RESUMEN
BACKGROUND: The World Health Organization (WHO) has developed the Integrated Care for Older People (ICOPE) strategy to face the challenges of ageing societies. This strategy is focused on person centered care and the assessment intrinsic capacity (IC). Early identification of five domains of IC (cognition, locomotion, vitality, sensory (hearing and vision), and psychological) has been shown to be related with adverse outcomes and can guide actions towards primary prevention and healthy ageing. IC assessment proposed by the WHO ICOPE guidelines is composed by two steps: First, Screening for decreased IC by the ICOPE Screening tool; second, by the reference standard methods. The aim was to assess the performance of diagnostic measures (sensibility, specificity, diagnostic accuracy, and agreement of the ICOPE Screening tool) compared to the reference standard methods in European community-dwelling older adults. METHODS: Cross-sectional analysis of the baseline of the ongoing VIMCI (Validity of an Instrument to Measure Intrinsic Capacity) cohort study, which was carried out in Primary Care centers and outpatient clinics from 5 rural and urban territories in Catalonia (Spain). Participants were 207community dwelling persons ≥ 70-year-old with Barthel ≥ 90, without dementia or advanced chronic conditions who provided their consent to participate. The 5 IC domains were assessed by the ICOPE Screening tool and the reference methods (SPPB, gait speed, MNA, Snellen chart, audiometry, MMSE, GDS5) during patients' visit. Agreement was assessed with the Gwet AC1 index. RESULTS: ICOPE Screening tool sensitivity was higher for cognition (0.889) and ranged between 0.438 and 0.569 for most domains. Specificity ranged from 0.682 to 0.96, diagnostic accuracy from 0.627 to 0.879, Youden index from 0.12 to 0.619, and Gwet AC1 from 0.275 to 0.842. CONCLUSION: The ICOPE screening tool showed fair performance of diagnostic measures; it was helpful to identify those participants with satisfactory IC and showed a modest ability to identify decreased IC in older people with high degree of autonomy. Since low sensitivities were found, a process of external validation would be recommended to reach better discrimination. Further studies about the ICOPE Screening tool and its performance of diagnostic measures in different populations are urgently required.
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Envejecimiento , Vida Independiente , Humanos , Anciano , Estudios de Cohortes , Estudios Transversales , EspañaRESUMEN
BACKGROUND: HIV-2 infection is characterized by low plasma viraemia and slower progression to AIDS in comparison with HIV-1 infection. However, antiretroviral therapy in patients with HIV-2 is less effective and often fails to provide optimal CD4 recovery. METHODS: We examined viral tropism in persons with HIV-2 infection enrolled in the HIV-2 Spanish cohort. Viral tropism was estimated based on V3 sequences obtained from plasma RNA and/or proviral DNA. RESULTS: From a total of 279 individuals with HIV-2 infection recorded in the Spanish national register, 58 V3 sequences belonging to 42 individuals were evaluated. X4 viruses were recognized in 14 patients (33%). Patients with X4 viruses had lower median CD4+ cell counts than patients with R5 viruses [130 (17-210) versus 359 (180-470) cells/mm(3); Pâ=â0.007]. This was true even considering only the subset of 19 patients on antiretroviral therapy [94 (16-147) versus 184 (43-368) cells/mm(3); Pâ=â0.041]. In multivariate analysis, significant differences in CD4+ cell counts between patients with X4 and R5 viruses remained after adjusting for age, gender, antiretroviral therapy and viral load. CONCLUSIONS: The presence of X4-tropic viruses in HIV-2 infection is associated with low CD4+ cell counts, regardless of antiretroviral treatment. Along with CD4+ cell counts, viral tropism testing may assist decisions about when to initiate antiretroviral therapy in HIV-2-infected individuals.
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Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-2/fisiología , Tropismo Viral/fisiología , Adulto , Antagonistas de los Receptores CCR5/uso terapéutico , Recuento de Linfocito CD4 , Ciclohexanos/uso terapéutico , Femenino , Proteína gp120 de Envoltorio del VIH/sangre , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , VIH-2/clasificación , VIH-2/inmunología , Humanos , Masculino , Maraviroc , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , ARN Viral/sangre , España , Triazoles/uso terapéutico , Carga Viral , Tropismo Viral/inmunología , Viremia/sangreRESUMEN
Interleukin 28B (IL28B) rs12979860 polymorphisms were examined in 41 individuals with human T-lymphotrophic virus type 1 (HTLV-1). The alleles CT/TT were more frequent in 12 individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis than in 29 asymptomatic carriers (80% vs 20%; P = .03), and median HTLV-1 proviral load was greater in CT/TT than CC carriers (P = .01). Thus, IL28B testing and closer follow-up of HTLV-1 asymptomatic CT/TT carriers is warranted.
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Virus Linfotrópico T Tipo 1 Humano , Interleucinas/genética , Paraparesia Espástica Tropical/genética , Paraparesia Espástica Tropical/inmunología , Adolescente , Adulto , Análisis de Varianza , Portador Sano/inmunología , Portador Sano/virología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Interferones , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Paraparesia Espástica Tropical/virología , Polimorfismo Genético , EspañaRESUMEN
HIV-specific T cells response and T cell activation are frequently seen in exposed seronegative individuals (ESN). In this study, we report HIV-specific response and level of T cell activation in ESN partners of HIV-infected patients presenting low or undetectable levels of HIV-RNA. We evaluated 24 HIV-serodiscordant couples. ESN were classified into three categories of exposure to HIV (very low, low, and moderate-high), considering levels of HIV-RNA in their infected partner and frequency of sexual high-risk practices within the last 12 mo. HIV-specific T cell responses and activation levels in T cell subsets were evaluated by flow cytometry. We reported that 54% of ESN had detectable HIV-specific T cells response, being the highest prevalence seen in the low exposure group (64%). Several T cell subsets were significantly increased in ESN when compared with controls: CD4(+)CD38(+) (p = 0.006), CD4(+)HLA-DR(-)CD38(+) (p = 0.02), CD4(+)CD45RA(+)CD27(+)HLA-DR(-)CD38(+) (p = 0.002), CD8(+)CD45RA(+)CD27(+)CD38(-)HLA-DR(+) (p = 0.02), and CD8(+)CD45RA(+)CD27(-)CD38(+)HLA-DR(+) (p = 0.03). Activation of CD8(+) T cells was increased in ESN with detectable HIV T cell responses compared with ESN lacking these responses (p = 0.04). Taken together, these results suggest that persistent but low sexual HIV exposure is able to induce virus-specific T cells response and immune activation in a high proportion of ESN, suggesting that virus exposure may occur even in conditions of maximal viral suppression in the HIV-infected partner.
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Seronegatividad para VIH/inmunología , VIH/inmunología , Activación de Linfocitos/inmunología , Linfocitos T/inmunología , ADP-Ribosil Ciclasa 1/sangre , Adulto , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Quimiocina CCL4/sangre , Femenino , Citometría de Flujo , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , Antígenos HLA-DR/sangre , Humanos , Interferón gamma/sangre , Masculino , Persona de Mediana Edad , Linfocitos T/citología , Linfocitos T/metabolismoRESUMEN
INTRODUCTION: Current information on cardiovascular risk (CVR) in HIV-infected patients in Spain is limited. METHODS: An analysis was made of a prospective multicentre cohort of Spanish HIV-infected patients (CoRIS) between January-2010 and July-2011. CVR was evaluated using Framingham, REGICOR and SCORE equations. RESULTS: The study included 1019 patients (76% males, mean age 40 years) recruited from 13 hospitals belonging to 10 autonomous communities in Spain. Almost two-thirds (65.4%) of patients were on antiretroviral therapy (ART), 36.7% with non-nucleoside analogs, 24% with protease inhibitors (PIs) (52% with atazanavir/r or darunavir/r) and 4,6% with raltegravir. More than half (56.2%) of the patients had an HIV viral load <50 copies/ml. Smoking prevalence was 46%, HDL cholesterol (HDL-C) <40mg/dl 36.1%, total cholesterol (total-C) >200mg/dl 27.8%, age >45years 27.2%, metabolic syndrome 11.5%, hypertension 9.4%, cocaine use 7%, and diabetes 2.9%. ART was associated with higher total-C and LDL-C concentrations, although also higher HDL-C and lower total-C/HDL-C ratio; patients receiving PIs boosted with a high ritonavir dose showed higher total-C levels and higher total-C/HDL-C ratio. According to Framingham cardiovascular, and coronary, REGICOR, and SCORE equations, 15.2%, 6.4%, 4.2% and 3.9% of patients, respectively, were classified as having moderate or high CVR. CONCLUSION: In HIV-infected patients from CoRIS, prevalence of modifiable CVR factors is still high. Commonly used scores identify a relatively low number of patients with high CVR.
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Enfermedades Cardiovasculares/etiología , Infecciones por VIH/complicaciones , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , EspañaRESUMEN
Studies in long-term non-progressors (LTNP) have suggested that the quality of the CD8(+) response may involve protective human leucocyte antigen (HLA) class I alleles. However, studies examining the expansion ability of different functional CD8(+) T cells and their association with HLA class I alleles are lacking. LTNP, untreated typical progressors (TP) and patients successfully on highly active retroviral therapy (HAART) during 1 year (HP) were included. HLA class I typing was performed using a sequence-specific primer assay. Functional subsets of Gag- and Nef-specific CD8(+) cells were analysed based on the production of macrophage inflammatory protein (MIP)-1ß, tumour necrosis factor (TNF)-α and interleukin (IL)-2. Their expansion abilities were evaluated after 10-day culture in the presence of Gag and Nef human immunodeficiency virus (HIV) peptides. No differences were seen when comparing quantitative and qualitative HIV-specific CD8(+) T cell responses according to the presence/absence of protective HLA alleles (B*58 and B*27 supertypes) in each group. However, LTNP with protective HLA alleles showed a higher expansion ability of Gag-specific MIP(+) TNF(+) IL-2(+) T cells and Nef-specific MIP(+) TNF(+) IL-2(+) . HLA-B*5701+LTNP displayed a higher expansion ability of Gag and Nef-specific MIP(+) TNF(-) IL-2(+) T cells than HLA-B*5701-LTNP. This was not so for HLA-B*2705. No differences were seen in the expansion ability according to the presence/absence of protective HLA alleles in TP and HP. The expansion ability of polyfunctional CD8(+) T cells is modulated by HLA class I alleles and targeted protein. LTNP with HLA class I protective alleles (mainly B*5701) display better expansion ability of polyfunctional HIV-specific CD8(+) T cells than the rest, suggesting that factors other than HLA-B*5701 must contribute to the control of viral replication in other LTNP. Furthermore, these attributes of HIV-specific CD8(+) T are not restored by HAART; thus, adjuvant therapies and vaccines that induce and/or normalize the expansion ability of HIV-specific T cells are required.
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Linfocitos T CD8-positivos/inmunología , Sobrevivientes de VIH a Largo Plazo , VIH/inmunología , Antígenos HLA-B/inmunología , Adulto , Alelos , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular , Células Cultivadas , Quimiocina CCL4/inmunología , Quimiocina CCL4/metabolismo , Femenino , Frecuencia de los Genes , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Antígenos HLA-B/genética , Antígeno HLA-B27/genética , Antígeno HLA-B27/inmunología , Humanos , Interleucina-2/inmunología , Interleucina-2/metabolismo , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Replicación Viral/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
Interleukin 17 (IL17) secreting T (Th17) cells play a protective role against bacterial infections at mucosal surfaces. Recent reports show Th17 cells are depleted in the gut associated lymphoid tissue of HIV+ patients, but their role in HIV disease progression is not well understood. Expression of the IL17 receptor (IL17R) and the production of IL17 were compared between two groups of HIV patients with different disease progression (long-term-nonprogressors, LTNP and typical-progressors, TP). IL17R expression was similar in LTNP and TP, whereas Th17 cell number was greater in LTNP than TP (p=0.015). An inverse correlation between the plasma HIV-RNA and both IL17R expression and Th17 cell number was found (p=0.001 and p=0.002, respectively). The increased number of Th17 cells in LTNP could lead to a more preserved immune response against bacterial infections. As a result, lower microbial translocation could explain the reduced immune activation and slower disease progression seen in LTNP.
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Progresión de la Enfermedad , Infecciones por VIH/inmunología , Sobrevivientes de VIH a Largo Plazo , Células Th17/inmunología , Adulto , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Estudios Transversales , Femenino , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Receptores de Interleucina-17/metabolismo , Carga Viral/inmunologíaRESUMEN
BACKGROUND: HIV accelerates hepatitis C virus (HCV)-induced liver fibrosis by mechanisms not well understood. As HIV dysregulates transforming growth factor-ß1 (TGF-ß1) and T regulatory (Treg) cells, both of which are involved in hepatic fibrogenesis, herein we describe their influence on liver fibrosis staging in patients with chronic hepatitis C with and without HIV coinfection. METHODS: Eighty-eight subjects (42 HIV/HCV co-infected patients, 20 HCV-monoinfected patients, and 26 healthy controls) were examined. Treg cells (CD4+Foxp3+) were measured in peripheral blood using flow cytometry. An enzyme immunoassay was used to measure TGF-ß1 in plasma. Liver fibrosis staging was estimated using elastometry and advanced liver fibrosis was considered for ≥ 9·5 kPa (F3-F4 Metavir estimates). RESULTS: Treg cells were increased in HIV/HCV-coinfected patients compared with HCV-monoinfected patients (P = 0·004), whereas TGF-ß1 levels were similar in both groups of patients. While Treg cells levels were similar in both null-mild and advanced liver fibrosis patients, a high level of TGF-ß1 was found in patients with low levels of liver fibrosis compared with those with advanced liver fibrosis [14·9 ng mL(-1) (5·6-37·9) vs. 5·5 ng mL(-1) (1·9-7·9) respectively P = 0·007]. In a multivariate logistic regression model, elevated TGF-ß1 levels were significantly associated with not having advanced liver fibrosis [OR: 0·13 (95% CI: 0·02-0·71), P = 0·019]. CONCLUSIONS: While Treg cells do not influence liver fibrosis staging, elevated TGF-ß1, probably through its anti-inflammatory effects, might protect HCV/HIV-coinfected patients from liver fibrosis.
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Infecciones por VIH/complicaciones , Hepatitis C Crónica/complicaciones , Factor de Crecimiento Transformador beta1/metabolismo , Adulto , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Técnicas para Inmunoenzimas , Cirrosis Hepática/complicaciones , Cirrosis Hepática/prevención & control , Masculino , Persona de Mediana Edad , Factor de Crecimiento Transformador beta1/sangreRESUMEN
Congenital hypopituitarism due to pituitary stalk and anterior pituitary hypoplasia accompanied by an ectopic posterior pituitary lobe is a rare disorder causing multiple hormone deficiencies. Clinical signs can be present at birth (hypoglycemia, prolonged jaundice and micropenis) and there can be severe growth restriction. Therefore, diagnosis is usually performed in childhood. We present the uncommon case of a 67-year-old man with hypopituitarism due to hypoplasia of the anterior pituitary and pituitary stalk together with an ectopic posterior pituitary who presented symptoms of hyponatremia due to adrenocorticotropic hormone deficiency.
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Encefalopatías/complicaciones , Coristoma/complicaciones , Hipopituitarismo/etiología , Adenohipófisis/anomalías , Neurohipófisis , Edad de Inicio , Anciano , Encefalopatías/diagnóstico , Encefalopatías/patología , Coristoma/diagnóstico , Coristoma/patología , Traumatismos Craneocerebrales/complicaciones , Trastorno Depresivo/complicaciones , Enanismo Hipofisario/etiología , Terapia de Reemplazo de Hormonas , Humanos , Hipopituitarismo/tratamiento farmacológico , Hipopituitarismo/epidemiología , MasculinoRESUMEN
Cellular immune responses play an important role in the control of HIV replication. Although clear evidence exists on its influence during acute HIV infection, its role during the chronic phase of the disease remains controversial. This review describes the cellular immune responses elicited against HIV mediated by CD8(+) T lymphocytes, and the mechanisms by which these cells are inefficient to completely control HIV replication and halt disease progression. The role of escape mutations as one of the most relevant mechanisms HIV has developed to evade host cellular immune responses is highlighted.
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Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , Inmunidad Celular/inmunología , Mutación/genética , VIH/fisiología , Infecciones por VIH/transmisión , Humanos , Replicación ViralRESUMEN
BACKGROUND: Human T cell lymphotropic virus type 2 (HTLV-2) infection is not rare among injection drug users with human immunodeficiency virus (HIV) infection and may exert a protective role in the progression of HIV disease. METHODS: Immunological and virological parameters were compared in HIV-HTLV-2-coinfected patients and a control group of HIV-monoinfected subjects. All individuals were antiretroviral therapy naive. HIV-specific CD8+ T cell levels were measured using an interferon-gamma assay in response to 125 optimally defined HIV peptides divided into 5 pools. Immune activation was evaluated by measuring levels of CD38 in different CD4+ and CD8+ T cell subsets. In a subgroup of patients, the production of CCL4 in parallel with interferon-gamma was assessed in response to Gag peptides. RESULTS: Lower plasma HIV-RNA levels were found in HIV-HTLV-2-coinfected patients than in HIV-monoinfected patients, despite the 2 groups having similar CD4+ T cell counts. Coinfected patients also had significantly lower levels of CD38 expression in total CD8+ T cells and in its naive subset. CD8+ T cell levels specific for each pool of peptides were similar in both groups, but cells mainly contributing to HIV Gag-specific responses in coinfected patients were CCL4 positive and interferon-gamma negative, whereas for HIV-monoinfected subjects, the response was dominated by CCL4-positive and interferon-gamma-positive cells. CONCLUSIONS: HTLV-2 coinfection may exert a protective role on HIV disease progression by lowering HIV replication and immune activation. A predominance of CCL4 single positive HIV-specific CD8+ T cells in HIV-HTLV-2-coinfected patients could explain this effect.
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Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/patogenicidad , Infecciones por HTLV-II/complicaciones , Interferón gamma/biosíntesis , Proteínas Inflamatorias de Macrófagos/metabolismo , Linfocitos T CD8-positivos/inmunología , Quimiocina CCL4 , Femenino , Infecciones por VIH/complicaciones , VIH-1/inmunología , VIH-1/fisiología , Virus Linfotrópico T Tipo 2 Humano/patogenicidad , Virus Linfotrópico T Tipo 2 Humano/fisiología , Humanos , Activación de Linfocitos , Masculino , ARN Viral/sangre , Linfocitos T/inmunología , Replicación ViralRESUMEN
To test the role of hepatitis C virus (HCV) in CD4 cell depletion in human immunodeficiency virus (HIV)-coinfected patients, T cell apoptosis was measured by annexin V labeling in 31 HIV-infected and 30 HIV-HCV-coinfected patients who were not receiving antiretroviral therapy. Apoptosis in naive CD4(+) T cells and in naive and memory CD8(+) T cells was significantly higher in HIV-HCV-coinfected than in monoinfected patients.
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Fármacos Anti-VIH/farmacología , Apoptosis/efectos de los fármacos , Infecciones por VIH/patología , Hepatitis C/patología , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/patología , Infecciones por VIH/inmunología , Hepatitis C/inmunología , HumanosRESUMEN
The role of cytotoxic T lymphocyte responses in controlling viral replication during chronic HIV infection remains controversial. Viral escape mutations driven by immune pressure have been postulated to be an important mechanism contributing to the evasion of CD8(+) T cell responses. To explore this issue in more detail, HIV-1 p17 sequence variability was examined in chronically HIV-infected patients, in parallel with the level, phenotype, and function of HIV-SL9-specific CD8(+) T cell. Thirty-one HLA-A*0201(+) (A2(+)) and 10 HLAA* 02() (A2()) patients were included. The phenotype of SL9-specific CD8(+) T cell and their ability to produce IFN-gamma were analyzed by multiparameter flow cytometry. The HIV Gag p17 was sequenced and the mean variability score for each residue within SL9 and the two epitope flanking regions were calculated using Shannon entropy. The mean variability of SL9 and the proportion of patients with amino acid changes within SL9 were similar in A2(+) and A2() patients. Patients without Tet(+) cells had a significantly higher prevalence of aminoacid changes in SL9 than patients with Tet(+) cells. Interestingly, in patients with Tet(+) cells, the Y79F mutation within SL9 tended to be associated with lower levels of Tet(+) cells. We did not find any association between amino acid changes within SL9 and the differentiation stage of Tet(+) cells, or with IFN-gamma production. A similar analysis within the epitope flanking sequences did not reveal differences in the variability of these regions. These results suggest that viral mutations driven by immune selection pressure may play an important role in evading the immunological response in chronically HIV-infected individuals.
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Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito T/inmunología , Productos del Gen gag/inmunología , Genes gag/genética , Infecciones por VIH/inmunología , VIH-1/genética , Fragmentos de Péptidos/inmunología , Linfocitos T CD8-positivos/virología , Distribución de Chi-Cuadrado , Productos del Gen gag/genética , Infecciones por VIH/genética , VIH-1/inmunología , Antígenos HLA-A/inmunología , Humanos , Datos de Secuencia Molecular , Mutación , Fragmentos de Péptidos/genética , Fenotipo , Receptores de Antígenos de Linfocitos T/inmunología , Selección Genética , Especificidad del Receptor de Antígeno de Linfocitos T/genética , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia HumanaRESUMEN
Both hydroxyurea (HU) and structured treatment interruptions (STI) have been investigated as therapeutic approaches to enhance immune responses in chronically HIV-infected individuals. HIV-specific T cell responses as well as T cell activation were analyzed longitudinally in 31 HIV-infected individuals who had been treated for the prior 12 months with didanosine (ddI) plus HU and thereafter completed three STI cycles consisting of 2 months off and 2 months on ddI-HU. Similar increases in plasma HIV-RNA were seen in each of the three cycles off therapy, whereas CD4 counts remained fairly stable along the study period. T cell activation paralleled the evolution of plasma HIV-RNA during the first STI cycle and waned afterward. At baseline most patients presented a high level of CD8+ responses to different HIV peptide pools and 23% of them had CD4+ responses to Gag and/or Env. The level of CD8+ responses against each pool was stable and did not increase during STI cycles, while CD4 responses tended to decline. However, the contribution of Nef-specific response to the total CD8 response tended to increase. In a multivariate model, both a higher baseline plasma HIV-RNA and a higher level of Nef-specific response contribution to the total CD8+ response were independently associated with lower plasma HIV-RNA increases during each of the three STI cycles. Nef-specific CD8+ responses might contribute to a better virological control of HIV replication following treatment interruptions in HIV-infected individuals and might be boosted by the immunomodulatory effect of HU.
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Fármacos Anti-VIH/administración & dosificación , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD8-positivos/efectos de los fármacos , Didanosina/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Hidroxiurea/administración & dosificación , ADP-Ribosil Ciclasa 1/metabolismo , Adulto , Fármacos Anti-VIH/inmunología , Terapia Antirretroviral Altamente Activa/métodos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Distribución de Chi-Cuadrado , Didanosina/inmunología , Quimioterapia Combinada , Femenino , Productos del Gen nef/sangre , Infecciones por VIH/inmunología , Humanos , Hidroxiurea/inmunología , Inmunidad Celular , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Análisis de Regresión , Productos del Gen nef del Virus de la Inmunodeficiencia HumanaRESUMEN
CD8+ T-cells with cytotoxic (CTL) activity play a pivotal role in controlling viral infections. Although most patients chronically infected with HIV have CTL response against the virus, for reasons that are not well understood this response is not able to successfully control viral replication. The crucial role of this type of response has been clearly demonstrated in the setting of acute infection using the simian model of AIDS, in which a strong CTL response develops, supporting its role in humans. This approach has been possible due to the development of new assays to quantify CTL activity with great sensitivity and specificity. The interaction of CTL response and HIV during this acute stage of infection is crucial, since it most probably determines the viral set-point and thus the rate of HIV disease progression. In the setting of chronic HIV infection, the use of tetrameric complexes and IFN-gamma production assays have made it possible to investigate the different functional aspects of these cells and have also facilitated the evaluation of this response in large patient populations. Defects in cytokine production and in perforin expression have been found, as well as alterations in phenotypic maturation and a low proliferation of these cells. All these findings have been cited to explain the inability of CTLs to efficiently control virus replication. Nonetheless, accumulating evidence points toward an important role for CTL response in the partial containment of HIV replication in chronic infection. An especially strong support for this observation derives from studies analyzing the selective pressure exerted by the immune response over viral evolution. Very recently, longitudinal and cross-sectional studies in large populations of patients have demonstrated that viral evolution is in part driven by HIV-specific T-cell responses.
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Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/crecimiento & desarrollo , Linfocitos T Citotóxicos/inmunología , Animales , Infecciones por VIH/virología , VIH-1/inmunología , Humanos , Activación de Linfocitos/inmunología , Macaca , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunologíaRESUMEN
BACKGROUND: The role of hydroxyurea (HU) in the treatment of HIV infection remains controversial. HU potentiates didanosine (ddI) antiviral activity and might exert immunomodulatory effects. PATIENTS AND METHODS: Immunologic parameters were examined in HIV-infected patients enrolled in a simplification trial in which ddI-HU was provided to subjects who had been on complete virus suppression under highly active antiretroviral therapy (HAART) for longer than 6 months. A total of 84 of these patients showed plasma viraemia repeatedly below 5000 HIV-RNA copies/ml, and were the main study population. A group of 22 patients who continued on HAART and another of 22 drug-naive HIV-positive individuals were taken as controls. RESULTS: At 12 months, the levels of naive and memory T-cell subsets were similar in patients on ddI-HU and under HAART, whereas immune activation tended to be lower in the former group. The frequency of HIV-specific CD8+ T cells (CTL) directed against 125 peptides derived from Gag, Pol, Env, Nef and HIV regulatory proteins was similar among patients on ddI-HU and untreated controls, and significantly higher than in patients under HAART. This higher CTL response in patients on ddI-HU was seen even when considering only subjects with undetectable viral load. HIV-specific CD4+ T-cell responses were absent in almost all patients on HAART, whereas they were present in up to 19% of patients on ddI-HU. CONCLUSION: Treatment with ddI-HU provides higher levels of HIV-specific CD8+ and CD4+ T-cell responses than standard triple drug regimens. Thus, hydroxyurea might exert a beneficial immunomodulatory effect in HIV infection.
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Fármacos Anti-VIH/uso terapéutico , Didanosina/uso terapéutico , Infecciones por VIH/inmunología , VIH-1/inmunología , Hidroxiurea/uso terapéutico , Inhibidores de la Síntesis del Ácido Nucleico/uso terapéutico , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Estudios de Casos y Controles , Estudios Transversales , Quimioterapia Combinada , Estudios de Seguimiento , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Inmunofenotipificación , Interferón gamma/inmunología , ARN Viral/análisis , Receptores de Antígenos de Linfocitos T/genética , Carga ViralRESUMEN
The level of CD8+ CD38+ T lymphocytes in blood correlates with disease progression in HIV-infected individuals, independently of the CD4 count. Effective antiretroviral therapy reduces this lymphocyte subset in parallel with plasma viremia, although CD38 expression on CD8+ cells does not normalize completely in most subjects, and might reflect residual HIV replication. The expression of CD38 on CD8+ cells (as number of CD38 molecules per CD8+ cell) was measured quantitatively by flow cytometry in 200 individuals, of whom 170 were HIV positive and 30 were HIV-uninfected controls. Forty-six HIV-infected subjects were on antiretroviral therapy and had undetectable viral load. The remaining 124 HIV-positive persons were not on therapy and had detectable plasma viremia. The mean level of CD38 on CD8+ cells was higher in HIV-positive, untreated patients than in subjects on antiviral therapy and controls (5023, 2029, and 1978 molecules per CD8+ cell, respectively, p < 0.01). In HIV-positive, untreated subjects, the higher CD38 expression mainly occurred on CD45RO+ CD8+ cells. The level of CD38 strongly correlated with plasma HIV-RNA (r = 0.63, p < 0.001). The levels of CD38 on CD8+ cells declined steadily in HIV-positive subjects after beginning antiretroviral therapy. A few individuals presented viral blips whereas being on antiviral treatment, levels of CD38 on CD8+ cells increased transiently in parallel with episodes of viral replication. Levels of CD38 on CD8+ cells are increased in chronic HIV infection, and strongly correlate with plasma viremia. The slow decline of CD38 expression on CD8+ cells over time in subjects with undetectable plasma viremia while being on antiretroviral therapy suggests that CD38 expression on CD8+ cells could be used as a marker of residual virus replication.
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ADP-Ribosil Ciclasa/metabolismo , Antígenos CD/metabolismo , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , ADP-Ribosil Ciclasa 1 , Terapia Antirretroviral Altamente Activa , Biomarcadores , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Infecciones por VIH/tratamiento farmacológico , Humanos , Glicoproteínas de Membrana , Viremia/inmunología , Viremia/virología , Replicación ViralRESUMEN
The mechanism of CD4(+) T cell depletion seen in HIV infection is largely mediated by increased apoptosis of these cells. The benefit of protease inhibitor (PI)-based antiretroviral therapy to CD4(+) T cell recovery seems to involve more than its antiviral activity, and a direct antiapoptotic effect of PIs has been proposed to explain it. To test this hypothesis we have analyzed directly, ex vivo, the effects of two different highly active antiretroviral therapy (HAART) regimens on the levels of activation and apoptosis of T lymphocytes. A total of 126 subjects (43 receiving PIs, 35 receiving NNRTIs, 27 untreated HIV carriers, and 21 uninfected control subjects) was included in the study. Apoptosis was measured in blood lymphocytes by flow cytometry, using annexin V labeling. A broad panel of monoclonal antibodies was used to characterize the different CD4(+) and CD8(+) lymphocyte subsets. Apoptosis was significantly increased in HIV-untreated subjects, whereas apoptosis levels did not differ when comparing HIV-positive subjects undergoing HAART and uninfected control subjects. Likewise, markers of activation were elevated in HIV-positive untreated patients, and declined in subjects receiving treatment. However, activated-memory CD8(+) T cells remained significantly higher in treated patients with respect to uninfected control subjects. No differences in the level of apoptosis or in immune activation markers were recognized when comparing subjects receiving PIs and those receiving NNRTIs. Antiretroviral therapy reduces apoptosis of CD4(+) and CD8(+) lymphocytes to normal levels without differences when comparing subjects receiving PI and NNRTI triple combinations. Despite complete suppression of viral replication, activated memory CD8(+) T cells remain significantly elevated in subjects receiving HAART, suggesting the persistence of residual HIV replication. If PIs provide a positive effect on CD4(+) counts beyond an antiviral effect, mechanisms other than apoptosis should be involved.
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Fármacos Anti-VIH/uso terapéutico , Apoptosis/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Activación de Linfocitos/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Fármacos Anti-VIH/farmacología , Quimioterapia Combinada , Citometría de Flujo , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Humanos , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/farmacología , Subgrupos de Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Although there is clear evidence of an accelerated progression of liver fibrosis in HIV-positive patients with chronic hepatitis C virus (HCV) infection, it is unclear whether HCV infection may influence HIV-1 disease progression. We have analyzed the impact of HCV on CD4 counts and plasma HIV RNA in a large group of HIV-positive individuals. METHOD: Epidemiological data, CD4 counts, and plasma HIV RNA values were recorded from 902 consecutive HIV-1-positive persons who attended our institution since 1998. RESULTS: HCV infection was documented (antibodies and/or HCV RNA) in 72% of the total study population. The higher rates were seen among intravenous drug users (97%) compared to other groups (17% in homosexual men, 23% in patients who acquired HIV heterosexually). In a cross-sectional analysis performed at the first trimester of 2000, the mean CD4 count was lower among HCV-positive than among HCV-negative individuals (518 +/- 282 cells/microL vs. 620 +/- 302 cells/microL; p <.001). The mean plasma HIV RNA was 11,188 +/- 55,301 copies/mL in HCV-positive persons versus 6,352 +/- 32,152 copies/mL in HCV-negative persons (p =.03). Undetectable plasma HIV RNA (<50 copies/mL) was recognized in 54% of HCV-positive persons versus 64% of HCV negative persons (p =.04); a similar proportion of patients in each group was on antiretroviral therapy (90% vs. 93%) or HAART (86% vs. 89%). When comparing data from 1998 and 2000, the CD4 count increased an average of 53 cells/microL (11%) in HCV-positive persons versus 111 (19%) in HIV-negative persons during this 2-year interval (p <.05). Plasma HIV RNA on average declined 606 copies/mL (5%) in HCV-positive persons versus 5,788 copies/mL (54%) in HCV-negative persons (p <.05). A significant association between HCV infection and CD4 counts was recognized in the multivariate analysis, which was independent of gender, age, plasma HIV RNA, use of HAART, and adherence to therapy. In contrast, no significant effect of HCV on HIV RNA was found. CONCLUSION: Hepatitis C may be associated with a poor immunologic outcome in HIV-infected persons. This worst influence is not explained by a lower rate of antiretroviral therapy among HCV-positive persons nor a much poorer drug adherence in this population. Therefore, hepatitis C may act as a direct cofactor for HIV disease progression. If so, treatment of chronic hepatitis C might indirectly benefit HIV disease.