RESUMEN

Although some individuals with HIV-2 develop severe immunodeficiency and AIDS-related complications, most may never progress to AIDS. Replication-competent HIV-2 isolated from asymptomatic long-term non-progressors (controllers) have lower replication rates than viruses from individuals who progress to AIDS (progressors). To investigate potential retroviral factors that correlate with disease progression in HIV-2, we sequenced the near full-length genomes of replication-competent viruses previously outgrown from controllers and progressors and used phylogeny to seek genotypic correlates of disease progression. We validated the integrity of all open reading frames and used cell-based assays to study the retroviral transcriptional activity of the long terminal repeats (LTRs) and Tat proteins of HIV-2 from controllers and progressors. Overall, we did not identify genotypic defects that may contribute to HIV-2 non-progression. Tat-induced, LTR-mediated transcription was comparable between viruses from controllers and progressors. Our results were obtained from a small number of participants and should be interpreted accordingly. Overall, they suggest that progression may be determined before or during integration of HIV-2.

Asunto(s)

Síndrome de Inmunodeficiencia Adquirida , Infecciones por VIH , Humanos , VIH-2/genética , Secuencia de Bases , Progresión de la Enfermedad

RESUMEN

BACKGROUND: HIV infection produces a chronic inflammation which leads to early aging of people living with HIV. Even though antiretroviral treatments (ART) have significantly increased HIV patient survival, an underlying chronic inflammation persists leading to HIV-related comorbidities. In this context, changes in microRNAs (miRNAs) expression may contribute to this inflammatory response. This study aims to detect differential expression of circulating miRNAs in treatment-naïve HIV-infected individuals compared to uninfected controls and evaluation of altered miRNAs after one year of ART. METHODS: Serum from patients and controls was collected at baseline and after 48-weeks on ART in HIV-treated patients. Circulating miRNAs were analysed using next generation sequencing. RESULTS: A total of 32 HIV patients and 10 controls were recruited. Of HIV+ individuals, 7 were long-term non-progressors (elite controllers), a group of HIV-infected individuals that spontaneously control the infection. Higher circulating levels of miR-21-5p, and lower levels of miR-6503-3p and miR-3135b were detected in HIV+ progressors. After one year of ART, these miRNAs remain altered. Moreover, miR-21-5p and miR-6503-3p were also altered in elite controllers compared to control group. In silico analyses showed that miR-21-5p target pathways are related to inflammation mechanisms and immune system. CONCLUSION: miR-21-5p circulating levels are involved in inflammation and oxidative stress mechanisms in HIV patients even after one year of ART or in elite controllers.

Asunto(s)

Infecciones por VIH , MicroARNs , Humanos , MicroARNs/metabolismo , Inflamación , Secuenciación de Nucleótidos de Alto Rendimiento

RESUMEN

HIV-exposed seronegative individuals (HESIs) are a small fraction of persons who are multiply exposed to human immunodeficiency virus (HIV), but do not exhibit serological or clinical evidence of HIV infection. In other words, they are groups of people maintaining an uninfected status for a long time, even after being exposed to HIV several times. The long-term non-progressors (LTNPs), on the other hand, are a group of HIV-infected individuals (approx. 5%) who remain clinically and immunologically stable for an extended number of years without combination antiretroviral therapy (cART). Meanwhile, elite controllers are comprise a much lower number (0.5%) of HIV-infected persons who spontaneously and durably control viremia to below levels of detection for at least 12 months, even when using the most sensitive assays, such as polymerase chain reaction (PCR) in the absence of cART. Despite the fact that there is no universal agreement regarding the mechanisms by which these groups of individuals are able to control HIV infection and/or disease progression, there is a general consensus that the mechanisms of protection are multifaceted and include genetic, immunological as well as viral factors. In this review, we analyze and compare the biological factors responsible for the control of HIV in these unique groups of individuals.

Asunto(s)

Infecciones por VIH , VIH-1 , Humanos , VIH-1/genética , VIH no-Progresivos , Controladores de Élite , Progresión de la Enfermedad , Carga Viral

RESUMEN

The gut is a major reservoir in HIV-infected individuals on antiretroviral therapy (ART) and in long-term non-progressors (LTNPs). Whether ART reduces gut infection and reservoirs in LTNPs is unknown. Herein, SIV-infected LTNP Rhesus macaques were treated with short- or long-term ART, and SIV envelope gp120 sequences obtained from single genome amplification were analyzed before and after ART in peripheral blood and the intestine. Although ART does not eliminate SIV in these LTNPs, a longer ART period dramatically reduces SIV infection in the gut. This study highlights the importance of long-term ART in LTNPs to minimize gut infection and prolong remission.

Asunto(s)

Infecciones por VIH , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios/genética , Macaca mulatta , Infecciones por VIH/tratamiento farmacológico , Antirretrovirales/uso terapéutico

RESUMEN

Strategies to reduce the human immunodeficiency virus (HIV) reservoir are urgently required. The antibody-dependent cellular cytotoxicity (ADCC)-mediating anti-HIV antibodies have shown an association with HIV control. We assessed if such antibodies can be generated in vitro and whether the generated antibodies can facilitate the reduction of reactivated HIV reservoir. We isolated HIV-1-gp140-specific memory B cells from HIV-1-infected long-term non-progressors (LTNPs) with or without plasma ADCC and cultured them to generate anti-HIV antibodies. The ability of the generated antibodies to mediate ADCC and facilitate NK cell-mediated lysis of reactivated HIV reservoir was assessed by the rapid fluorometric antibody-dependent cellular cytotoxicity assay and a flow-based novel latency reduction assay, respectively. All LTNPs showed the presence of gp140-specific memory B cells [median: 0.79% (0.54%-1.225%)], which were successfully differentiated into plasma cells [median 72.0% (68.7-82.2%)] in an in-vitro culture and secreted antibodies [median OD: 0.253 (0.205-0.274)]. The HIV-gp140-specific antibodies were generated from 11/13 LTNPs irrespective of their plasma ADCC status. The generated antibodies from LTNPs with plasma ADCC showed higher ADCC potency (median: 37.6%, IQR: 32.95%-51%) and higher reduction in reactivated HIV reservoir (median: 62.5%, IQR: 58.71%-64.92%) as compared with the antibodies generated from LTNPs without plasma ADCC (ADCC: median: 8.85%, IQR: 8%-9.7%; and % p24 reduction median: 13.84, IQR: 9.863%-17.81%). The potency of these antibodies to reduce latent reservoir was two-fold higher than the respective plasma ADCC. The study showed that the potent ADCC-mediating antibodies could be generated from memory B cells of the LTNPs with plasma ADCC activity. These antibodies also showed potent ability to facilitate NK cell-mediated lysis of reactivated HIV reservoirs. It also indicated that memory B cells from individuals with plasma ADCC activity should be preferentially used for such antibody generation. The important role of these antibodies in the reduction of latent reservoirs needs to be further evaluated as a useful strategy to obtain a functional cure for HIV infection.

Asunto(s)

Controladores de Élite , Anticuerpos Anti-VIH , Infecciones por VIH , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos , Infecciones por VIH/inmunología , VIH-1 , Humanos

RESUMEN

BACKGROUND: Long-term non-progressors (LTNPs) are small subsets of HIV-infected subjects that can control HIV-1 replication for several years without receiving ART. The exact mechanism of HIV-1 suppression has not yet been completely elucidated. Although the modulatory role of microRNAs (miRNAs) in HIV-1 replication has been reported, their importance in LTNPs is unclear. OBJECTIVE: The aim of this cross-sectional study was to assess the expression pattern of miR-27b, -29, -150, and -221, as well as their relationship with CD4+ T-cell count, HIV-1 viral load, and nef gene expression in peripheral blood mononuclear cells (PBMCs) of untreated viremic patients and in LTNPs. METHODS: MiRNAs expression levels were evaluated with real-time PCR assay using RNA isolated from PBMCs of LTNPs, HIV-1 infected naive patients, and healthy people. Moreover, CD4 T-cell count, HIV viral load, and nef gene expression were assessed. RESULTS: The expression level of all miRNAs significantly decreased in the HIV-1 patient group compared to the control group, while the expression pattern of miRNAs in the LNTPs group was similar to that in the healthy subject group. In addition, there were significant correlations between some miRNA expression with viral load, CD4+ T-cell count, and nef gene expression. CONCLUSION: The significant similarity and difference of the miRNA expression pattern between LNTPs and healthy individuals as well as between elite controllers and HIV-infected patients, respectively, showed that these miRNAs could be used as diagnostic biomarkers. Further, positive and negative correlations between miRNAs expression and viral/cellular factors could justify the role of these miRNAs in HIV-1 disease monitoring.

Asunto(s)

Infecciones por VIH , VIH-1 , MicroARNs , Recuento de Linfocito CD4 , Estudios Transversales , VIH-1/genética , Humanos , Leucocitos Mononucleares , MicroARNs/genética , MicroARNs/metabolismo , Carga Viral

RESUMEN

OBJECTIVES: Regulatory T cells (Tregs) are widely recognised as a subset of CD4+CD25+FOXP3+ T cells that have a key role in maintaining immune homeostasis. The impact of HIV-1 infection on immunological properties and effector functions of Tregs has remained the topic of debate and controversy. In the present study, we investigated transcriptional profile and functional properties of Tregs in HIV-1-infected individuals either receiving antiretroviral therapy (ART, n = 50) or long-term non-progressors (LTNPs, n = 24) compared to healthy controls (HCs, n = 38). METHODS: RNA sequencing (RNAseq), flow cytometry-based immunophenotyping and functional assays were performed to study Tregs in different HIV cohorts. RESULTS: Our RNAseq analysis revealed that Tregs exhibit different transcriptional profiles in HIV-infected individuals. While Tregs from patients on ART upregulate pathways associated with a more suppressive (activated) phenotype, Tregs in LTNPs exhibit upregulation of pathways associated with impaired suppressive properties. These observations may explain a higher propensity for autoimmune diseases in LTNPs. Also, we found substantial upregulation of HLA-F mRNA and HLA-F protein in Tregs from HIV-infected subjects compared to healthy individuals. These observations highlight a potential role for this non-classical HLA in Tregs in the context of HIV infection, which should be investigated further in other chronic viral infections and cancer. CONCLUSION: Our study has provided a novel insight into Tregs at the transcriptional and functional levels in different HIV-infected groups.

RESUMEN

HIV-1 infection in human beings has been an outcome of cross-species transmission event of simian immunodeficiency virus from chimpanzees (SIVcpz). Present study reveals differential features of envelope genes representing different categories of HIV-1 disease progression in human beings, namely, rapid progressors (RP), slow progressors (SP) and long-term non-progressors (LTNP) with respect to SIVcpz, based on their amino acid usage patterns. It was evident that SP, LTNP and SIVcpz envelope genes displayed similar patterns of amino acid usage which strongly contrasted with the features exhibited by the envelope genes representing RP category. Robust analysis revealed that selection constraint of human host on SP and LTNP associated envelope genes and chimpanzee host on SIVcpz envelope genes were more severe compared to selection pressure operational on RP associated envelope genes. Evolutionary forces of selection appeared to be comparatively more relaxed on the RP envelope genes in contrast to SP, LTNP and SIVcpz types. Better binding of RP envelope glycoprotein 120 (gp120) compared to envelope gp120 representing SP, LTNP and SIVcpz with host cellular receptor CD4, as inferred employing molecular docking approaches, promises to confer meaningful insights into the event of speedy progression of HIV in rapid progressors. It was interesting to note that envelope glycoprotein exhibited a tendency of hindering proper interaction of host (human/chimpanzee) CD4 and major histocompatibility complex II (MHC II), with a better efficacy in rapid progressors, thus, facilitating highest degrees of immune suppression. Proper identification of the contrasting features might confer a scope to modulate rapid progression of HIV to a long-term non-progressive controlled case, as observed in LTNP and SIVcpz infection, simultaneously aiding therapeutic research against AIDS targeted at drug and vaccine development.Communicated by Ramaswamy H. Sarma.

Asunto(s)

Infecciones por VIH , VIH-1 , Virus de la Inmunodeficiencia de los Simios , Animales , VIH-1/genética , Humanos , Simulación del Acoplamiento Molecular , Pan troglodytes , Virus de la Inmunodeficiencia de los Simios/genética

RESUMEN

HIV infection predisposes latent tuberculosis-infected (LTBI) subjects to active TB. This study is designed to determine whether HIV infection of LTBI subjects compromises the balanced Mycobacterium tuberculosis (Mtb)-specific T helper 17 (Th17) response of recognized importance in anti-TB immunity. Comparative analysis of Mtb- and cytomegalovirus (CMV)-specific CD4+ T cell responses demonstrates a marked dampening of the Mtb-specific CD4+ T cell effectors and polyfunctional cells while preserving CMV-specific response. Additionally, HIV skews the Mtb-specific Th17 response in chronic HIV-infected LTBI progressors, but not long-term non-progressors (LTNPs), with preservation of pro-inflammatory interferon (IFN)-γ+/interleukin-17+ (IL-17+) and significant loss of anti-inflammatory IL-10+/IL-17+ effectors that is restored by anti-retroviral therapy (ART). HIV-driven impairment of Mtb-specific response cannot be attributed to preferential infection as cell-associated HIV DNA and HIV RNA reveal equivalent viral burden in CD4+ T cells from different antigen specificities. We therefore propose that beyond HIV-induced loss of Mtb-specific CD4+ T cells, the associated dysregulation of Mtb-specific T cell homeostasis can potentially enhance the onset of TB in LTBI subjects.

Asunto(s)

Infecciones por VIH/genética , Interleucina-17/metabolismo , Tuberculosis Latente/complicaciones , Carga Viral/métodos , Adulto , Femenino , Humanos , Masculino , Adulto Joven

RESUMEN

Long-term non-progressors (LTNP) and elite controllers (EC) represent spontaneous natural models of efficient HIV-1 response in the absence of treatment. The main purposes of this work are to describe the miRNome of HIV-1 infected patients with different extreme phenotypes and identify potentially altered pathways regulated by differentially expressed (DE) miRNAs. The miRNomes from peripheral blood mononuclear cells (PBMCs) of dual phenotype EC-LTNP or LTNP with detectable viremia and HIV-infected patients with typical progression before and after treatment, were obtained through miRNA-Seq and compared among them. The administration of treatment produces 18 DE miRNAs in typical progressors. LTNP condition shows 14 DE miRNA when compared to typical progressors, allowing LTNP phenotype differentiation. A set of four miRNAs: miR-144-3p, miR-18a-5p, miR-451a, and miR-324 is strongly downregulated in LTNP and related to protein regulation as AKT, mTOR, ERK or IKK, involved in immune response pathways. Deregulation of 28 miRNA is observed between EC-LTNP and viremic-LTNP, including previously described anti-HIV miRNAs: miR-29a, associated with LTNP phenotype, and miR-155, targeting different pre-integration complexes such as ADAM10 and TNPO3. A holistic perspective of the changes observed in the miRNome of patients with different phenotypes of HIV-control and non-progression is provided.

RESUMEN

Viremic non-progressors (VNPs), a distinct group of HIV-1-infected individuals, exhibit no signs of disease progression and maintain persistently elevated CD4+ T cell counts for several years despite high viral replication. Comprehensive characterization of homeostatic cellular immune signatures in VNPs can provide unique insights into mechanisms responsible for coping with viral pathogenesis as well as identifying strategies for immune restoration under clinically relevant settings such as antiretroviral therapy (ART) failure. We report a novel homeostatic signature in VNPs, the preservation of the central memory CD4+ T cell (CD4+ T CM ) compartment. In addition, CD4+ TCM preservation was supported by ongoing interleukin-7 (IL-7)-mediated thymic repopulation of naive CD4+ T cells leading to intact CD4+ T cell homeostasis in VNPs. Regulatory T cell (Treg) expansion was found to be a function of preserved CD4+ T cell count and CD4+ T cell activation independent of disease status. However, in light of continual depletion of CD4+ T cell count in progressors but not in VNPs, Tregs appear to be involved in lack of disease progression despite high viremia. In addition to these homeostatic mechanisms resisting CD4+ T cell depletion in VNPs, a relative diminution of terminally differentiated effector subset was observed exclusively in these individuals that might ameliorate consequences of high viral replication. VNPs also shared signatures of impaired CD8+ T cell cytotoxic function with progressors evidenced by increased exhaustion (PD-1 upregulation) and CD127 (IL-7Rα) downregulation contributing to persistent viremia. Thus, the homeostatic immune signatures reported in our study suggest a complex multifactorial mechanism accounting for non-progression in VNPs.

Asunto(s)

Progresión de la Enfermedad , Sobrevivientes de VIH a Largo Plazo , Seropositividad para VIH/inmunología , VIH-1/inmunología , Homeostasis/inmunología , Adolescente , Adulto , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/inmunología , Femenino , Genotipo , Seropositividad para VIH/sangre , Seropositividad para VIH/virología , VIH-1/genética , Humanos , Interleucina-7/sangre , Masculino , Persona de Mediana Edad , Receptores de Interleucina-7/metabolismo , Linfocitos T Reguladores/inmunología , Carga Viral , Viremia/inmunología , Replicación Viral , Adulto Joven

RESUMEN

BACKGROUND: Disease progression in the absence of therapy varies significantly in mono-HIV and HCV infected individuals. Virus-specific CD8+ T cells play an important role in restricting lentiviral replication and determining the rate of disease progression during HIV and HCV mono- and co-infection. Thus, understanding the similarities in the characteristics of CD8+ T cells in mono-HIV and HCV infection at the transcriptomic level contributes to the development of antiviral therapy. In this study, a meta-analysis of CD8+ T cell gene expression profiles derived from mono-HIV and HCV infected individuals at different stages of disease progression, was conducted to understand the common changes experienced by CD8+ T cells. METHODS: Five microarray datasets, reporting CD8+ T cell mRNA expression of the mono-HIV and HCV infected patients, were retrieved from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified via integrative meta-analysis of expression data (INMEX) program. Network analysis methods were used to assess protein-protein interaction (PPI) networks, Gene Ontology (GO) terms and pathway enrichment for DEGs. MirDIP and miRDB online prediction tools were used to predict potential microRNAs (miRNAs) targeting hub genes. RESULTS: First, we identified 625 and 154 DEGs in the CD8+ T cells originating from mono-HIV and HCV chronic progressor patients, respectively, compared to healthy individuals. Among them, interferon-stimulated genes (ISGs) including ISG15, IFIT3, ILI44L, CXCL8, FPR1 and TLR2, were upregulated after mono-HIV and HCV infection. Pathway enrichment analysis of DEGs showed that the "cytokine-cytokine receptor interaction" and "NF-kappa B" signaling pathways were upregulated after mono-HIV and HCV infection. In addition, we identified 92 and 50 DEGs in the CD8+ T cells of HIV non-progressor and HCV resolver patients, respectively, compared with corresponding chronic progressors. We observed attenuated mitosis and reduced ISG expression in HIV non-progressors and HCV resolvers compared with the corresponding chronic progressors. Finally, we identified miRNA-143-3p, predicted to target both IFIT3 in HIV and STAT5A in HCV infection. CONCLUSIONS: We identified DEGs and transcriptional patterns in mono-HIV and HCV infected individuals at different stages of disease progression and identified miRNA-143-3p with potential to intervene disease progression, which provides a new strategy for developing targeted therapies.

Asunto(s)

Coinfección , Infecciones por VIH , Hepatitis C , Linfocitos T CD8-positivos , Perfilación de la Expresión Génica , Infecciones por VIH/genética , Hepatitis C/genética , Humanos

RESUMEN

Bone marrow stromal cell antigen 2 (BST2) is an interferon induced host restriction factor for HIV-1 that blocks the release of nascent virions from infected T cells. We aimed to characterize BST2 gene variants in HIV-1 positive individuals in Indian cohort and study the association of these variants with disease progression in long term non progressors (LTNPs) and progressors. Archived samples of 32 LTNPs, 17 progressors, and 78 controls were screened for BST2 gene polymorphisms using Sanger's sequencing method. Frequency distribution, survival analysis and bioinformatics tools were used to study the association of BST2 variants with disease progression. Eighteen variants of BST2 gene were observed in Indian cohort. Intronic SNP rs919267T/C (OR = 4.489 [0.8494-27.03], p = .04157) and exonic SNP rs13485C/G (OR = 3.887 [0.8262-25.56], p = .0488) were found to be significantly associated with disease progression. Also, rs13485C/C genotype in combination with rs919267C/T (OR = 9.406 [1.384-111], p = .0085) and rs145303329 Δ19bp (OR = 3.887 [0.826-25.5], p = .048) were found to be significantly associated with disease progression. 19 bp indel rs145303329 and its allele c.1-443_1-442insCGCCCCCAGAC[C/T]CAGGCCC from BST2 promoter also showed association with disease progression (OR = 12.97 [0.9731-850.5], p = .026). Docking of AP2 repressor with above allele showed the total binding energy of LTNPs and progressors to be -2581.42 kcal/mol and -3563.27/-3562.84 kcal/mol respectively. We have identified the novel association of three BST2 gene SNPs; rs919267, rs13485 and indel rs145303329 from Indian cohort to be associated with the risk of HIV-1 disease progression for the first time.

Asunto(s)

Antígenos CD/genética , Susceptibilidad a Enfermedades , Variación Genética , Infecciones por VIH/genética , Infecciones por VIH/virología , VIH-1 , Alelos , Antígenos CD/química , Antígenos CD/metabolismo , Sitios de Unión , Biología Computacional/métodos , Progresión de la Enfermedad , Exones , Proteínas Ligadas a GPI/química , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Predisposición Genética a la Enfermedad , Genotipo , Infecciones por VIH/mortalidad , Humanos , India , Estimación de Kaplan-Meier , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Unión Proteica , Relación Estructura-Actividad , Factor de Transcripción AP-2/química , Factor de Transcripción AP-2/metabolismo

RESUMEN

La Guía Colombiana de práctica clínica para la atención de la infección por VIH / Sida en adolescentes y adultos incluye como primera línea de tratamiento el uso de Inhibidores de integrasa; sin embargo, no incluye recomendaciones que soporten la decisión de tratar a los pacientes controladores elite (CE). La definición de controladores elite es confusa pues varía de un estudio a otro y se desconoce si las recomendaciones de tratamiento, se pueden aplicar a los controladores de forma similar; tampoco existen mecanismos apropiados para el seguimiento sistemático de los controladores elite cuando se inicia en ellos una terapia antirretroviral. Este artículo es una revisión bibliográfica de la información disponible sobre la definición de los pacientes controladores, y los controladores elite, su evolución clinica e inmunológica, el tratamiento y las terapias disponibles en Colombia.

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The Colombian Guide to Clinical Practice for HIV / AIDS Care in Adolescents and Adults, includes as first line of treatment the use of integrase inhibitors; however, there is no information to support the decision to treat elite control patients (EC). The definition of elite controller is confusing, because of the changes in definitions between studies, and it is unknown whether these recommendations apply to these patients in a similar way; and how should be systematic follow-up of elite controllers when antiretroviral therapy is initiated. Present paper is a bibliographic review of the available information on the definition of the controllers, and elite controllers its clinical and immunological evolution, the treatment and therapies available in Colombia.

Asunto(s)

Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Síndrome de Inmunodeficiencia Adquirida , VIH , Guía de Práctica Clínica , Inhibidores de Integrasa , Evolución Clínica , Revisión , Control de Infecciones , Cuidados Posteriores , Integrasas , Infecciones

RESUMEN

BACKGROUND: In the absence of antiretroviral treatments (ARTs), a small group of individuals infected with HIV, including long-term non-progressors (LTNPs) who maintain high levels of CD4+ T cells for more than 7-10 years in the absence of ART and in particular a subgroup of LTNPs, elite controllers (ECs), who have low levels of viremia, remain clinically and/or immunologically stable for years. However, the mechanism of stable disease progression in LTNPs and ECs needs to be elucidated to help those infected with HIV-1 remain healthy. In this study, to identify the characteristics of gene expression profiles and biomarkers in LTNPs, we performed a meta-analysis using multiple gene expression profiles among LTNPs, individuals infected with HIV-1 without ART, individuals infected with HIV-1 with ART, and healthy controls. METHODS: The gene expression profiles obtained from the Gene Expression Omnibus (GEO) microarray data repositories were classified into three groups: LTNPs versus healthy controls (first group, 3 studies), LTNPs versus patients infected with HIV-1 without ART (second group, 3 studies), and LTNPs versus patients infected with HIV-1 with ART (third group, 3 studies). In addition, we considered a fourth group, patients infected with HIV-1 without ART versus healthy controls (3 studies), to exclude genes associated with HIV-1 infection in the three groups. For each group, we performed a meta-analysis using the RankProd method to identify and compare the differentially expressed genes (DEGs) in the three groups. RESULTS: We identified the 14 common DEGs in the three groups when comparing them with each other. Most belonged to immune responses, antigen processing and presentation, the interferon-gamma-mediated signaling pathway, and T cell co-stimulation. Of these DEGs, PHLDA1 was up-regulated and ACTB and ACTG1 were down-regulated in all three groups. However, the rest of the up- or down-regulated genes were discordant in the three groups. Additionally, ACTB and ACTG1 are known to inhibit viral assembly and production, and THBS1 is known to inhibit HIV-1 infection. CONCLUSIONS: These results suggest that significant genes identified in a meta-analysis provide clues to the cause of delayed disease progression and give a deeper understanding of HIV pathogenesis in LTNPs.

Asunto(s)

Perfilación de la Expresión Génica , Infecciones por VIH/genética , VIH-1/fisiología , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos

RESUMEN

Background: CD1d restricted invariant natural killer T (iNKT) cells are important in the activation and regulation of immune responses. Limited information is available regarding the functional role of iNKT cells in the human immunodeficiency virus (HIV) disease progression. Methodology: α-GalCer stimulated iNKT cells were characterized for their functionality in terms of cytokine production (IFN-γ, TNF-α, IL-2, IL-4, and IL-21) and CD107a expression in HIV-1 infected [23 long-term non progressors (LTNPs), 28 progressors, 18 patients before and after suppressive anti-retroviral treatment (ART)] along with 25 HIV-1 negative subjects using multicolor flow cytometry. Results: The functional profile of α-GalCer stimulated iNKT cells was similar in LTNPs and healthy controls. The number of LTNPs showing functional response in terms of secretion of cytokines (IFN-γ/IL2/TNF-α) and CD107a expression was significantly higher than seen in the progressors. The cytokine secretion by the stimulated iNKT cells was predominantly Th1 type. The frequencies of iNKT cells showing secretion of IFN-γ or IL2 or TNF-α or expression of CD107a were higher in LTNPs (p < 0.05 for all) and also significantly associated with lower plasma viral load (p value ranged from 0.04 to 0.003) and higher CD4 count (p value ranged from 0.02 to <0.0001). The functional profile of the iNKT cells before and after ART did not differ significantly indicating absence of restoration of iNKT cells functionality after suppressive ART. The IL-4 and IL-21 secreting iNKT cells were rare in all study populations. Conclusion: The presence of functional iNKT cells secreting number of cytokines in non-progressive HIV infection could be one of the multiple factors required to achieve HIV control and hence have relevance in understanding the immunity in HIV infection. The failure of restoration of the iNKT functionality after ART should be potential area of future research.

Asunto(s)

Citocinas/metabolismo , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , VIH-1/inmunología , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Terapia Antirretroviral Altamente Activa , Biomarcadores , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Inmunohistoquímica , Masculino , Carga Viral

RESUMEN

BACKGROUND: Few reports suggest the association of killer immunoglobulin-like receptors of natural killer cells with human immunodeficiency virus infection. India with world's third largest population of human immunodeficiency virus / acquired immunodeficiency syndrome, offers scope to study such association. OBJECTIVE: Current study (2010-2015) was designed to evaluate if killer immunoglobulin-like receptors gene polymorphisms are associated with HIV infection outcomes specifically, with long term non progressors. METHODS: Killer immunoglobulin-like receptors genotyping was done using polymerase chain reaction - sequence-specific primer method. Viral load was measured by Cobas Taqman HIV-1 test. Estimation of CD4 counts was done using BD FACS CD4 count reagent. RESULTS: The activating gene frequencies identified were 3DS1 (53.8%), 2DS3 (69.2%), 2DS4 (76.9%), 2DS5 (69.2%), 2DS1 (76.9%) and 2DS2 (92.3%). The inhibitory gene frequencies were 2DL2 (92.3%), 2DL5 (76.9%), 2DL3 (69.5%), 3DL1 (84.6%), 3DL2 (92.3%) and 2DL1 (100%). The results highlight high frequency of 3DS1/3DL1 heterozygote and killer immunoglobulin-like receptor 2DS1, among these long term non progressors indicating their possible association with slow progression. Genotype analysis shows total 13 genotypes, of which 8 genotypes were identified for the first time from India. Two genotypes were unique/novel, which were unreported. All genotypes observed in this study were considered to be Bx genotype (100 %). LIMITATIONS: A small sample size (n=13, due to a rare cohort) and the absence of control group were the limitations of this study. CONCLUSIONS: The present study highlights the distribution of killer immunoglobulin-like receptor genes in a very rare group of human immunodeficiency virus -1 infected individuals - long term non progressors. All the long term non progressors tested show the presence of Bx haplotype and each long term non progressors has a different killer immunoglobulin-like receptor genotype.

Asunto(s)

Infecciones por VIH/epidemiología , Infecciones por VIH/genética , VIH-1/genética , Receptores KIR/genética , Adolescente , Adulto , Niño , Estudios de Cohortes , Progresión de la Enfermedad , Infecciones por VIH/diagnóstico , Humanos , India/epidemiología , Polimorfismo Genético/genética , Estudios Prospectivos , Factores de Tiempo

RESUMEN

Human immunodeficiency virus (HIV)-infected long-term non-progressors (LTNPs) are of particular importance because of their unique disease progression characteristics. Defined by the maintenance of normal CD4+T cells after more than 8 years of infection, these LTNPs are heterogeneous. Some LTNPs exhibit ongoing viral production, while others do not and are able to control viral production. The underlying basis for this heterogeneity has not been clearly elucidated. In this study, the miRNA expression profiles of LTNPs were assessed. The levels of microRNA-19b (miR-19b) were found to be significantly increased in peripheral blood mononuclear cells of LTNPs with lower rather than higher viral load. We made clear that miR-19b may regulate CD8+T cell functions in HIV infection, which has not been addressed before. Overexpression of miR-19b promoted CD8+T cell proliferation, as well as interferon-γ and granzyme B expression, while inhibiting CD8+T cells apoptosis induced by anti-CD3/CD28 stimulation. The target of miR-19b was found to be the "phosphatase and tensin homolog", which regulates CD8+T cells function during HIV infections. Furthermore, we found that miR-19b can directly inhibit viral production in in-vitro HIV infected T cells. These results highlight the importance of miR-19b to control viral levels, which facilitate an understanding of human immunodeficiency virus pathogenesis and provide potential targets for improved immune intervention.

Asunto(s)

Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , MicroARNs/genética , Fosfohidrolasa PTEN/genética , Terapia Antirretroviral Altamente Activa , Apoptosis/genética , Apoptosis/inmunología , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Infecciones por VIH/tratamiento farmacológico , Sobrevivientes de VIH a Largo Plazo , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Respuesta Virológica Sostenida , Carga Viral , Replicación Viral

RESUMEN

Several B cell defects are reported in HIV-1 infected individuals including variation in B cell subsets, polyclonal B cell activation and exhaustion, with broadly neutralizing antibodies elicited in less than 10-20% of the infected population. HIV-1 disease progression is faster in children than adults. B Lymphocyte Stimulator (BLyS), expressed on dendritic cells (DCs), is a key regulator of B cell homeostasis. Understanding how DCs influence B cell phenotype and functionality (viral neutralization), thereby HIV-1 disease outcome in infected children, is important to develop interventional strategies for restoration of B cell function. In this study, a total of 38 vertically transmitted HIV-1 infected antiretroviral therapy (ART) naïve children and 25 seronegative controls were recruited. Based on the CD4 counts and years post-infection, infected children were categorized as long-term non-progressors (LTNPs) (n = 20) and progressors (n = 18). Eight of these progressors were followed up at 6-12 months post-ART. Percentages (%) of DCs, B cell subsets, and expression of BLyS on DCs were analyzed by flow-cytometry. Plasma levels of B cell growth factors were measured by ELISA and viral neutralization activity was determined using TZM-bl assay. Lower (%) of myeloid DCs (mDCs), plasmacytoid DCs, and high expression of BLyS on mDCs were observed in HIV-1 infected progressors than seronegative controls. Progressors showed lower % of naive B cells, resting memory B cells and higher % of mature activated, tissue-like memory B cells as compared to seronegative controls. Higher plasma levels of IL-4, IL-6, IL-10, and IgA were observed in progressors vs. seronegative controls. Plasma levels of IgG were high in progressors and in LTNPs than seronegative controls, suggesting persistence of hypergammaglobulinemia at all stages of disease. High plasma levels of BLyS in progressors positively correlated with poor viral neutralizing activity. Interestingly on follow up, treatment naïve progressors, post-ART showed increase in resting memory B cells along with reduction in plasma BLyS levels that correlated with improvement in viral neutralization. This is the first study to demonstrate that reduction in plasma BLyS levels correlates with restoration of B cell function, in terms of viral neutralization in HIV-1-infected children.

RESUMEN

Antibodies (Abs) play a central role in human immunodeficiency virus (HIV) protection due to their multiple functional inhibitory activities. W614A-3S Abs recognize a specific form of a highly conserved motif of the gp41 envelope protein and can elicit viral neutralization to protect CD4+ T cells. Here, we describe in detail the neutralizing profile of W614A-3S Abs in untreated long-term non-progressor (LTNP) HIV-infected patients. W614A-3S Abs were detected in 23.5% (16/68) of untreated LTNP patients compared with <5% (5/104) of HIV-1 progressor patients. The W614A-3S Abs had efficient neutralizing activity that inhibited transmitted founder primary viruses and exhibited Fc-mediated inhibitory functions at low concentrations in primary monocyte-derived macrophages. The neutralizing capacity of W614A-3S Abs was inversely correlated with viral load (r=-0.9013; p<0.0001), viral DNA (r=-0.7696; p=0.0005) and was associated the preservation of high CD4+ T-cell counts and T-cell responses. This study demonstrates that W614A-3S neutralizing Abs may confer a crucial advantage to LTNP patients. These results provide insights for both pathophysiological research and the development of vaccine strategies.

Asunto(s)

Anticuerpos Neutralizantes/metabolismo , Proteína gp41 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Adulto , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , ADN Viral , Femenino , Infecciones por VIH/virología , Sobrevivientes de VIH a Largo Plazo , VIH-1/fisiología , Humanos , Masculino , Carga Viral