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1.
Lancet HIV ; 8(5): e294-e305, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33915101

RESUMEN

Around 2·5 million deaths and more than 110 million COVID-19 cases have been reported globally. Although it initially appeared that HIV infection was not a risk factor for COVID-19 or more severe disease, more recent large studies suggest that people living with HIV (particularly with low CD4 cell counts or untreated HIV infection) might have a more severe clinical course than those who are HIV-negative. Moreover, the COVID-19 pandemic has disrupted HIV prevention and treatment services worldwide, creating huge challenges to the continuity of essential activities. We have reviewed the most relevant features of COVID-19 in people living with HIV and highlighted topics where further research is required.


Asunto(s)
/complicaciones , Infecciones por VIH/complicaciones , Inmunidad Adaptativa , /inmunología , /normas , Comorbilidad , Progresión de la Enfermedad , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , Humanos , Masculino , Pronóstico , /inmunología
2.
Medicine (Baltimore) ; 100(17): e25678, 2021 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-33907138

RESUMEN

ABSTRACT: HIV infection has become a chronic disease, with a lower mortality, but a consequent increase in age-related noninfectious comorbidities. Metabolic disorders have been linked to the effect of cART as well to the effects of immune activation and chronic inflammation. Whereas it is known that aging is intrinsically associated with hyperinflammation and immune system deterioration, the relative impact of chronic HIV infection on such inflammatory and immune activation has not yet been studied focusing on an elderly HIV-infected population.The objectives of the study were to assess 29 blood markers of immune activation and inflammation using an ultrasensitive technique, in HIV-infected patients aged ≥75 years with no or 1 comorbidity (among hypertension, renal disease, neoplasia, diabetes mellitus, cardiovascular disease, stroke, dyslipidemia, and osteoporosis), in comparison with age-adjusted HIV-uninfected individuals to identify whether biomarkers were associated with comorbidities. Wilcoxon nonparametric tests were used to compare the levels of each marker between control and HIV groups; logistic regression to identify biomarkers associated to comorbidity in the HIV group and principal component analysis (PCA) to determine clusters associated with a group or a specific comorbidity.A total of 111 HIV-infected subjects were included from the Dat'AIDS cohort and compared to 63 HIV-uninfected controls. In the HIV-infected group, 4 biomarkers were associated with the risk of developing a comorbidity: monocyte chemoattractant protein-1 (MCP-1), neurofilament light chain (NF-L), neopterin, and soluble CD14. Six biomarkers (interleukin [IL]-1B, IL-7, IL-18, neopterin, sCD14, and fatty acid-binding protein) were significantly higher in the HIV-infected group compared to the control group, 11 biomarkers (myeloperoxydase, interleukin-1 receptor antagonist, tumor necrosis factor receptor 1, interferon-gamma, MCP-1, tumor necrosis factor receptor 2, IL-22, ultra sensitivity C-reactive protein, fibrinogen, IL-6, and NF-L) were lower. Despite those differences, PCA to determine clusters associated with a group or a specific comorbidity did not reveal clustering nor between healthy control and HIV-infected patients neither between the presence of comorbidity within HIV-infected group.In this highly selected geriatric HIV population, HIV infection does not seem to have an additional impact on age-related inflammation and immune disorder. Close monitoring could have led to optimize prevention and treatment of comorbidities, and have limited both immune activation and inflammation in the aging HIV population.


Asunto(s)
Envejecimiento/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , VIH/inmunología , Mediadores de Inflamación/inmunología , Anciano , Envejecimiento/sangre , Biomarcadores/sangre , Enfermedad Crónica , Estudios de Cohortes , Comorbilidad , Femenino , Francia , Evaluación Geriátrica , Humanos , Inmunidad Activa , Inflamación , Mediadores de Inflamación/sangre , Modelos Logísticos , Masculino , Análisis de Componente Principal , Estadísticas no Paramétricas
3.
Front Immunol ; 12: 649567, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33841434

RESUMEN

Both coronavirus disease 2019 (COVID-19) and mycobacterial immune reconstitution inflammatory syndrome (IRIS) in patients with HIV-1 infection result from immunopathology that is characterized by increased production of multiple pro-inflammatory chemokines and cytokines associated with activation of myeloid cells (monocytes, macrophages and neutrophils). We propose that both conditions arise because innate immune responses generated in the absence of effective adaptive immune responses lead to monocyte/macrophage activation that is amplified by the emergence of a pathogen-specific adaptive immune response skewed towards monocyte/macrophage activating activity by the immunomodulatory effects of cytokines produced during the innate response, particularly interleukin-18. In mycobacterial IRIS, that disease-enhancing immune response is dominated by a Th1 CD4+ T cell response against mycobacterial antigens. By analogy, it is proposed that in severe COVID-19, amplification of monocyte/macrophage activation results from the effects of a SARS-CoV-2 spike protein antibody response with pro-inflammatory characteristics, including high proportions of IgG3 and IgA2 antibodies and afucosylation of IgG1 antibodies, that arises from B cell differentiation in an extra-follicular pathway promoted by activation of mucosa-associated invariant T cells. We suggest that therapy for the hyperinflammation underlying both COVID-19 and mycobacterial IRIS might be improved by targeting the immunomodulatory as well as the pro-inflammatory effects of the 'cytokine storm'.


Asunto(s)
/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Síndrome Inflamatorio de Reconstitución Inmune/inmunología , /inmunología , Humanos , Inmunidad Innata , Activación de Macrófagos , Macrófagos/inmunología , Monocitos/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Células TH1/inmunología
4.
Nat Commun ; 12(1): 2147, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33846309

RESUMEN

Tissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. As such they deliver HIV to its primary target cells; CD4 T cells. Most MNP HIV transmission studies have focused on epithelial MNPs. However, as mucosal trauma and inflammation are now known to be strongly associated with HIV transmission, here we examine the role of sub-epithelial MNPs which are present in a diverse array of subsets. We show that HIV can penetrate the epithelial surface to interact with sub-epithelial resident MNPs in anogenital explants and define the full array of subsets that are present in the human anogenital and colorectal tissues that HIV may encounter during sexual transmission. In doing so we identify two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14+CD1c+ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 (cDC2).


Asunto(s)
Canal Anal/citología , Antígenos CD/metabolismo , Células Dendríticas/metabolismo , Genitales/citología , VIH-1/fisiología , Lectinas Tipo C/metabolismo , Lectinas de Unión a Manosa/metabolismo , Monocitos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Forma de la Célula , Colagenasas/metabolismo , Dermis/metabolismo , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Receptores de Lipopolisacáridos/metabolismo , Membrana Mucosa/metabolismo , Fagocitos/metabolismo , Fenotipo , Receptores CCR5/metabolismo , Lectina 1 Similar a Ig de Unión al Ácido Siálico/metabolismo , Transcripción Genética
5.
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
6.
Medicine (Baltimore) ; 100(10): e25140, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33725916

RESUMEN

BACKGROUND: Human immunodeficiency virus (HIV)-associated distal symmetric peripheral neuropathy (DSPN) is one of the most frequent neurological complications of HIV infection, and causes pain and dysaesthesias in millions globally. Many individuals with this infection report using acupuncture to manage their symptoms, but evidence supporting the use of acupuncture is limited. This systematic review will assess the effectiveness and safety of acupuncture for patients with HIV-associated DSPN. METHODS: Databases including MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Scopus, Web of science, AMED (Allied and Complementary Medicine), the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, Wanfang Database, VIP Database and clinical trials registers (the WHO International Clinical Trials Registry Platform portal and www.ClinicalTrials.gov) will be electronically searched from inception to December 1, 2020. All randomized controlled trials in English or Chinese without restriction on publication status will be included. Selection of studies, extraction of data, and assessment of studies quality will be independently performed by 2 reviewers. The primary outcome measure will be the change in pain intensity assessed by validated scales. Secondary outcomes include change in neurologic summary scores, quality of life, physical function evaluated by admitted tools, and adverse events related to acupuncture reported in the included trials. If possible, a meta-analysis will be conducted to provide an estimate of the pooled treatment effect using Review Manager 5.3 statistical software. Otherwise, qualitative descriptive analysis will be given. The results will be presented as the risk ratio for binary data and the mean difference (MD) or standardized MD for continuous data. RESULTS: The results of the systematic review will be disseminated via publication in a peer-reviewed journal and presented at a relevant conference. CONCLUSION: This review will be the first review entirely focused on assessing the effectiveness and safety of acupuncture for HIV-associated DSPN. PROSPERO REGISTRATION NUMBER: CRD42020210994.


Asunto(s)
Terapia por Acupuntura/efectos adversos , Infecciones por VIH/complicaciones , Neuralgia/terapia , Parestesia/terapia , Polineuropatías/terapia , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Metaanálisis como Asunto , Neuralgia/diagnóstico , Neuralgia/inmunología , Neuralgia/virología , Dimensión del Dolor , Parestesia/diagnóstico , Parestesia/inmunología , Parestesia/virología , Polineuropatías/diagnóstico , Polineuropatías/inmunología , Polineuropatías/virología , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Revisiones Sistemáticas como Asunto , Resultado del Tratamiento
7.
Expert Rev Clin Immunol ; 17(3): 201-208, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33538189

RESUMEN

INTRODUCTION: In people living with HIV (PLWH), immune activation and inflammation levels are high even when viral suppression is maintained, potentially contributing to several comorbidities, and hampering the immune response to infections such as the recent SARS-CoV-2 disease 2019 (COVID-19). AREAS COVERED: Immune activation and inflammation play a role in SARS-CoV-2 infection. Severe COVID-19 patients may experience cytokine release syndrome (CRS), leading to alveolar damage, pulmonary fibrinolysis, dysregulated coagulation, and pulmonary injury. Into the systemic circulation, cytokines in excess might leak out of pulmonary circulation, causing systemic symptoms and possibly a multiple-organ dysfunction syndrome. Preexisting comorbidities are also linked to worse COVID-19 outcome: studies suggest that diabetes and hypertension are linked to higher mortality rates. Such comorbidities are more frequent in PLWH, but it is unclear if they have worse outcomes in the case of COVID-19. The literature was searched in PubMed/MEDLINE and EMBASE, and manually in COVID-19 resources. EXPERT OPINION: A body of evidence shows that HIV and SARS-CoV-2 are able to activate inflammatory pathways, acute in the case of SARS-CoV-2, chronic in the case of HIV, while the comorbidities seem to represent, in the first case, a contributory cause, in the second an effect of the virus-induced damage.


Asunto(s)
/epidemiología , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , Trastornos de la Coagulación Sanguínea/epidemiología , Trastornos de la Coagulación Sanguínea/inmunología , Comorbilidad , Citocinas/inmunología , Diabetes Mellitus/epidemiología , Diabetes Mellitus/inmunología , Humanos , Hiperglucemia/epidemiología , Hiperglucemia/inmunología , Hipertensión/epidemiología , Hipertensión/inmunología , Inflamación , Síndrome Metabólico/epidemiología , Síndrome Metabólico/inmunología
8.
Lancet HIV ; 8(2): e87-e95, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33539762

RESUMEN

BACKGROUND: Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation. METHODS: We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037. FINDINGS: Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (>0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p<0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR. INTERPRETATION: High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa. FUNDING: The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Dispositivos Anticonceptivos Femeninos , Infecciones por VIH/prevención & control , Pirimidinas/uso terapéutico , Tenofovir/uso terapéutico , Administración Intravaginal , Adulto , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Humanos , Malaui , Cooperación del Paciente/estadística & datos numéricos , Seguridad del Paciente , Seroconversión , Sudáfrica , Resultado del Tratamiento , Uganda , Zimbabwe
9.
Lancet HIV ; 8(2): e77-e86, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33539761

RESUMEN

BACKGROUND: The Ring Study, a phase 3 trial in 1959 sexually active women (randomised 2:1), showed a favourable safety profile and a 31% HIV-1 infection risk reduction for a vaginal ring containing 25 mg of dapivirine, compared with a placebo ring. We report here the DREAM study, which aimed to evaluate safety, adherence, and HIV-1 incidence in those using the dapivirine vaginal ring (DVR) in open-label use. METHODS: The DREAM study is an open-label extension of The Ring Study, done at five research centres in South Africa and one research centre in Uganda. Former participants from The Ring Study, who remained HIV-negative and who did not discontinue the study due to an adverse event or safety concern that was considered to be related to the investigational product, were eligible. Women who were pregnant, planning to become pregnant, or breastfeeding at screening for DREAM were excluded. All participants received the DVR for insertion at the enrolment visit. Participants attended a 1-month follow-up visit and could either proceed with visits once every 3 months or attend monthly visits up to month 3 and then continue with visits once every 3 months. At each visit, HIV testing and safety evaluations were done, and residual dapivirine measured in used rings (approximately 4 mg is released from the DVR over 28 days of consistent use). HIV-1 incidence was compared descriptively with the simulated incidence rate obtained from bootstrap sampling of participants in the placebo group of The Ring Study, matched for research centre, age, and presence of sexually transmitted infections at enrolment. This study is registered with ClinicalTrials.gov, NCT02862171. FINDINGS: Between July 12, 2016, and Jan 11, 2019, 1034 former participants from The Ring Study were screened, 941 were enrolled and 848 completed the trial. 616 (65·5%) of 941 participants reported treatment-emergent adverse events. Of these, six (0·6%) had events considered to be treatment-related. No treatment-related serious adverse events were reported. Measurements of monthly ring residual amounts in participants enrolled in both trials showed consistently lower mean values in DREAM than in The Ring Study. Arithmetic mean ring residual amounts of participants in The Ring Study DVR group who enrolled in DREAM were 0·25 mg lower (95% CI 0·03-0·47; p=0·027) than the mean ring residual amounts of these participants in The Ring Study. 18 (1·9%) HIV-1 infections were confirmed during DVR use, resulting in an incidence of 1·8 (95% CI 1·1-2·6) per 100 person-years, 62% lower than the simulated placebo rate. INTERPRETATION: Although efficacy estimation is limited by the absence of a placebo group, the observed low HIV-1 incidence and improved adherence observed in DREAM support the hypothesis that increased efficacy due to improved adherence occurs when women know the demonstrated safety and efficacy of the DVR. The feasibility of a visit schedule of once every 3 months was shown, indicating that the DVR can be used in a real-world situation in usual clinical practice. FUNDING: The Ministry of Foreign Affairs (MFA) Denmark, Flanders MFA, Irish Aid, Dutch MFA, UK Aid from the UK Government's Foreign, Commonwealth and Development Office, and the US President's Emergency Plan for AIDS Relief through the US Agency for International Development.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Dispositivos Anticonceptivos Femeninos , Infecciones por VIH/prevención & control , Pirimidinas/uso terapéutico , Tenofovir/uso terapéutico , Administración Intravaginal , Adolescente , Adulto , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Humanos , Persona de Mediana Edad , Cooperación del Paciente/estadística & datos numéricos , Seguridad del Paciente , Seroconversión , Sudáfrica , Resultado del Tratamiento , Uganda
10.
Drug Discov Ther ; 15(1): 42-43, 2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33390569

RESUMEN

Most studies have described worse outcomes with coronavirus disease 2019 (COVID-19) in patients with human immunodeficiency virus (HIV). This has been attributed to COVID-19 associated lymphopenia (resulting in lower CD4 count), higher prevalence of comorbidities (established risk factors for severity in COVID-19) and pre-existing lung damage. The problem has been further aggravated by the lack in the access to routine care in HIV patients due to diversion of resources. In this article, we discuss the impact of COVID-19 on patients with HIV infection.


Asunto(s)
/epidemiología , Coinfección/inmunología , Infecciones por VIH/epidemiología , Recuento de Linfocito CD4 , Infecciones por VIH/inmunología , Accesibilidad a los Servicios de Salud , Humanos , Pronóstico , Factores Socioeconómicos
11.
Int J Med Sci ; 18(3): 846-851, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33437221

RESUMEN

In the last 50 years we have experienced two big pandemics, the HIV pandemic and the pandemic caused by SARS-CoV-2. Both pandemics are caused by RNA viruses and have reached us from animals. These two viruses are different in the transmission mode and in the symptoms they generate. However, they have important similarities: the fear in the population, increase in proinflammatory cytokines that generate intestinal microbiota modifications or NETosis production by polymorphonuclear neutrophils, among others. They have been implicated in the clinical, prognostic and therapeutic attitudes.


Asunto(s)
/epidemiología , Infecciones por VIH/epidemiología , VIH-1/patogenicidad , Pandemias/historia , /patogenicidad , /inmunología , /transmisión , Citocinas/sangre , Citocinas/inmunología , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Miedo , Carga Global de Enfermedades/estadística & datos numéricos , Infecciones por VIH/inmunología , Infecciones por VIH/psicología , Infecciones por VIH/transmisión , VIH-1/inmunología , VIH-1/aislamiento & purificación , Historia del Siglo XX , Historia del Siglo XXI , Interacciones Huésped-Patógeno/inmunología , Humanos , Mediadores de Inflamación/sangre , Mediadores de Inflamación/inmunología , Mortalidad , Neutrófilos/inmunología , Neutrófilos/metabolismo , Pandemias/estadística & datos numéricos , Pronóstico , /aislamiento & purificación
12.
Int J Infect Dis ; 104: 306-314, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33444750

RESUMEN

OBJECTIVES: Human immunodeficiency virus (HIV) quasispecies diversity presents a large barrier to the eradication of HIV. The aim of this study was to investigate intrahost HIV quasispecies diversity and evolutionary patterns underpinning the mechanisms of viral pathogenesis during antiretroviral therapy (ART). METHODS: Forty-five participants with HIV-1 infection were enrolled in a follow-up cohort for >84 months in 2004, and received a lamivudine-based first-line ART regimen. Blood samples were collected every 6 months to measure viral load and CD4+ cell count. Ultra-deep sequencing and phylogenetic analysis were used to characterize the dynamics governing quasispecies diversity of HIV-1 circulating between plasma RNA and cellular DNA of participants with treatment failure (TF, n = 20) or virologic suppression (VS, n = 25). RESULTS: Analysis of the distribution of intrahost single-nucleotide variations (iSNVs) and their mutated allele frequencies revealed that approximately 65% of the quasispecies co-occurred in plasma HIV RNA and cellular DNA either before or after ART. The number and frequency of iSNVs are more representative of intrahost HIV diversity, and have better generalizability than phylogenetic inference by measurement of phylogenetic associations. Furthermore, drug-resistance-associated mutations (DRAMs) accumulated to high levels, dramatically increasing the DRAM-to-total-mutation ratio for TF patients. Linear regression analysis revealed that emergent mutations accumulated faster in TF patients compared with VS patients, at a rate of 0.02 mutations/day/kb. CONCLUSIONS: Based on iSNV analysis, the results demonstrate the dynamics of intrahost HIV quasispecies diversity in patients on ART, and provide a novel insight into the persistence of HIV and development of DRAMs.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/virología , VIH-1/genética , Cuasiespecies , Adulto , Recuento de Linfocito CD4 , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/clasificación , VIH-1/efectos de los fármacos , Humanos , Masculino , Filogenia , Carga Viral
13.
J Med Virol ; 93(5): 2971-2978, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33506953

RESUMEN

The aim of this study was to describe the clinical characteristics and outcomes of coronavirus disease 2019 (COVID-19) among people living with HIV (PLWH) in Belgium. We performed a retrospective multicenter cohort analysis of PLWH with either laboratory-confirmed, radiologically diagnosed, or clinically suspected COVID-19 between February 15, 2020 and May 31, 2020. The primary endpoint was outcome of COVID-19. Secondary endpoints included rate of hospitalization and length of hospital stay and rate of Intensive Care Unit (ICU) admission and mechanical ventilation. One hundred and one patients were included in this study. Patients were categorized as having either laboratory-confirmed (n = 65), radiologically-diagnosed (n = 3), or clinically suspected COVID-19 (n = 33). The median age was 51.3 years (interquartile range [IQR] 41.3-57.3) and 44% were female. Ninety-four percent of patients were virologically suppressed and 67% had a CD4+ cell count more than or equal to 500 cells/µl. Overall, 46% of patients required hospitalization and the median length of hospital stay was 6 days (IQR 3-15). Age more than or equal to 50 years, Black Sub-Saharan African patients, and being on an integrase strand transfer inhibitor-based regimen were associated with being hospitalized. ICU admission and mechanical ventilation was required for 15% and 10% of all patients respectively. Overall, 9% of patients died while 78 (77%) patients made a full recovery. HIV patients with COVID-19 experienced a high degree of hospitalization despite having elevated CD4+ cell counts and a high rate of virologic suppression. Matched case-control studies are warranted to measure the impact that HIV may have on patients with COVID-19.


Asunto(s)
/diagnóstico , Infecciones por VIH/epidemiología , Adulto , Bélgica/epidemiología , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Femenino , Infecciones por VIH/inmunología , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento
14.
Clin Pharmacol Ther ; 109(4): 829-840, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33410134

RESUMEN

Modern viral kinetic modeling and its application to therapeutics is a field that attracted the attention of the medical, pharmaceutical, and modeling communities during the early days of the AIDS epidemic. Its successes led to applications of modeling methods not only to HIV but a plethora of other viruses, such as hepatitis C virus (HCV), hepatitis B virus and cytomegalovirus, which along with HIV cause chronic diseases, and viruses such as influenza, respiratory syncytial virus, West Nile virus, Zika virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which generally cause acute infections. Here we first review the historical development of mathematical models to understand HIV and HCV infections and the effects of treatment by fitting the models to clinical data. We then focus on recent efforts and contributions of applying these models towards understanding SARS-CoV-2 infection and highlight outstanding questions where modeling can provide crucial insights and help to optimize nonpharmaceutical and pharmaceutical interventions of the coronavirus disease 2019 (COVID-19) pandemic. The review is written from our personal perspective emphasizing the power of simple target cell limited models that provided important insights and then their evolution into more complex models that captured more of the virology and immunology. To quote Albert Einstein, "Everything should be made as simple as possible, but not simpler," and this idea underlies the modeling we describe below.


Asunto(s)
/epidemiología , Modelos Teóricos , Antirretrovirales/uso terapéutico , /prevención & control , Enfermedades Transmisibles/epidemiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , Hepatitis C/epidemiología , Hepatitis C/inmunología , Humanos , Pandemias , Carga Viral
15.
PLoS Pathog ; 17(1): e1008748, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33465149

RESUMEN

The biomolecular mechanisms controlling latent HIV-1 infection, despite their importance for the development of a cure for HIV-1 infection, are only partially understood. For example, ex vivo studies have recently shown that T cell activation only triggered HIV-1 reactivation in a fraction of the latently infected CD4+ T cell reservoir, but the molecular biology of this phenomenon is unclear. We demonstrate that HIV-1 infection of primary T cells and T cell lines indeed generates a substantial amount of T cell receptor (TCR)/CD3 activation-inert latently infected T cells. RNA-level analysis identified extensive transcriptomic differences between uninfected, TCR/CD3 activation-responsive and -inert T cells, but did not reveal a gene expression signature that could functionally explain TCR/CD3 signaling inertness. Network analysis suggested a largely stochastic nature of these gene expression changes (transcriptomic noise), raising the possibility that widespread gene dysregulation could provide a reactivation threshold by impairing overall signal transduction efficacy. Indeed, compounds that are known to induce genetic noise, such as HDAC inhibitors impeded the ability of TCR/CD3 activation to trigger HIV-1 reactivation. Unlike for transcriptomic data, pathway enrichment analysis based on phospho-proteomic data directly identified an altered TCR signaling motif. Network analysis of this data set identified drug targets that would promote TCR/CD3-mediated HIV-1 reactivation in the fraction of otherwise TCR/CD3-reactivation inert latently HIV-1 infected T cells, regardless of whether the latency models were based on T cell lines or primary T cells. The data emphasize that latent HIV-1 infection is largely the result of extensive, stable biomolecular changes to the signaling network of the host T cells harboring latent HIV-1 infection events. In extension, the data imply that therapeutic restoration of host cell responsiveness prior to the use of any activating stimulus will likely have to be an element of future HIV-1 cure therapies.


Asunto(s)
Complejo CD3/metabolismo , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , Proteoma , Receptores de Antígenos de Linfocitos T/metabolismo , Transcriptoma , Latencia del Virus , Complejo CD3/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Regulación Viral de la Expresión Génica , Redes Reguladoras de Genes , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , VIH-1/fisiología , Humanos , Activación de Linfocitos , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal , Activación Viral , Replicación Viral
16.
PLoS Pathog ; 17(1): e1009214, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33465157

RESUMEN

The precise role of CD4 T cell turnover in maintaining HIV persistence during antiretroviral therapy (ART) has not yet been well characterized. In resting CD4 T cell subpopulations from 24 HIV-infected ART-suppressed and 6 HIV-uninfected individuals, we directly measured cellular turnover by heavy water labeling, HIV reservoir size by integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA), and HIV reservoir clonality by proviral integration site sequencing. Compared to HIV-negatives, ART-suppressed individuals had similar fractional replacement rates in all subpopulations, but lower absolute proliferation rates of all subpopulations other than effector memory (TEM) cells, and lower plasma IL-7 levels (p = 0.0004). Median CD4 T cell half-lives decreased with cell differentiation from naïve to TEM cells (3 years to 3 months, p<0.001). TEM had the fastest replacement rates, were most highly enriched for intDNA and caRNA, and contained the most clonal proviral expansion. Clonal proviruses detected in less mature subpopulations were more expanded in TEM, suggesting that they were maintained through cell differentiation. Earlier ART initiation was associated with lower levels of intDNA, caRNA and fractional replacement rates. In conclusion, circulating integrated HIV proviruses appear to be maintained both by slow turnover of immature CD4 subpopulations, and by clonal expansion as well as cell differentiation into effector cells with faster replacement rates.


Asunto(s)
Antirretrovirales/uso terapéutico , Linfocitos T CD4-Positivos/patología , Diferenciación Celular , Infecciones por VIH/virología , VIH-1/inmunología , Carga Viral , Replicación Viral , Adulto , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , Estudios de Casos y Controles , ADN Viral/análisis , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/patología , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad
17.
PLoS Pathog ; 17(1): e1009190, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33476323

RESUMEN

Gag polymerization with viral RNA at the plasma membrane initiates HIV-1 assembly. Assembly processes are inefficient in vitro but are stimulated by inositol (1,3,4,5,6) pentakisphosphate (IP5) and inositol hexakisphosphate (IP6) metabolites. Previous studies have shown that depletion of these inositol phosphate species from HEK293T cells reduced HIV-1 particle production but did not alter the infectivity of the resulting progeny virions. Moreover, HIV-1 substitutions bearing Gag/CA mutations ablating IP6 binding are noninfectious with destabilized viral cores. In this study, we analyzed the effects of cellular depletion of IP5 and IP6 on HIV-1 replication in T cells in which we disrupted the genes encoding the kinases required for IP6 generation, IP5 2-kinase (IPPK) and Inositol Polyphosphate Multikinase (IPMK). Knockout (KO) of IPPK from CEM and MT-4 cells depleted cellular IP6 in both T cell lines, and IPMK disruption reduced the levels of both IP5 and IP6. In the KO lines, HIV-1 spread was delayed relative to parental wild-type (WT) cells and was rescued by complementation. Virus release was decreased in all IPPK or IPMK KO lines relative to WT cells. Infected IPMK KO cells exhibited elevated levels of intracellular Gag protein, indicative of impaired particle assembly. IPMK KO compromised virus production to a greater extent than IPPK KO suggesting that IP5 promotes HIV-1 particle assembly in IPPK KO cells. HIV-1 particles released from infected IPPK or IPMK KO cells were less infectious than those from WT cells. These viruses exhibited partially cleaved Gag proteins, decreased virion-associated p24, and higher frequencies of aberrant particles, indicative of a maturation defect. Our data demonstrate that IP6 enhances the quantity and quality of virions produced from T cells, thereby preventing defects in HIV-1 replication.


Asunto(s)
Linfocitos T CD4-Positivos/virología , Infecciones por VIH/virología , VIH-1/fisiología , Fosfatos de Inositol/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/virología , Ensamble de Virus , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Productos del Gen gag/metabolismo , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Células Tumorales Cultivadas , Virión/fisiología
18.
PLoS One ; 16(1): e0244823, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33481813

RESUMEN

INTRODUCTION: It has been estimated that between 15% and 18% of patients who start antiretroviral therapy (ART) do not achieve a successful immune recovery despite complete virological suppression. In the literature this phenomenom is known as poor immune recovery or immunovirological discordance (IVD). Zinc has an immunomodulatory role associated with T lymphocytes and its supplementation could enhance immune recovery. OBJECTIVE: To determine if zinc supplementation on IVD patients prevents immune failure after 12 months of supplementation. Secondary objectives were to determine serum zinc levels in HIV patients with and without IVD and the frequency of hypozincemia in discordant patients. METHOD: We reviewed the historical record of patients under care at Arriarán Foundation. Following inclusion criteria were defined: 1) age ≥ 18 years, 2) standard ART (three effective drugs) for at least 18 months, 3) virologically suppressed for 12 months, 3) persistence of CD4 count ≤200 cells/mm3 and/or increase ≤ 80 cells/mm3 after one year of viral undetectability. A control group was assigned paired 1:1 by sex, age (± 2 years) that did achieved an increase of CD4> 350 cells/ mm3. In both groups plasma zinc levels were determined. In a later phase, patients with IVD were randomized to receive zinc (15 mg daily) versus placebo. Patients were followed for 12 months with CD4 count, viral load and zinc levels determinations every 4-6 months. RESULTS: A total of 80 patients, 40 patients with IVD criteria and 40 controls were included. 92.5% were men, and age average was 47.5 years. The median baseline CD4 was 189 cells/mm3 (71-258) in the cases vs. 552.5 cells/ mm3 (317-400) in the control group with a median increase at the end of the study of 39 cell/mm3 and 19 cell/mm3 respectively. There was no difference in baseline plasma zinc levels between both groups (81.7 + 18.1 in cases versus 86.2 + 11.0 in controls). In the 40 patients with IVD, the median absolute increase in CD4 after annual zinc supplementation was 31.5 cells/mm3 in the treated group versus 50 cells/mm3 in the placebo group, this difference being statistically not significant (p = 0.382). CONCLUSIONS: Patients with IVD have plasma zinc levels similar to those who achieve adequate immune recovery. Zinc supplementation in IVD patients showed a statistically non-significant difference in in CD4 levels between cases and controls. The results warrant a comparative study with a larger number of patients.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Zinc/administración & dosificación , Adulto , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Suplementos Dietéticos , Método Doble Ciego , Femenino , Infecciones por VIH/inmunología , VIH-1/fisiología , Humanos , Masculino , Persona de Mediana Edad , Estado Nutricional , Efecto Placebo , Resultado del Tratamiento , Carga Viral , Zinc/sangre
19.
J Acquir Immune Defic Syndr ; 86(2): 224-230, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33433966

RESUMEN

BACKGROUND: Limited data exist about clinical outcomes and levels of inflammatory and immune markers among people hospitalized with COVID-19 by HIV serostatus and by HIV viral suppression. SETTING: Large tertiary care health system in the Bronx, NY, USA. METHODS: We conducted a retrospective cohort study of 4613 SARS-CoV-2 PCR-positive patients admitted between March 10, 2020, and May 11, 2020. We examined in-hospital intubation, acute kidney injury (AKI), hospitalization length, and in-hospital mortality by HIV serostatus, and by HIV-viral suppression and CD4 counts among people living with HIV (PLWH) using adjusted competing risks regression. We also compared immune and inflammatory marker levels by HIV serostatus and viral suppression. RESULTS: Most patients were either non-Hispanic Black (36%) or Hispanic (37%); 100/4613 (2.2%) were PLWH, among whom 15 had detectable HIV viral load. PLWH compared to patients without HIV had increased intubation rates (adjusted hazard ratio 1.73 [95% CI: 1.12 to 2.67], P = 0.01). Both groups had similar rates of AKI, length of hospitalization, and death. No (0%) virally unsuppressed PLWH were intubated or died, versus 21/81 (26%, P = 0.04) and 22/81 (27%, P = 0.02) of virally suppressed PLWH, respectively. Among PLWH, higher CD4 T-cell counts were associated with increased intubation rates. C-reactive protein, IL-6, neutrophil counts, and ferritin levels were similar between virally suppressed PLWH and patients without HIV, but significantly lower for unsuppressed PLWH (all P < 0.05). CONCLUSIONS: PLWH had increased risk of intubation but similarly frequent rates of AKI and in-hospital death as those without HIV. Findings of no intubations or deaths among PLWH with unsuppressed HIV viral load warrant further investigation.


Asunto(s)
Biomarcadores/sangre , Infecciones por VIH/inmunología , Anciano , Recuento de Linfocito CD4 , /mortalidad , Estudios de Cohortes , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/mortalidad , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Carga Viral
20.
Arch Virol ; 166(5): 1273-1282, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33507389

RESUMEN

In 2006 we discovered a new type of mucosal vaccine against simian immunodeficiency virus (SIV) in Chinese macaques. Here, we review 15 years of our published work on this vaccine, which consists of inactivated SIVmac239 particles adjuvanted with Bacillus Calmette-Guérin, Lactobacillus plantarum, or Lactobacillus rhamnosus. Without adjuvant, the vaccine administered by the intragastric route induced the usual SIV-specific humoral and cellular immune responses but provided no protection against intrarectal challenge with SIVmac239. In contrast, out of 24 macaques immunized with the adjuvanted vaccine and challenged intrarectally with SIVmac239 or SIVB670, 23 were sterilely protected for up to five years, while all control macaques were infected. This protection was confirmed by an independent group from the Pasteur Institute. During the past 15 years, we have identified the mechanism of action of the vaccine and discovered that the vaccinated macaques produced a previously unrecognized class of MHC-Ib/E-restricted CD8+ T cells (which we refer to as tolerogenic CD8+ T cells) that suppressed the activation of SIV-RNA-infected CD4+ T cells and thereby inhibited the (activation-dependent) reverse transcription of the virus, which in turn prevented the establishment of SIV infection. Importantly, we discovered also that the tolerogenic CD8+ T cell subset observed in vaccinated Chinese macaques could also be found in human elite controllers, a small group of HIV-infected patients in whom these tolerogenic CD8+ T cells were shown to naturally suppress viral replication. Given that SIV and HIV require activated immune cells in which to replicate, the specific prevention of activation of SIV-RNA-containing CD4+ T cells by a tolerogenic vaccine approach offers an exciting new avenue in HIV vaccine research.


Asunto(s)
Vacunas contra el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida/inmunología , Infecciones por VIH/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas contra el SIDA/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida/prevención & control , Síndrome de Inmunodeficiencia Adquirida/virología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Humanos , Macaca mulatta , Virus de la Inmunodeficiencia de los Simios/fisiología , Replicación Viral
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