RESUMEN
BACKGROUND: Good's syndrome (GS) is a rare immune deficiency described almost 6 decades ago. Despite numerous published individual case reports and data collected in cross-sectional studies of small cohorts, the natural history and long-term outcomes of this disease remain unknown. OBJECTIVE: We aimed to determine the clinical and laboratory evolution of 8 adults diagnosed with GS and consecutively evaluated between 1983 and 2023. METHODS: In this prospective, longitudinal cohort study, newly diagnosed patients with GS were followed through repeated measures of clinical, immune, and hematologic changes, as well as targeted genetic screening. RESULTS: All patients reported a healthy childhood and adolescence with symptom onset during the third or fourth decade of life. All presented to our center with recurrent bacterial sinopulmonary infections, thymoma, hypogammaglobulinemia, and absence of B cells. The median age of GS diagnosis was 57 years. During follow-up, immunoglobin replacement therapy effectively minimized sinopulmonary infections. However, the majority experienced severe and systemic viral or fungal infections, 3 developed basal cell carcinomas, and 5 had progressive bronchiectasis and persistent splenomegaly. The most notable clinical feature was opportunistic infections and in vitro evidence of cellular immune deficiency, which resulted in the death of 2 individuals. We also report a statistically significant, multidecade progressive decline in lymphocytes, platelets, hemoglobin, and red blood cells in our cohort, suggesting gradual bone marrow failure. CONCLUSIONS: Knowledge of the unique phenotype and temporal evolution of GS has allowed us to develop a more comprehensive diagnostic framework. It can be investigated as part of broader research into disease pathophysiology.
Asunto(s)
Agammaglobulinemia , Síndromes de Inmunodeficiencia , Enfermedades de Inmunodeficiencia Primaria , Timoma , Neoplasias del Timo , Adulto , Humanos , Niño , Persona de Mediana Edad , Estudios Prospectivos , Estudios Transversales , Estudios Longitudinales , Neoplasias del Timo/diagnóstico , Neoplasias del Timo/patología , Timoma/diagnóstico , Timoma/patología , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/terapia , Enfermedades de Inmunodeficiencia Primaria/diagnósticoRESUMEN
BACKGROUND: Evaluating age as a risk factor for susceptibility to infectious diseases, particularly coronavirus disease 2019 (COVID-19), is critical. Cytomegalovirus (CMV) serologic prevalence increases with age and associates with inflammatory-mediated diseases in the elderly. However, little is known regarding the subclinical impact of CMV and risk it poses to healthy older adults. Prior to the COVID-19 pandemic we conducted a study to determine the association of CMV to biologic age and immune dysregulation. METHODS: Community-dwelling, healthy adults older than 60 years were evaluated using DNA methylation assays to define epigenetic age (EpiAge) and T-cell immunophenotyping to assess immune dysregulation. RESULTS: All subjects were healthy and asymptomatic. Those CMV seropositive had more lymphocytes, CD8 T cells, CD28- T cells, decreased CD4:CD8 cell ratios, and had higher average EpiAge (65.34 years) than those CMV seronegative (59.53 years). Decreased percent CD4 (Pâ =â .003) and numbers of CD4 T cells (Pâ =â .0199) correlated with increased EpiAge. CONCLUSIONS: Our novel findings distinguish altered immunity in the elderly based on CMV status. Chronic CMV infection in healthy, older adults is associated with indicators of immune dysregulation, both of which correlate to differences in EpiAge.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Infecciones por Citomegalovirus , Epigénesis Genética , Anciano , Infecciones Asintomáticas , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/inmunología , Metilación de ADN , Humanos , Persona de Mediana EdadRESUMEN
NKG2C is an activating NK cell receptor encoded by a gene having an unexpressed deletion variant. Cytomegalovirus (CMV) infection expands a population of NKG2C+ NK cells with adaptive-like properties. Previous reports found that carriage of the deleted NKG2C- variant was more frequent in people living with HIV (PLWH) than in HIV- controls unexposed to HIV. The frequency of NKG2C+ NK cells positively correlated with HIV viral load (VL) in some studies and negatively correlated with VL in others. Here, we investigated the link between NKG2C genotype and HIV susceptibility and VL set point in PLWH. NKG2C genotyping was performed on 434 PLWH and 157 HIV-exposed seronegative (HESN) subjects. Comparison of the distributions of the three possible NKG2C genotypes in these populations revealed that the frequencies of NKG2C+/+ and NKG2C+/- carriers did not differ significantly between PLWH and HESN subjects, while that of NKG2C-/- carriers was higher in PLWH than in HESN subjects, in which none were found (P = 0.03, χ2 test). We were unable to replicate that carriage of at least 1 NKG2C- allele was more frequent in PLWH. Information on the pretreatment VL set point was available for 160 NKG2C+/+, 83 NKG2C+/-, and 6 NKG2C-/- PLWH. HIV VL set points were similar between NKG2C genotypes. The frequency of NKG2C+ CD3- CD14- CD19- CD56dim NK cells and the mean fluorescence intensity (MFI) of NKG2C expression on NK cells were higher on cells from CMV+ PLWH who carried 2, versus 1, NKG2C+ alleles. We observed no correlations between VL set point and either the frequency or the MFI of NKG2C expression. IMPORTANCE We compared NKG2C allele and genotype distributions in subjects who remained HIV uninfected despite multiple HIV exposures (HESN subjects) with those in the group PLWH. This allowed us to determine whether NKG2C genotype influenced susceptibility to HIV infection. The absence of the NKG2C-/- genotype among HESN subjects but not PLWH suggested that carriage of this genotype was associated with HIV susceptibility. We calculated the VL set point in a subset of 252 NKG2C-genotyped PLWH. We observed no between-group differences in the VL set point in carriers of the three possible NKG2C genotypes. No significant correlations were seen between the frequency or MFI of NKG2C expression on NK cells and VL set point in cytomegalovirus-coinfected PLWH. These findings suggested that adaptive NK cells played no role in establishing the in VL set point, a parameter that is a predictor of the rate of treatment-naive HIV disease progression.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Infecciones por VIH/genética , Subfamília C de Receptores Similares a Lectina de Células NK/genética , Carga Viral/genética , Alelos , Coinfección/genética , Coinfección/inmunología , Coinfección/virología , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Femenino , Frecuencia de los Genes , Genotipo , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Seronegatividad para VIH/genética , Seronegatividad para VIH/inmunología , Humanos , Células Asesinas Naturales/metabolismo , Masculino , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismoRESUMEN
For seven decades, the pathophysiology of Good's syndrome (GS) has remained a mystery, with few attempts to solve it. Initially described as an association between hypogammaglobulinemia and thymoma, controversy exists whether this is a unique disease, or a subgroup of Common Variable Immune Deficiency (CVID). Recently, some distinguishing aspects of both syndromes have come to light reflecting fundamental differences in their underlying pathophysiology. GS and CVID differ in demographic features and immune phenotype. GS is found almost exclusively in adults and is characterized by a significantly reduced or absence of peripheral B cells. In CVID, which also occurs in children, most patients have normal or slightly reduced peripheral B cells, with a distinguishing feature of low memory B cells. Similarly, differences in T cell dysregulation and manifestations of hematologic cytopenias may further distinguish GS from CVID. Knowledge of the clinical phenotype of this rare adult immune deficiency stems from individual case reports, retrospective, and cross-sectional data on a few cohorts with a limited number of well characterized patients. The understanding of pathophysiology in GS is hampered by the incomplete and inconsistent reporting of clinical and laboratory data, with a limited knowledge of its natural history. In this mini review, we discuss current state of the art data and identify research gaps. In order to resolve controversies and fill in knowledge gaps, we propose a coordinated paradigm shift from incidence reporting to robust investigative studies, addressing mechanisms of disease. We hope this novel approach sets a clear direction to solve the current controversies.
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Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/etiología , Autoinmunidad , Biomarcadores , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Susceptibilidad a Enfermedades/inmunología , Humanos , Síndromes de Inmunodeficiencia/epidemiología , Síndromes de Inmunodeficiencia/terapia , Especificidad de Órganos/inmunología , Fenotipo , Evaluación de SíntomasRESUMEN
Previously, we showed that Killer Immunoglobulin-like Receptor (KIR)3DS1 homozygotes (hmz) are more frequent in HIV exposed seronegative (HESN) than in recently HIV infected (HIV+) individuals. KIR3DS1 encodes an activating Natural Killer (NK) cell receptor (NKR). The link between KIR genotype and HIV outcomes likely arises from the function that NK cells acquire through expression of particular NKRs. An initial screen of 97 HESN and 123 HIV+ subjects for the frequency of KIR region gene carriage observed between-group differences for several telomeric KIR region loci. In a larger set of up to 106 HESN and 439 HIV+ individuals, more HESN than HIV+ subjects were KIR3DS1 homozygotes, lacked a full length KIR2DS4 gene and carried the telomeric group B KIR haplotype motif, TB01. TB01 is characterized by the presence of KIR3DS1, KIR2DL5A, KIR2DS3/5 and KIR2DS1, in linkage disequilibrium with each other. We assessed which of the TB01 encoded KIR gene products contributed to NK cell responsiveness by stimulating NK cells from 8 HIV seronegative KIR3DS1 and TB01 motif homozygotes with 721.221 HLA null cells and evaluating the frequency of KIR3DS1+/-KIR2DL5+/-, KIR3DS1+/-KIR2DS1+/-, KIR3DS1+/-KIR2DS5+/- NK cells secreting IFN-γ and/or expressing CD107a. A higher frequency of NK cells expressing, versus not, KIR3DS1 responded to 721.221 stimulation. KIR2DL5A+, KIR2DS1+ and KIR2DS5+ NK cells did not contribute to 721.221 responses or modulate those by KIR3DS1+ NK cells. Thus, of the TB01 KIR gene products, only KIR3DS1 conferred responsiveness to HLA-null stimulation, demonstrating its ligation can activate ex vivo NK cells.
Asunto(s)
Infecciones por VIH/inmunología , Seronegatividad para VIH , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Receptores KIR3DS1/genética , Receptores KIR3DS1/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Frecuencia de los Genes , Carga Genética , Infecciones por VIH/genética , Antígenos HLA/inmunología , Haplotipos , Humanos , Desequilibrio de Ligamiento , Estudios Prospectivos , Receptores KIR/genética , Receptores KIR/metabolismo , Receptores KIR2DL5/genética , Receptores KIR2DL5/metabolismo , Receptores KIR3DS1/química , TelómeroRESUMEN
BACKGROUND: Despite successful treatment and CD4+ T-cell recovery, HIV-infected individuals often experience a profound immune dysregulation characterized by a persistently low CD4:CD8 T-cell ratio. This residual immune dysregulation is reminiscent of the Immune Risk Phenotype (IRP) previously associated with morbidity and mortality in the uninfected elderly (>85 years). The IRP consists of laboratory markers that include: a low CD4:CD8 T-cell ratio, an expansion of CD8+CD28- T-cells and cytomegalovirus (CMV) seropositivity. Despite the significant overlap in immunological phenotypes between normal aging and HIV infection, the IRP has never been evaluated in HIV-infected individuals. In this pilot study we characterized immune changes associated with the IRP in a sample of successfully treated HIV-infected subjects. METHODS: 18 virologically suppressed HIV-infected subjects were categorized into 2 groups based on their IRP status; HIV+IRP+, (n = 8) and HIV+IRP-, (n = 10) and compared to 15 age-matched HIV uninfected IRP negative controls. All individuals were assessed for functional and phenotypic immune characteristics including: pro-inflammatory cytokine production, antigen-specific proliferation capacity, replicative senescence, T-cell differentiation and lymphocyte telomere length. RESULTS: Compared to HIV-infected subjects without an IRP, HIV+IRP+ subjects exhibited a higher frequency of TNF-α-producing CD8+ T-cells (p = 0.05) and a reduced proportion of CD8+ naïve T-cells (p = 0.007). The IRP status was also associated with a marked up-regulation of the replicative senescence markers CD57 and KLGR1, on the surface of CD8+T-cells (p = 0.004). Finally, HIV+IRP+ individuals had a significantly shorter mean lymphocyte telomere length than their non-IRP counterparts (p = 0.03). CONCLUSIONS: Our findings suggest that, despite similar levels of treatment-mediated viral suppression, the phenotypic and functional immune characteristics of HIV+IRP+ individuals are distinct from those observed in non-IRP individuals. The IRP appears to identify a subset of treated HIV-infected individuals with a higher degree of immune senescence.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Adulto , Anciano , Terapia Antirretroviral Altamente Activa , Relación CD4-CD8 , Linfocitos T CD4-Positivos/efectos de los fármacos , Antígenos CD57/inmunología , Senescencia Celular/efectos de los fármacos , Citocinas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Telómero/química , Telómero/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Natural killer (NK) cells play a role in the clearance of viral infections. Combinations of alleles at the polymorphic HLA-B locus and the NK cell surface killer immunoglobulin-like receptor locus KIR3DL1/S1 have been shown to influence time to AIDS in HIV-infected individuals and risk of seroconversion in HIV exposed seronegative (HESN) subjects. Here, we assessed time to seroconversion or duration of seronegative status in a group of 168 HIV exposed individuals, including 74 seroconverters and 94 HESN based on carriage or not of KIR3DL1/S1/HLA-B genotypes previously shown to be associated with protection from infection and/or slow time to AIDS. KIR3DL1/S1 genotyping was performed by sequence-specific primer polymerase chain reaction using two pairs of specific primers for each locus. The MHC class IB locus was typed to four-position resolution to resolve Bw4 and Bw6 alleles and the amino acid present at position 80. KIR3DL1/S1 heterozygotes became HIV infected significantly faster than KIR3DS1 homozygotes. Individuals who carried both KIR3DS1 and Bw4*80I did not remain HIV seronegative longer than those from a control group who were homozygous for HLA-Bw6 and carried no HLA-A locus Bw4 alleles Subjects who were *h/*y+B*57 showed a trend towards slower time to serconversion than those with other KIR3DL1 homozygous and KIR3DL1/S1 heterozygous genotypes. Thus, KIR3DS1 homozygosity is associated with protection from HIV infection while co-carriage of KIR3DS1 and Bw4*80I is not. The requirements for protection from HIV infection can differ from those that influence time to AIDS in HIV infected individuals.
Asunto(s)
Infecciones por VIH/genética , Seropositividad para VIH/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Receptores KIR3DL1/genética , Adulto , Alelos , Femenino , Estudios de Asociación Genética , Genotipo , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Seropositividad para VIH/inmunología , VIH-1/genética , VIH-1/inmunología , VIH-1/patogenicidad , Antígenos HLA-A/inmunología , Antígenos HLA-B/inmunología , Humanos , Células Asesinas Naturales/inmunología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Successful combination antiretroviral therapy (cART) increases levels of CD4+ T-cells, however this increase may not accurately reflect long-term immune recovery since T-cell dysregulation and loss of T-cell homeostasis often persist. We therefore assessed the impact of a decade of effective cART on immune regulation, T-cell homeostasis, and overall T-cell phenotype. METHODS: We conducted a retrospective study of 288 HIV+ cART-naïve patients initiating therapy. We identified 86 individuals who received cART for at least a decade, of which 44 consistently maintained undetectable plasma HIV-RNA levels throughout therapy. At baseline, participants were classified into three groups according to pre-treatment CD4+ T-cell counts: Group I (CD4<200 cells/mm3); Group II (CD4: 200-350 cells/mm3); Group III (CD4>350 cells/mm3). Outcomes of interest were: (1) CD4+ T-cell count restoration (CD4>532 cells/mm3); (2) normalization of CD4:CD8 T-cell ratio (1.2-3.3); (3) maintenance of CD3+ T-cell homeostasis (CD3: 65%-85% of peripheral lymphocytes); (4) normalization of the complete T-cell phenotype (TCP). RESULTS: Despite a decade of sustained successful cART, complete T-cell phenotype normalization only occurred in 16% of patients, most of whom had initiated therapy at high CD4+ T-cell counts (>350 cells/mm3). The TCP parameter that was the least restored among patients was the CD4:CD8 T-cell ratio. CONCLUSIONS: Failure to normalize the complete T-cell phenotype was most apparent in patients who initiated cART with a CD4+ T-cell count <200 cells/mm3. The impact of this impaired T-cell phenotype on life-long immune function and potential comorbidities remains to be elucidated.
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Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/tratamiento farmacológico , Sistema Inmunológico/efectos de los fármacos , Adulto , Recuento de Linfocito CD4 , Infecciones por VIH/inmunología , Humanos , Sistema Inmunológico/inmunología , Masculino , Persona de Mediana Edad , Fenotipo , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND: More than 200 primary immune deficiencies have been described. In adults, their identification can be difficult. The lack of timely referrals, diagnostic facilities, and available expertise often delay appropriate treatment. Because an increasing number of adults are now diagnosed with immune deficiencies, there is a need to better understand the immune deficits in this age group. The study objective was to analyze the diagnostic spectrum of adults with primary immune deficiency and to determine the presumptive diagnostic accuracy of the referring physicians. METHODS: We conducted a retrospective chart review over a 10-year period of all individuals referred to a dedicated center for adults with primary immune deficiency. Suspected cases were confirmed using standard clinical criteria and state of the art immune assays. RESULTS: Of the 381 individuals studied, 244 were diagnosed as immune deficient. Of these, 210 had primary immune deficiency classified as novel, defined, and undefined. Forty-three patients had a prior diagnosis and were referred for follow-up care, and 201 patients were newly diagnosed. Most patients had common variable immune deficiency. Despite an apparent high index of suspicion in initiating the referrals, only one third of these patients had a prior quantitative assessment of serum immunoglobulins. CONCLUSIONS: In this first known analysis of a large cohort of adults with suspected immune deficiency using established diagnostic criteria, we confirmed the diagnosis in two thirds of all patients. Our findings highlight the wide spectrum of primary immune deficiency states seen in adult medical practices and the need for increased awareness of their existence.
Asunto(s)
Síndromes de Inmunodeficiencia/diagnóstico , Centros Médicos Académicos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Diagnóstico Precoz , Femenino , Humanos , Síndromes de Inmunodeficiencia/clasificación , Síndromes de Inmunodeficiencia/epidemiología , Síndromes de Inmunodeficiencia/inmunología , Masculino , Persona de Mediana Edad , Pronóstico , Quebec , Derivación y Consulta , Estudios Retrospectivos , Adulto JovenRESUMEN
Expression of major histocompatibility complex (MHC) class I alleles such as B*57 and B*27 are associated with slow HIV disease progression. HIV-specific immune responses in slow progressors (SP) are characterized by a poly-functional profile. We previously observed within infected subjects that HIV peptide-specific responses could differ from each other in their functional composition. We investigate here whether responses restricted by MHC class I alleles associated with slow disease progression have a more poly-functional profile than responses restricted by other alleles. We stimulated peripheral blood mononuclear cells (PBMCs) isolated from 36 chronically HIV-infected individuals with a panel of optimal peptides restricted by the HLA alleles expressed by each subject, and assessed the contribution of single IL-2-, single IFN-γ-, and IFN-γ/IL-2-secreting lymphocytes to the total response measured using a dual color ELISPOT assay. The contribution of functional subsets to responses restricted by HLA B*57/B*27 was similar in SP and progressors. For responses restricted by other MHC class I alleles, dual IFN-γ/IL-2-secreting lymphocytes contributed significantly more to the total response in SP than progressors. Within SP subjects, peptides restricted by both B*57/B*27 and other alleles stimulated responses with similar functional profiles. In progressors, peptides restricted by B*57/B*27 stimulated responses composed of a significantly greater proportion of IFN-γ/IL-2-secreting cells than peptides restricted by other alleles. Within progressors, the contribution of IFN-γ/IL-2-secreting lymphocytes was greater to epitopes restricted by protective HLA alleles compared with responses restricted by other alleles. HLA haplotypes influence the relative functional composition of HIV-specific responses.
Asunto(s)
Infecciones por VIH/inmunología , VIH/inmunología , Antígenos HLA/inmunología , Subgrupos Linfocitarios/inmunología , Alelos , Antígenos Virales/inmunología , Células Cultivadas , Citocinas/metabolismo , Ensayo de Immunospot Ligado a Enzimas , Femenino , Sobrevivientes de VIH a Largo Plazo , Humanos , MasculinoRESUMEN
BACKGROUND: Elite controllers (EC) are a rare subset of HIV infected individuals who control viral load below 50 copies/ml of plasma without treatment. METHODS: Thirty four EC were studied. The slope of CD4 count change was available for 25 of these subjects. We assessed immune activation by measuring the percent of CD38+HLA-DR+CD8+ T cells in the EC group and comparing it with that in 24 treatment-naïve HIV disease progressors and 13 HIV uninfected healthy controls. RESULTS: Compared to HIV uninfected subjects, EC had higher percentages of CD38+HLA-DR+CD8+ T cells (p < 0.001) that was lower than that observed in progressors (p < 0.01). Fifteen of 25 EC had a slope of CD4 count change that was not significantly different from 0 while 3 had a positive and 7 a negative CD4 count slope. Immune activation did not distinguish EC subsets with stable/increasing versus declining CD4 counts. CONCLUSIONS: Elevated immune activation in ECs is not associated with a faster rate of CD4 decline.
RESUMEN
Carriage of the natural killer (NK) receptor genotype KIR3DL1*h/*y with its HLA-B*57 ligand (*h/*y+B*57) is associated with slow time to AIDS and low viral load (VL). To provide a functional basis for these epidemiological observations, we assessed whether HIV-1-infected slow progressors (SP) carrying the *h/*y+B*57 compound genotype would have increased NK cell polyfunctional potential in comparison to SP with other killer immunoglobulin-like receptor (KIR)/HLA compound genotypes and whether this enhanced polyfunctionality was dependent upon the coexpression of both KIR3DL1*h/*y and HLA-B*57. The functional potential of NK cells was investigated by stimulating peripheral blood mononuclear cells with HLA-devoid targets or single HLA transfectants. Multiparametric flow cytometry was used to detect NK cells with seven functional profiles representing all permutations of CD107a expression and gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) secretion. NK cells from individuals carrying KIR3DL1 receptor-HLA-Bw4 ligand pairs had greater trifunctional responses than those from KIR3DL1 homozygotes (hmz), who were Bw6 homozygotes. NK cells from subjects carrying the *h/*y+B*57 genotypes exhibited the highest trifunctional potential, and this was dependent on cocarriage of the NK receptor and its ligand. Trifunctional cells secreted more of each function tested on a per-cell basis than each corresponding monofunctional NK subset. Although VL influenced NK functionality, individuals with defined KIR/HLA genotypes exhibited differences in NK cell polyfunctionality that could not be accounted for by VL alone. The protective effect of HLA-B*57 on slow progression to AIDS and low VL may be mediated through its interaction with KIR3DL1 alleles to educate NK cells for potent activity upon stimulation.
Asunto(s)
Infecciones por VIH/inmunología , Sobrevivientes de VIH a Largo Plazo , VIH-1/inmunología , Antígenos HLA-B/metabolismo , Células Asesinas Naturales/inmunología , Receptores KIR3DL1/metabolismo , Adulto , Anciano , Femenino , Infecciones por VIH/virología , Antígenos HLA-B/genética , Humanos , Ligandos , Masculino , Persona de Mediana Edad , Receptores KIR3DL1/genética , Adulto JovenRESUMEN
Several combinations of genes encoding KIR3DL1 alleles and their HLABw4 ligands have been linked with favorable outcomes upon exposure to or infection with human immunodeficiency virus (HIV). Some protective KIR3DL1/HLABw4 combinations confer elevated natural killer (NK) cell functional potential. The K562stimulated functionality of NK cells from KIR3DL1*004/HLABw4 and control genotype carriers was assessed by flow cytometry and found to be higher in KIR3DL1*004/HLABw4 carriers. However, a comparison of the frequency of this combined genotype among HIVexposed uninfected and HIVinfected subjects revealed no betweengroup differences. Thus, despite its ability to license NK cells, KIR3DL1*004/HLABw4 is not associated with a reduced risk of infection.
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Infecciones por VIH/genética , Infecciones por VIH/inmunología , VIH/inmunología , Antígenos HLA-B/genética , Inmunidad Innata , Células Asesinas Naturales/inmunología , Receptores KIR3DL1/genética , Frecuencia de los Genes , HumanosRESUMEN
Epidemiological studies in humans have implicated carriage of combinations of genes encoding certain KIR3DL1 (killer Ig-like receptor 3DL1) alleles and their HLA-Bw4 ligands in slower progression to AIDS, lower viral load and protection from infection. Given that the KIR3DL1*h/*y/HLA-B*57 genetic combination is strongly associated with favorable HIV outcomes, we measured responses from NK cells isolated from these individuals by multiparametric flow cytometry for cytokine secretion and degranulation in response to stimulation with HLA-devoid cells to assess whether the KIR/HLA compound genotypes linked to better HIV outcome favor increased NK cell functional potential. Our results indicate that NK cells from these individuals had increased functional potential, particularly in the KIR3DL1(+) NK cell subset. These results support a link between KIR/HLA genotypes and NK cell function and could provide an explanation for the observation that some KIR/HLA combinations are associated protective phenotypes in the context of host-HIV interactions.
Asunto(s)
Infecciones por VIH/genética , Infecciones por VIH/inmunología , Antígenos HLA-B/genética , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Receptores KIR3DL1/genética , Línea Celular Transformada , Genotipo , Infecciones por VIH/prevención & control , VIH-1/inmunología , Antígenos HLA-B/metabolismo , Prueba de Histocompatibilidad , Humanos , Células K562 , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/virología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/virología , Activación de Linfocitos/genética , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Subgrupos Linfocitarios/virología , Receptores KIR3DL1/metabolismoRESUMEN
BACKGROUND: Despite the contraindications, stopping treatment for HIV infection continues to be a common practice. Understanding whether T-cell proliferative capacity and phenotypic markers before treatment interruption (TI) can predict CD4+ T-cell count change and nadir during TI would be clinically useful. METHODS: This retrospective study included 27 HIV-infected patients in the chronic phase of infection while on combination antiretroviral therapy (cART) who underwent a TI. Peripheral blood mononuclear cells from a baseline pre-TI time point were screened for T-cell proliferation to cytomegalovirus (CMV) lysate, an HIV Gag p55 peptide pool as well as positive and negative control stimuli. CD28 and CD57 expression on CD4+ and CD8+ T-cells were measured. RESULTS: Baseline viral load, CD4+ T-cell count, pre-cART nadir CD4+ T-cell and percentage CD4+CD28+ T-cells were all predictive of the lowest CD4+ T-cell count during TI (Spearman's correlation P<0.05 for all analyses). In addition, CD4+ and CD8+ T-cells proliferation to CMV lysate, baseline CD4+ T-cell count and percentage CD4+CD57+ T-cells correlated negatively with CD4+ T-cell decrease during TI (Spearman's correlation P<0.05 for all analyses). CONCLUSIONS: In treated chronic HIV-infected patients, pre-TI immune parameters are potential predictors for both the nadir CD4+ T-cell count and CD4+ T-cell count decrease during TI.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Carga Viral , Adulto , Biomarcadores/análisis , Antígenos CD28/metabolismo , Recuento de Linfocito CD4 , Antígenos CD57/metabolismo , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Células Cultivadas , Enfermedad Crónica , Infecciones por VIH/virología , Humanos , Valor Predictivo de las Pruebas , Estudios RetrospectivosRESUMEN
OBJECTIVES: Coexpression of certain combinations of natural killer cell receptor KIR3DL1 and HLA-B alleles is associated with slower time to AIDS. The strongest protection in terms of disease outcome in KIR3DL1 homozygotes (3DL1 hmz) is coexpression of HLA-B*57 and a set of KIR3DL1 genotypes (3DL1*h/*y) lacking alleles expressed at low levels on natural killer cells. We questioned whether this allele combination could also influence resistance to infection. DESIGN: The genetic distribution of 3DL1*h/*y and HLA-B*57 was compared in 41 HIV-exposed uninfected and 186 recently HIV-infected 3DL1 hmz. METHODS: KIR3DL1 subtyping was performed by sequencing the exons 3, 4, 5, 7-9. The major histocompatibility complex class IB locus was typed by sequence specific oligonucleotide PCR and sequencing to resolve Bw4 and Bw6 alleles and the amino acid present at position 80. RESULTS: Percentage carriers of HLA-B*57 in HIV-exposed uninfected and individuals in a primary infection cohort was 12.2 and 4.3%, respectively (P = 0.0631), whereas that of 3DL1*h/*y was similar in both populations (P = 0.221). The 3DL1*h/*y-HLA-B*57 combined genotype was more frequent in exposed uninfected individuals (12.2%) than individuals in primary infection (2.7%) (P = 0.019; odds ratio, 5.03; 95% confidence intervals, 1.38-18.3). CONCLUSION: Coexpression of 3DL1*h/*y and B*57, which has been associated with a reduced risk of progressing to AIDS in HIV-infected individuals also lowers the risk of HIV infection in exposed uninfected individuals.
Asunto(s)
Infecciones por VIH/genética , VIH-1 , Antígenos HLA-B/genética , Receptores KIR3DL1/genética , Alelos , Células Cultivadas , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Infecciones por VIH/inmunología , Humanos , Inmunidad Innata/genéticaRESUMEN
In the present study, we assessed whether Gag-specific interferon (IFN)-gamma secreting responses correlate with the rate of disease progression as defined by the annual rate of CD4 decline. Although neither the breadth nor the magnitude of the proteome-wide HIV-specific IFN-gamma response correlated with viral load or rate of CD4 decline, the preferential targeting of Gag is associated with slower annual CD4 T cell decline.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Genes gag/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Interferón gamma/metabolismo , Linfopenia/inmunología , Adolescente , Adulto , Progresión de la Enfermedad , Humanos , Inmunidad Celular , Persona de Mediana Edad , Carga ViralRESUMEN
BACKGROUND: The advantage of treatment interruptions (TIs) in salvage therapy remains controversial. Regardless, characterizations of the correlates of CD4 count fall during TI are important to identify since patients with virologic failure commonly stop antiretroviral (ARV) therapy. The objective of this study was to determine the predictive value of pre-TI proliferative capacity and cell surface markers for CD4 count change in HIV-infected patients experiencing virologic failure before undergoing TI. METHODS: Peripheral blood mononuclear cells (PBMCs) from 13 HIV-infected patients experiencing virologic failure at baseline time points before the TI were tested for proliferation using the 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution assay and a Gag p55 peptide pool, staphylococcus enterotoxin B (SEB), cytomegalovirus (CMV) recall antigen, and anti-CD3 antibody as stimuli. CD28 and CD57 expression on CD4+ and CD8+ T-cells was measured. RESULTS: The median changes in the CD4+ T-cell count and viral load from baseline to the TI time point corresponding to the CD4 count nadir were -44 cells/mm3 {Interquartile range (IQR) -17, -104} and +85,332 copies/mL (IQR +11,198, +283,327), respectively. CD4+ T-cell proliferation to CMV, pre-TI CD4+ T-cell count, and percent CD4+CD57+ cells correlated negatively with CD4 count change during TI (r = -0.59, p = 0.045, r = -0.61, p = 0.030 and r = -0.69, p = 0.0095, respectively; Spearman correlation). The presence of HIV-specific proliferative responses was not associated with a reduced decline in CD4 count during TI. CONCLUSION: The use of pre-TI immune proliferative responses and cell surface markers may have predictive value for CD4 count decline during TI.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Antígenos CD57/metabolismo , Farmacorresistencia Viral , Infecciones por VIH , Activación de Linfocitos/inmunología , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Citomegalovirus/inmunología , Esquema de Medicación , Quimioterapia Combinada , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Humanos , Masculino , Valor Predictivo de las Pruebas , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Terapia Recuperativa , Carga ViralRESUMEN
Evidences have recently suggested that the preservation of vaccine-induced memory rather than effector T cells is essential for better outcome and survival following pathogenic SIV challenge in macaques. However, an equivalent demonstration in humans is missing, and the immune correlates of HIV-1 control have been only partially characterized. We focused on the quantification of Ag-specific T cell precursors with high proliferative capacity (PHPC) using a peptide-based cultured IFN-gamma ELISPOT assay (PHPC assay), which has been shown to identify expandable memory T cells. To determine which responses correlate with viral suppression and positive immunologic outcome, PBMC from 32 chronically untreated HIV-1-infected individuals were evaluated in response to peptide pools, representing the complete HIV-1 Gag, Nef, and Rev proteins, by PHPC and IFN-gamma ELISPOT assay, which instead identifies effector T cells with low proliferative capacity. High magnitude of Gag-specific PHPC, but not ELISPOT, responses significantly correlated with low plasma viremia, due to responses directed toward p17 and p15 subunits. Only Gag p17-specific PHPC response significantly correlated with high CD4 counts. Analysis of 20 additional PBMC samples from an independent cohort of chronically untreated HIV-1-infected individuals confirmed the correlation between Gag p17-specific PHPC response and either plasma viremia (inverse correlation) or CD4 counts (direct correlation). Our results indicate that the PHPC assay is quantitatively and qualitatively different from the ELISPOT assay, supporting that different T cell populations are being evaluated. The PHPC assay might be an attractive option for individual patient management and for the design and testing of therapeutic and prophylactic vaccines.
Asunto(s)
Recuento de Linfocito CD4 , Proliferación Celular , Infecciones por VIH/inmunología , VIH-1/inmunología , Células Precursoras de Linfocitos T/inmunología , Viremia/inmunología , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/metabolismo , Animales , Enfermedad Crónica , Estudios de Cohortes , Femenino , Proteína p24 del Núcleo del VIH/inmunología , Proteína p24 del Núcleo del VIH/metabolismo , Infecciones por VIH/sangre , Infecciones por VIH/prevención & control , VIH-1/metabolismo , Humanos , Memoria Inmunológica , Interferón gamma/inmunología , Interferón gamma/metabolismo , Macaca , Masculino , Células Precursoras de Linfocitos T/metabolismo , Células Precursoras de Linfocitos T/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Virus de la Inmunodeficiencia de los Simios/metabolismo , Viremia/prevención & controlRESUMEN
OBJECTIVES: Natural killer (NK) cell activity is increased in individuals who remain uninfected despite repeated exposures to HIV. Given that a combined major histocompatibility complex (MHC) class I and killer immunoglobulin-like receptor (KIR) KIR3D genotype has been linked to rate of HIV disease progression, we assessed whether these genotypes played a role in protection from infection. DESIGN: The study genotyped 80 HIV-exposed uninfected (EU) and 304 subjects in HIV primary infection (PI) at the MHC class IB and KIR3DS/L1 loci. METHODS: KIR3D genotyping was performed by sequence-specific primer polymerase chain reaction using two pairs of specific primers for each locus. The MHC class IB locus was typed by sequence-specific oligonucleotide polymerase chain reaction and sequencing to resolve Bw4 and Bw6 alleles and the amino acid present at position 80. RESULTS: Comparison of the genetic distribution of KIR3D, HLA Bw4 and HLA Bw4-I80 genotypes in EU versus PI subjects reveal an increased proportion of KIR3DS1 homozygotes in EU (11/80, 13.8%) compared to subjects in PI (16/304, 5.3%). Analyses of combined MHC class I and KIR3D expression show no differences between the two populations. CONCLUSIONS: Homozygosity for the activating NK receptor KIR3DS1, may contribute to the more active NK cell function observed in EU and their relative resistance to HIV infection.