and perturbances in the CD4+ T cell and B cell compartments compared to single variant infection, which were reversible upon control of viremia. Strategies aimed at identifying and mitigating multivariant infection could contribute toward improving HIV-1 prognosis and this may involve strategies that tighten the stringency of the transmission bottleneck such as treatment of STI. Furthermore, the sequences and chimeric viruses help with TF based experimental vaccine immunogen design and can be used in functional assays to probe effective immune responses against TF.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Efecto Fundador , Infecciones por VIH , VIH-1/fisiología , Replicación Viral , Productos del Gen gag del Virus de la Inmunodeficiencia Humana , Enfermedad Aguda , Adolescente , Adulto , Linfocitos B/inmunología , Linfocitos B/patología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/virología , Femenino , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Humanos , Masculino , Persona de Mediana Edad , Viremia/genética , Viremia/inmunología , Viremia/patología , Replicación Viral/genética , Replicación Viral/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología
16.
Nat Med ; 26(9): 1339-1350, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32895573

RESUMEN

Therapeutic strategies are being clinically tested either to eradicate latent HIV reservoirs or to achieve virologic control in the absence of antiretroviral therapy. Attaining this goal will require a consensus on how best to measure the numbers of persistently infected cells with the potential to cause viral rebound after antiretroviral-therapy cessation in assessing the results of cure-directed strategies in vivo. Current measurements assess various aspects of the HIV provirus and its functionality and produce divergent results. Here, we provide recommendations from the BEAT-HIV Martin Delaney Collaboratory on which viral measurements should be prioritized in HIV-cure-directed clinical trials.


Asunto(s)
Antirretrovirales/uso terapéutico , Reservorios de Enfermedades/virología , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , Ensayos Clínicos como Asunto , Humanos , Tamizaje Masivo/métodos , Carga Viral/efectos de los fármacos , Latencia del Virus/efectos de los fármacos
18.
Med Microbiol Immunol ; 209(6): 681-691, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32918599

RESUMEN

Chimeric Antigen Receptor (CAR)-redirected T cells show great efficacy in the patient-specific therapy of hematologic malignancies. Here, we demonstrate that a DARPin with specificity for CD4 specifically redirects and triggers the activation of CAR engineered T cells resulting in the depletion of CD4+ target cells aiming for elimination of the human immunodeficiency virus (HIV) reservoir.


Asunto(s)
Repetición de Anquirina , Linfocitos T CD4-Positivos/virología , Infecciones por VIH/inmunología , VIH/aislamiento & purificación , Inmunoterapia Adoptiva , Depleción Linfocítica/métodos , Péptidos/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Relación Dosis-Respuesta Inmunológica , Evaluación Preclínica de Medicamentos , Gammaretrovirus/genética , Vectores Genéticos/genética , Células HEK293 , Infecciones por VIH/virología , Humanos , Activación de Linfocitos , Péptidos/química , Anticuerpos de Cadena Única/inmunología , Transducción Genética
19.
Clin Immunol ; 220: 108591, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32920210

RESUMEN

Most severe cases with COVID-19, especially those with pulmonary failure, are not a consequence of viral burden and/or failure of the 'adaptive' immune response to subdue the pathogen by utilizing an adequate 'adaptive' immune defense. Rather it is a consequence of immunopathology, resulting from imbalanced innate immune response, which may not be linked to pathogen burden at all. In fact, it might be described as an autoinflammatory disease. The Kawasaki-like disease seen in children with SARS-CoV-2 exposure might be another example of similar mechanism.


Asunto(s)
Autoinmunidad/genética , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Interacciones Huésped-Patógeno/inmunología , Neumonía Viral/inmunología , Insuficiencia Respiratoria/inmunología , Enfermedad Aguda , Inmunidad Adaptativa , Betacoronavirus/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/virología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/fisiopatología , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/fisiopatología , Interacciones Huésped-Patógeno/genética , Humanos , Inmunidad Innata , Activación de Linfocitos , Síndrome Mucocutáneo Linfonodular/genética , Síndrome Mucocutáneo Linfonodular/inmunología , Síndrome Mucocutáneo Linfonodular/fisiopatología , Pandemias , Neumonía Viral/genética , Neumonía Viral/fisiopatología , Insuficiencia Respiratoria/genética , Insuficiencia Respiratoria/fisiopatología , Índice de Severidad de la Enfermedad
20.
Signal Transduct Target Ther ; 5(1): 179, 2020 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-32868756
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