RESUMEN
HIV-associated neurocognitive disorders (HAND) persist under antiretroviral therapy as a complex pathology that has been difficult to study in cellular and animal models. Therefore, we generated an ex vivo human brain slice model of HIV-1 infection from surgically resected adult brain tissue. Brain slice cultures processed for flow cytometry showed >90% viability of dissociated cells within the first three weeks in vitro, with parallel detection of astrocyte, myeloid, and neuronal populations. Neurons within brain slices showed stable dendritic spine density and mature spine morphologies in the first weeks in culture, and they generated detectable activity in multi-electrode arrays. We infected cultured brain slices using patient-matched CD4+ T-cells or monocyte-derived macrophages (MDMs) that were exposed to a GFP-expressing R5-tropic HIV-1 in vitro. Infected slice cultures expressed viral RNA and developed a spreading infection up to 9 days post-infection, which were significantly decreased by antiretrovirals. We also detected infected myeloid cells and astrocytes within slices and observed minimal effect on cellular viability over time. Overall, this human-centered model offers a promising resource to study the cellular mechanisms contributing to HAND (including antiretroviral toxicity, substance use, and aging), infection of resident brain cells, and new neuroprotective therapeutics.
Asunto(s)
Encéfalo , Infecciones por VIH , VIH-1 , Humanos , Encéfalo/virología , Encéfalo/patología , VIH-1/fisiología , Infecciones por VIH/virología , Infecciones por VIH/patología , Adulto , Neuronas/virología , Neuronas/metabolismo , Macrófagos/virología , Macrófagos/metabolismo , Astrocitos/virología , Linfocitos T CD4-Positivos/virología , Técnicas de Cultivo de TejidosRESUMEN
Men who have sex with men (MSM) with HIV are at high risk for squamous intraepithelial lesion (SIL) and anal cancer. Identifying local immunological mechanisms involved in the development of anal dysplasia could aid treatment and diagnostics. Here, we studied 111 anal biopsies obtained from 101 MSM with HIV, who participated in an anal screening program. We first assessed multiple immune subsets by flow cytometry, in addition to histological examination, in a discovery cohort. Selected molecules were further evaluated by immunohistochemistry in a validation cohort. Pathological samples were characterized by the presence of resident memory T cells with low expression of CD103 and by changes in natural killer cell subsets, affecting residency and activation. Furthermore, potentially immunosuppressive subsets, including CD15+CD16+ mature neutrophils, gradually increased as the anal lesion progressed. Immunohistochemistry verified the association between the presence of CD15 in the epithelium and SIL diagnosis for the correlation with high-grade SIL. A complex immunological environment with imbalanced proportions of resident effectors and immune-suppressive subsets characterized pathological samples. Neutrophil infiltration, determined by CD15 staining, may represent a valuable pathological marker associated with the grade of dysplasia.
Asunto(s)
Neoplasias del Ano , Infecciones por VIH , Antígeno Lewis X , Humanos , Masculino , Infecciones por VIH/inmunología , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Neoplasias del Ano/patología , Neoplasias del Ano/inmunología , Adulto , Persona de Mediana Edad , Antígeno Lewis X/metabolismo , Homosexualidad Masculina , Lesiones Intraepiteliales Escamosas/patología , Canal Anal/patología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Antígenos CD/metabolismo , Neutrófilos/inmunología , Neutrófilos/patología , Neutrófilos/metabolismo , Biopsia , Inmunohistoquímica , Cadenas alfa de Integrinas/metabolismoRESUMEN
This review comprehensively explores the dysregulation of Gamma Delta T-cells, CD8+ T Cells, and Natural Killer T Cells in the context of Human Immunodeficiency Virus (HIV) infection and its implications for brain pathology. It encompasses an overview of the HIV disease process, immune cell dysregulation, association with neurological diseases, and the critical role of Glutathione (GSH) in T-cell function. The alterations in Gamma Delta T-cells during chronic infection, the intricate dynamics of Vδ1 and Vδ2 subsets, and the potential of Vγ9Vδ2 T cells in inhibiting HIV replication are discussed. Additionally, the review addresses the exhaustion, impaired cytotoxicity, and premature senescence of CD8+ T cells, as well as the dysregulation of Natural Killer Cells (NKCs) and their impact on overall immune system activity. Furthermore, it examines the role of Gamma Delta (γδ) T-cells in brain injuries, infections, and tumors and highlights the therapeutic implications of elevated GSH levels in promoting a T helper 1 (Th1) immune response. However, HIV-infected patients with decreased GSH exhibit a T helper 2 (Th2) bias, compromising protection against intracellular pathogens. Finally, the review discusses studies in murine models demonstrating the impact of GSH levels on immune responses and underscores the therapeutic potential of targeting GSH to enhance immunity in HIV patients. Overall, this review provides valuable insights into the complex interplay between immune dysregulation, GSH levels, and HIV-associated brain pathology, offering insights into potential therapeutic avenues for mitigating immune compromise and neurological impairments in HIV patients.
Asunto(s)
Encéfalo , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Glutatión , Infecciones por VIH , Humanos , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Glutatión/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD4-Positivos/inmunología , Encéfalo/inmunología , Encéfalo/patología , Células Asesinas Naturales/inmunología , AnimalesRESUMEN
Penile squamous cell carcinoma (PSCC) occurs more frequently in some developing countries compared to developed countries. Infection with HIV and/or high-risk human papillomavirus (hrHPV) are risk factors for penile cancer development. The tumor microenvironment of PSCC may predict prognosis and may inform on the best targets for immunotherapy. We evaluated the immune microenvironment of penile tumors histologically, and determined whether and/or how HIV and/or hrHPV infections affect this tumor microenvironment. We conducted a prospective analytical cross-sectional study in which penile cancer tumors from 35 patients presenting at the University Teaching Hospital in Lusaka, Zambia were histologically staged and assessed for presence of tumor infiltrating immune cells and expression of immune checkpoints. Immunohistochemistry was used to evaluate immune checkpoints and infiltrating immune cells, while multiplex real-time polymerase chain reaction was used for hrHPV genotyping. The median age of all participants was 55 years. About 24% had advanced histological stage, 83% were HIV+, and 63% had hrHPV detected in their tumors using multiplex real-time polymerase chain reaction. PDL1 expression was significantly higher in HIV- participants than HIV+ participants (p = 0.02). Tumors with multiple hrHPV infections had a significantly higher number of cells expressing TIM3 than those with one hrHPV (p = 0.04). High grade tumors had a significantly higher infiltrate of FoxP3+ cells (p = 0.02), CD68+ cells (p = 0.01), CD163+ cells (p = 0.01), LAG3+ cells (p = 0.01), PD1+ cells (p = 0.01) and TIM3+ cells (p = 0.03) when compared with low grade tumours. There was significant moderate to strong positive correlation of cells expressing PD1 and LAG3 (â´ = 0.69; p = 0.0001), PD1 and TIM3 (â´ = 0.49; p = 0.017) and TIM3 and LAG3 PDL1 (â´ = 0.61; p = 0.001). In conclusion, the tumor microenvironment of penile squamous cell carcinoma seems to be affected by both HIV and HPV infections. TIM3 appears to be a potential therapeutic target in PSCC patients with hrHPV infections.
Asunto(s)
Carcinoma de Células Escamosas , Infecciones por VIH , Infecciones por Papillomavirus , Neoplasias del Pene , Microambiente Tumoral , Adulto , Anciano , Humanos , Masculino , Persona de Mediana Edad , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Carcinoma de Células Escamosas/virología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Estudios Transversales , Infecciones por VIH/inmunología , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Infecciones por VIH/patología , Virus del Papiloma Humano , Linfocitos Infiltrantes de Tumor/inmunología , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/patología , Neoplasias del Pene/virología , Neoplasias del Pene/patología , Neoplasias del Pene/inmunología , Estudios Prospectivos , Microambiente Tumoral/inmunologíaRESUMEN
The diagnosis of intrathoracic non-tuberculous mycobacteriosis (NTM) is challenging. We report a case of a pediatric pulmonary NTM with endobronchial lesion and lymphadenitis in a child with HIV infection diagnosed by bronchoscopic biopsy, EBUS-TBNA and probe-based confocal laser endomicroscopy (pCLE). The pCLE showed a large number of highly fluorescent cells and zones of density and disorganized elastin fibers at alveolar areas. A combination of diagnostic endoscopic procedures is required to establish the diagnosis of NTM.
Asunto(s)
Broncoscopía , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico , Infecciones por VIH , Microscopía Confocal , Infecciones por Mycobacterium no Tuberculosas , Humanos , Broncoscopía/métodos , Niño , Microscopía Confocal/métodos , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/patología , Masculino , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Biopsia/métodosRESUMEN
The development of 3D-organoid models has revolutionized the way diseases are studied. Recently, our brain organoid model has been shown to recapitulate in in vitro the human brain cytoarchitecture originally encountered in HIV-1 neuropathogenesis, allowing downstream applications. Infected monocytes, macrophages, and microglia are critically important immune cells for infection and dissemination of HIV-1 throughout brain during acute and chronic phase of the disease. Once in the brain parenchyma, long-lived infected monocytes/macrophages along with resident microglia contribute to the establishment of CNS latency in people with HIV (PWH). Hence, it is important to better understand how HIV-1 enters and establishes infection and latency in CNS to further develop cure strategies. Here we detailed an accessible protocol to incorporate monocytes (infected and/or labeled) as a model of transmigration of peripheral monocytes into brain organoids that can be applied to characterize HIV-1 neuroinvasion and virus dissemination.
Asunto(s)
Encéfalo , Infecciones por VIH , VIH-1 , Monocitos , Organoides , Organoides/virología , Organoides/patología , Humanos , VIH-1/fisiología , VIH-1/patogenicidad , Monocitos/virología , Monocitos/inmunología , Infecciones por VIH/virología , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Encéfalo/virología , Encéfalo/patología , Encéfalo/inmunología , Microglía/virología , Microglía/inmunología , Microglía/patología , Macrófagos/virología , Macrófagos/inmunología , Latencia del VirusRESUMEN
While CD4+ T cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of "natural" hosts such as sooty mangabeys does not cause CD4+ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T cell activation abolishes CARD8 function and increases permissiveness to infection. In humanized mice reconstituted with CARD8-deficient cells, CD4+ depletion is delayed despite high viremia. Finally, we discovered loss-of-function mutations in CARD8 from "natural hosts," which may explain the peculiarly non-pathogenic nature of these infections. Our study suggests that CARD8 drives CD4+ T cell depletion during pathogenic HIV/SIV infections.
Asunto(s)
Infecciones por VIH , Inflamasomas , Síndrome de Inmunodeficiencia Adquirida del Simio , Animales , Humanos , Ratones , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Progresión de la Enfermedad , Infecciones por VIH/patología , Inflamasomas/metabolismo , Proteínas de Neoplasias/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios/fisiología , Viremia , VIH/fisiologíaRESUMEN
Renal involvement is very common in patients with HIV infection. The phenotype varies from the most frequently "collapsing" variant of focal and segmental glomerulosclerosis (FSGS) to "lupus-like HIV-immune complex kidney disease" (HIVICK). The latter is characterized by a histological picture that recalls lupus nephropathy. Through a clinical case, we underline the importance of urinary sediment analysis in patients with suspected glomerulopathy. Findings such as the characteristic cells that show the typical appearance of Herpes virus (HSV) infection or LE cells have significantly supported the diagnosis of HIVICK. In light of the present observations, we suggest systematically carrying out a cytological examination of the urinary sediment to confirm diagnostic hypotheses of rare pathologies.
Asunto(s)
Glomeruloesclerosis Focal y Segmentaria , Infecciones por VIH , Enfermedades Renales , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Complejo Antígeno-Anticuerpo , VIH , Riñón/patología , Glomeruloesclerosis Focal y Segmentaria/patología , Enfermedades Renales/patologíaRESUMEN
CCR5-tropic simian/human immunodeficiency viruses (SHIV) with clade C transmitted/founder envelopes represent a critical tool for the investigation of HIV experimental vaccines and microbicides in nonhuman primates, although many such isolates lead to spontaneous viral control post infection. Here, we generated a high-titer stock of pathogenic SHIV-C109p5 by serial passage in two rhesus macaques (RM) and tested its virulence in aged monkeys. The co-receptor usage was confirmed before infecting five geriatric rhesus macaques (four female and one male). Plasma viral loads were monitored by reverse transcriptase-quantitative PCR (RT-qPCR), cytokines by multiplex analysis, and biomarkers of gastrointestinal damage by enzyme-linked immunosorbent assay. Antibodies and cell-mediated responses were also measured. Viral dissemination into tissues was determined by RNAscope. Intravenous SHIV-C109p5 infection of aged RMs leads to high plasma viremia and rapid disease progression; rapid decrease in CD4+ T cells, CD4+CD8+ T cells, and plasmacytoid dendritic cells; and wasting necessitating euthanasia between 3 and 12 weeks post infection. Virus-specific cellular immune responses were detected only in the two monkeys that survived 4 weeks post infection. These were Gag-specific TNFα+CD8+, MIP1ß+CD4+, Env-specific IFN-γ+CD4+, and CD107a+ T cell responses. Four out of five monkeys had elevated intestinal fatty acid binding protein levels at the viral peak, while regenerating islet-derived protein 3α showed marked increases at later time points in the three animals surviving the longest, suggesting gut antimicrobial peptide production in response to microbial translocation post infection. Plasma levels of monocyte chemoattractant protein-1, interleukin-15, and interleukin-12/23 were also elevated. Viral replication in gut and secondary lymphoid tissues was extensive.IMPORTANCESimian/human immunodeficiency viruses (SHIV) are important reagents to study prevention of virus acquisition in nonhuman primate models of HIV infection, especially those representing transmitted/founder (T/F) viruses. However, many R5-tropic SHIV have limited fitness in vivo leading to many monkeys spontaneously controlling the virus post acute infection. Here, we report the generation of a pathogenic SHIV clade C T/F stock by in vivo passage leading to sustained viral load set points, a necessity to study pathogenicity. Unexpectedly, administration of this SHIV to elderly rhesus macaques led to extensive viral replication and fast disease progression, despite maintenance of a strict R5 tropism. Such age-dependent rapid disease progression had previously been reported for simian immunodeficiency virus but not for R5-tropic SHIV infections.
Asunto(s)
Infecciones por VIH , VIH , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Replicación Viral , Animales , Femenino , Masculino , Proteínas Adaptadoras Transductoras de Señales/inmunología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Envejecimiento , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Quimiocina CCL2/inmunología , Quimiocina CCL2/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/patología , Progresión de la Enfermedad , VIH/clasificación , VIH/crecimiento & desarrollo , VIH/patogenicidad , VIH/fisiología , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Infecciones por VIH/virología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucinas/inmunología , Interleucinas/metabolismo , Intestinos/virología , Tejido Linfoide/virología , Macaca mulatta/inmunología , Macaca mulatta/metabolismo , Pase Seriado , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/clasificación , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Virus de la Inmunodeficiencia de los Simios/fisiología , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Carga Viral , Tropismo Viral , Virulencia , Receptores CCR5/metabolismoRESUMEN
BACKGROUND & AIMS: Persons with chronic HBV infection coinfected with HIV experience accelerated progression of liver fibrosis compared to those with HBV monoinfection. We aimed to determine whether HIV and its proteins promote HBV-induced liver fibrosis in HIV/HBV-coinfected cell culture models through HIF-1α and TGF-ß1 signaling. METHODS: The HBV-positive supernatant, purified HBV viral particles, HIV-positive supernatant, or HIV viral particles were directly incubated with cell lines or primary hepatocytes, hepatic stellate cells, and macrophages in mono or 3D spheroid coculture models. Cells were incubated with recombinant cytokines and HIV proteins including gp120. HBV sub-genomic constructs were transfected into NTCP-HepG2 cells. We also evaluated the effects of inhibitor of HIF-1α and HIV gp120 in a HBV carrier mouse model that was generated via hydrodynamic injection of the pAAV/HBV1.2 plasmid into the tail vein of wild-type C57BL/6 mice. RESULTS: We found that HIV and HIV gp120, through engagement with CCR5 and CXCR4 coreceptors, activate AKT and ERK signaling and subsequently upregulate hypoxia-inducible factor-1α (HIF-1α) to increase HBV-induced transforming growth factor-ß1 (TGF-ß1) and profibrogenic gene expression in hepatocytes and hepatic stellate cells. HIV gp120 exacerbates HBV X protein-mediated HIF-1α expression and liver fibrogenesis, which can be alleviated by inhibiting HIF-1α. Conversely, TGF-ß1 upregulates HIF-1α expression and HBV-induced liver fibrogenesis through the SMAD signaling pathway. HIF-1α small-interfering RNA transfection or the HIF-1α inhibitor (acriflavine) blocked HIV-, HBV-, and TGF-ß1-induced fibrogenesis. CONCLUSIONS: Our findings suggest that HIV coinfection exacerbates HBV-induced liver fibrogenesis through enhancement of the positive feedback between HIF-1α and TGF-ß1 via CCR5/CXCR4. HIF-1α represents a novel target for antifibrotic therapeutic development in HBV/HIV coinfection. IMPACT AND IMPLICATIONS: HIV coinfection accelerates the progression of liver fibrosis compared to HBV monoinfection, even among patients with successful suppression of viral load, and there is no sufficient treatment for this disease process. In this study, we found that HIV viral particles and specifically HIV gp120 promote HBV-induced hepatic fibrogenesis via enhancement of the positive feedback between HIF-1α and TGF-ß1, which can be ameliorated by inhibition of HIF-1α. These findings suggest that targeting the HIF-1α pathway can reduce liver fibrogenesis in patients with HIV and HBV coinfection.
Asunto(s)
Coinfección , Infecciones por VIH , Virus de la Hepatitis B , Subunidad alfa del Factor 1 Inducible por Hipoxia , Cirrosis Hepática , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones , Cirrosis Hepática/metabolismo , Cirrosis Hepática/virología , Cirrosis Hepática/patología , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/metabolismo , Infecciones por VIH/patología , Virus de la Hepatitis B/genética , Coinfección/virología , Ratones Endogámicos C57BL , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/metabolismo , Hepatitis B Crónica/patología , Hepatitis B Crónica/virología , Proteína gp120 de Envoltorio del VIH/metabolismo , Hepatocitos/metabolismo , Hepatocitos/virología , Hepatocitos/patología , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/virología , Modelos Animales de Enfermedad , Células Hep G2 , MasculinoRESUMEN
PURPOSE OF REVIEW: HIV reservoirs are the main barrier to cure. CD4+ T cells have been extensively studied as the primary HIV-1 reservoir. However, there is substantial evidence that HIV-1-infected myeloid cells (monocytes/macrophages) also contribute to viral persistence and pathogenesis. RECENT FINDINGS: Recent studies in animal models and people with HIV-1 demonstrate that myeloid cells are cellular reservoirs of HIV-1. HIV-1 genomes and viral RNA have been reported in circulating monocytes and tissue-resident macrophages from the brain, urethra, gut, liver, and spleen. Importantly, viral outgrowth assays have quantified persistent infectious virus from monocyte-derived macrophages and tissue-resident macrophages. The myeloid cell compartment represents an important target of HIV-1 infection. While myeloid reservoirs may be more difficult to measure than CD4+ T cell reservoirs, they are long-lived, contribute to viral persistence, and, unless specifically targeted, will prevent an HIV-1 cure.
Asunto(s)
Infecciones por VIH , Seropositividad para VIH , VIH-1 , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Humanos , Infecciones por VIH/patología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Macrófagos , Linfocitos T CD4-Positivos , Latencia del Virus , Carga ViralRESUMEN
Cognitive impairment remains a persistent challenge in people living with HIV (PWLH) despite antiretroviral therapy (ART) due to ART's inability to eliminate brain HIV. HIV-induced cognitive dysfunction results from immune dysregulation, ongoing neuroinflammation, and the continuous virus presence, collectively contributing to cognitive deficits. Therefore, adjunctive therapies are needed to reduce cerebral HIV reservoirs, mitigate neuroinflammation, and impede cognitive dysfunction progression. Our study focused on Honokiol, known for its anti-inflammatory and neuroprotective properties, in an experimental mouse model simulating HIV-induced cognitive dysfunction. Using Honokiol Hexafluoro (HH), a synthetic analogue, we comprehensively evaluated its potential to ameliorate cognitive dysfunction and cerebral pathology in HIV-associated cognitive dysfunction. Our findings showed that HH treatment effectively reversed HIV-induced cognitive dysfunction, concurrently suppressing astrocyte activation, restoring neuronal dendritic arborization, and reducing microglial activation. Furthermore, HH remodeled the metabolic profile of HIV-infected human monocyte-derived macrophages, resulting in decreased activation and the promotion of a quiescent state in vitro.
Asunto(s)
Compuestos Alílicos , Compuestos de Bifenilo , Infecciones por VIH , Fenoles , Humanos , Ratones , Animales , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Enfermedades Neuroinflamatorias , Ratones SCID , MacrófagosRESUMEN
Heterozygosity of Human leukocyte antigen (HLA) class I genes is linked to beneficial outcomes after HIV infection, presumably through greater breadth of HIV epitope presentation and cytotoxic T cell response. Distinct allotype pairs, however, differ in the extent to which they bind shared sets of peptides. We developed a functional divergence metric that measures pairwise complementarity of allotype-associated peptide binding profiles. Greater functional divergence for pairs of HLA-A and/or HLA-B allotypes was associated with slower AIDS progression and independently with enhanced viral load control. The metric predicts immune breadth at the peptide level rather than gene level and redefines HLA heterozygosity as a continuum differentially affecting disease outcome. Functional divergence may affect response to additional infections, vaccination, immunotherapy, and other diseases where HLA heterozygote advantage occurs.
Asunto(s)
Infecciones por VIH , Antígenos HLA-B , Heterocigoto , Humanos , Alelos , Progresión de la Enfermedad , Infecciones por VIH/genética , Infecciones por VIH/patología , Antígenos HLA-B/genética , Péptidos/genética , Péptidos/inmunología , Masculino , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , AncianoRESUMEN
OBJECTIVE: Bone marrow examination is valuable for identifying the cause of fever of unknown origin (FUO) in HIV-infected patients. Based on the outcomes of bone marrow examination of patients with FUO, we aimed to develop a predictive model for identifying the factors that can increase the diagnostic yield of bone marrow examination. DESIGN: For this retrospective cohort study, we enrolled HIV-infected patients, aged more than 15âyears and diagnosed with FUO, at Songklanakarind Hospital in Southern Thailand, between January 2009 and December 2019. METHODS: Evaluations were based on bone marrow aspiration, biopsy, and culture; any missing data were imputed with regression imputation. RESULTS: Among the final 108 included patients, 44 (40.74%) showed positive bone marrow results. The diagnoses mainly comprised histoplasmosis, penicilliosis, and tuberculosis. Bone marrow examination led to treatment modifications in approximately 33% patients. Platelet count less than 150â000âcells/µl, alkaline phosphatase (ALP) level at least 200âU/l, and no previous antibiotic treatment were significantly associated with higher diagnostic yields. The HIV bone marrow (HIVBM) model, comprising of spleen size, hematocrit (Hct), platelet count before bone marrow examination, ALP level at admission, and previous antibiotic treatment, was generated as a nomogram to predict the diagnostic yield of bone marrow examination in HIV-infected patients with FUO. CONCLUSION: The results of this study indicate that the HIVBM model can be used to predict the diagnostic yield of bone marrow examination, and therefore assist in clinical decision-making regarding bone marrow procedures, to be performed for identifying the origin of fever in HIV-infected patients.
Asunto(s)
Fiebre de Origen Desconocido , Infecciones por VIH , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Examen de la Médula Ósea/efectos adversos , Fiebre de Origen Desconocido/diagnóstico , Fiebre de Origen Desconocido/etiología , Fiebre de Origen Desconocido/patología , Estudios Retrospectivos , VIH , AntibacterianosRESUMEN
Adult T cell leukemia/lymphoma is a malignancy with a poor prognosis caused by human T lymphocyte virus type 1 (HTLV-1) infection. Tax and HBZ are two major viral proteins that may be involved in oncogenesis by disrupting apoptosis. Because Bcl-xL plays an integral role in the anti-apoptotic pathway, this study examines the interaction between host apoptosis and oncoproteins. We investigated 37 HTLV-1-infected individuals, including 18 asymptomatic and 19 adult T cell leukemia/lymphoma (ATLL) subjects. mRNA was extracted and converted to cDNA from peripheral blood mononuclear cells, and then gene expression was determined using TaqMan q-PCR. Moreover, the HTLV-1 proviral load (PVL) was also measured using a commercial absolute quantification kit (Novin Gene, Iran). Data analysis revealed that the mean of TAX, HBZ, and PVL was significantly higher among the study groups (ATLL and carrier groups p = .003, p = .000, and p = .002 respectively). There was no statistical difference in Bcl-xL gene expression between the study groups (p = .323). It is proposed that this anti-apoptotic pathway may not be directly involved in the development of ATLL lymphoma. Bcl-xL, TAX, HBZ gene expression, and PVL can be utilized as prognostic markers.
Asunto(s)
Infecciones por VIH , Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Linfoma , Adulto , Humanos , Leucemia-Linfoma de Células T del Adulto/genética , Virus Linfotrópico T Tipo 1 Humano/genética , Leucocitos Mononucleares , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Proteínas de los Retroviridae/genética , Proteínas de los Retroviridae/metabolismo , Infecciones por VIH/patología , Linfoma/patología , Expresión Génica , Productos del Gen tax/genética , Productos del Gen tax/metabolismoRESUMEN
To support a strategy to eliminate cervical cancer as a public health problem, the World Health Organisation (WHO) reviewed its guidelines for screening and treatment of cervical pre-cancerous lesions in 2021. Women living with HIV have 6-times the risk of cervical cancer compared to women in the general population, and we harnessed a model platform ('Policy1-Cervix-HIV') to evaluate the benefits and harms of a range of screening strategies for women living with HIV in Tanzania, a country with endemic HIV. Assuming 70% coverage, we found that 3-yearly primary HPV screening without triage would reduce age-standardised cervical cancer mortality rates by 72%, with a number needed to treat (NNT) of 38.7, to prevent a cervical cancer death. Triaging HPV positive women before treatment resulted in minimal loss of effectiveness and had more favorable NNTs (19.7-33.0). Screening using visual inspection with acetic acid (VIA) or cytology was less effective than primary HPV and, in the case of VIA, generated a far higher NNT of 107.5. These findings support the WHO 2021 recommendation that women living with HIV are screened with primary HPV testing in a screen-triage-and-treat approach starting at 25 years, with regular screening every 3-5 years.
Asunto(s)
Infecciones por VIH , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Humanos , Femenino , Cuello del Útero/patología , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/terapia , Triaje , Detección Precoz del Cáncer/métodos , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Ácido Acético , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patologíaRESUMEN
IMPORTANCE: Our mouse model is a powerful tool for investigating the genetic mechanisms governing central nervous system (CNS) human immunodeficiency virus type-1 (HIV-1) infection and latency in the CNS at a single-cell level. A major advantage of our model is that it uses induced pluripotent stem cell-derived microglia, which enables human genetics, including gene function and therapeutic gene manipulation, to be explored in vivo, which is more challenging to study with current hematopoietic stem cell-based models for neuroHIV. Our transgenic tracing of xenografted human cells will provide a quantitative medium to develop new molecular and epigenetic strategies for reducing the HIV-1 latent reservoir and to test the impact of therapeutic inflammation-targeting drug interventions on CNS HIV-1 latency.
Asunto(s)
Infecciones por VIH , VIH-1 , Células Madre Pluripotentes Inducidas , Microglía , Animales , Humanos , Ratones , Sistema Nervioso Central , Infecciones por VIH/metabolismo , Infecciones por VIH/patología , VIH-1/fisiología , Microglía/virología , Latencia del Virus , XenoinjertosRESUMEN
INTRODUCTION: The link between fatty liver diseases and cognitive impairment among people living with HIV (PLWH) remains unclear. We investigated the association of steatotic liver disease (SLD), advanced liver fibrosis and non-alcoholic steatohepatitis (NASH) with significant activity and liver fibrosis with cognitive impairment in PLWH. METHODS: Cognitive performance was assessed for PLWH aged ≥50 years on stable antiretroviral therapy (ART) with the Thai-validated version of the Montreal Cognitive Assessment (MoCA), and a cut-off of <25/30 was used to define cognitive impairment. SLD and NASH with significant activity and liver fibrosis were defined as having a controlled attenuation parameter value ≥248 dB/m and a FibroScan-AST (FAST) score ≥0.67, respectively. Multivariable logistic regression was employed to investigate the association of cognitive impairment with SLD or NASH. RESULTS: Of the 319 PLWH (63.3% male and 98% had HIV-1 RNA ≤50 copies/mL) included, 74 (38%) had SLD. NASH with significant activity and liver fibrosis was present in 66 (20.1%) participants. Some 192 (60.2%) participants had cognitive impairment. In a multivariable analysis, NASH with significant activity and liver fibrosis was significantly associated with cognitive impairment (adjusted odds ratio [aOR] 2.01, 95% CI 1.02-3.98, p = 0.04), after adjusting for HIV-related parameters, age, sex, body mass index, employment status, education, income level, smoking, alcohol use, diabetes mellitus, hypertension and HIV-related parameters. The association of a lone diagnosis of SLD and cognitive impairment was not statistically significant. CONCLUSIONS: NASH with significant activity and liver fibrosis was associated with lower cognitive performance, even after controlling for demographics and HIV disease parameters. Additional research is needed to better understand the underlying mechanisms.
Asunto(s)
Disfunción Cognitiva , Infecciones por VIH , Enfermedad del Hígado Graso no Alcohólico , Humanos , Masculino , Femenino , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Estudios Transversales , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/epidemiología , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Hígado/patologíaRESUMEN
BACKGROUND: Lung cavitation is associated with heightened TB transmission and poor treatment outcomes. This study aimed to determine the relationship between systemic inflammation and lung cavitation in drug-resistant TB patients with and without HIV co-infection. METHODS: Plasma samples were obtained from 128 participants from the CAPRISA 020 Individualized M(X)drug-resistant TB Treatment Strategy Study (InDEX) prior to treatment initiation. Lung cavitation was present in 61 of the 128 drug-resistant TB patients with 93 being co-infected with HIV. The plasma cytokine and chemokine levels were measured using the 27-Plex Human Cytokine immunoassay. Modified Poisson regression models were used to determine the association between plasma cytokine/chemokine expression and lung cavitation in individuals with drug-resistant TB. RESULTS: Higher Interleukin-6 plasma levels (adjusted risk ratio [aRR] 1.405, 95% confidence interval [CI] 1.079-1.829, p = 0.011) were associated with a higher risk of lung cavitation in the multivariable model adjusting for age, sex, body mass index, HIV status, smoking and previous history of TB. Smoking was associated with an increased risk of lung cavitation (aRR 1.784, 95% CI 1.167-2.729, p = 0.008). An HIV positive status and a higher body mass index, were associated with reduced risk of lung cavitation (aRR 0.537, 95% CI 0.371-0.775, p = 0.001 and aRR 0.927, 95% CI 0.874-0.983, p = 0.012 respectively). CONCLUSION: High plasma interleukin-6 levels are associated with an increased risk of cavitary TB highlighting the role of interleukin-6 in the immunopathology of drug-resistant TB.