RESUMO
A small animal model that could be infected with human immunodeficiency virus 1 (HIV-1) after peripheral inoculation would greatly facilitate the study of the pathophysiology of acute HIV-1 infection. The utility of SCID mice implanted with human fetal thymus and liver (SCID-hu mice) for studying peripheral HIV-1 infection in vivo has been hampered by the requirement for direct intraimplant injection of HIV-1 and the continued restriction of the resultant HIV-1 infection to the human thymus and liver (hu-thy/liv) implant. This may have been due to the very low numbers of human T cells present in the SCID-hu mouse peripheral lymphoid compartment. Since the degree of the peripheral reconstitution of SCID-hu mice with human T cells may be a function of the hu-thy/liv implant size, we increased the quantity of hu-thy/liv tissue implanted under the renal capsule and implanted hu-thy/liv tissue under the capsules of both kidneys. This resulted in SCID-hu mice in which significant numbers of human T cells were detected in the peripheral blood, spleens, and lymph nodes. After intraimplant injection of HIV-1 into these modified SCID-hu mice, significant HIV-1 infection was detected by quantitative coculture not only in the hu-thy/liv implant, but also in the spleen and peripheral blood. This indicated that HIV-1 infection can spread from the thymus to the peripheral lymphoid compartment. More importantly, a similar degree of infection of the hu-thy/liv implant and peripheral lymphoid compartment occurred after peripheral intraperitoneal inoculation with HIV-1. Active viral replication was indicated by the detection of HIV-1 gag DNA, HIV-1 gag RNA, and spliced tat/rev RNA in the hu-thy/liv implants, peripheral blood mononuclear cells (PBMC), spleens, and lymph nodes of these HIV-1-infected SCID-hu mice. As a first step in using our modified SCID-hu mouse model to investigate the pathophysiological consequences of HIV-1 infection, the effect of HIV-1 infection on the expression of human cytokines shown to enhance HIV-1 replication was examined. Significantly more of the HIV-1-infected SCID-hu mice expressed mRNA for human tumor necrosis factors alpha and beta, and interleukin 2 in their spleens, lymph nodes, and PBMC than did uninfected SCID-hu mice. This suggested that HIV-1 infection in vivo can stimulate the expression of cytokine mRNA by human T cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Modelos Animais de Doenças , Infecções por HIV/fisiopatologia , HIV-1 , Animais , Sequência de Bases , Transplante de Células , Quimera , Citocinas/biossíntese , Citocinas/genética , DNA , Expressão Gênica , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Fígado/citologia , Camundongos , Camundongos SCID , Dados de Sequência Molecular , Linfócitos T/transplante , Timo/citologiaRESUMO
BACKGROUND AND OBJECTIVES: Total parenteral nutrition (TPN) is a lifesaving therapy in children with intestinal failure, frequently complicated by liver dysfunction. Plant sterols (phytosterols) of lipid emulsions have been supposed to contribute to cholestasis in TPN-treated children. The present study aimed to evaluate the plasma and red blood cell membrane (RBCM) phytosterol levels in newborns after a short period of TPN. PATIENTS AND METHODS: Phytosterols, cholesterol, and other sterol levels were quantified by gas chromatography-mass spectrometry in 15 healthy control infants, 22 patients after TPN, and 11 patients before TPN. Sterols of lipid emulsions were quantified. RESULTS: Plasma and RBCM phytosterol levels were, respectively, on average 56 micromol/L and 83 micromol/g per protein in patients after TPN, 13 micromol/L and 15 micromol/g per protein in patients before TPN, and 9 micromol/L and 13 micromoL/g per protein in control infants (P < 0.05 for differences). The days of TPN and the total amount of infused lipids correlated significantly with RBCM phytosterol (P < 0.05); correlations for plasma were positive but not significant. No correlation was observed with plasma bilirubin, gamma-glutamyltransferase, or alanine transaminase. CONCLUSIONS: Plasma and RBCM phytosterols increase significantly in newborns after a short period of TPN. Higher phytosterol levels were observed in some patients that could have been due to their individual variability in phytosterol metabolism and/or clearance. A greater accumulation of phytosterols in membranes may induce TPN-related cholestasis.
Assuntos
Membrana Eritrocítica/química , Recém-Nascido Prematuro , Nutrição Parenteral Total , Esteróis/sangue , Alanina Transaminase/sangue , Bilirrubina/sangue , Humanos , Recém-Nascido , Fitosteróis/sangue , gama-Glutamiltransferase/sangueRESUMO
Child maltreatment is a complex life experience occurs when a parent or caregiver does an intentional or potential damage to a child, including acts of commission and omission. Child abuse is not an uncommon event, but it is not always recognized. Identifying the real number of maltreated children is a challenge because of the large variability in reported prevalence data across studies. Unfortunately, in the United States, it affects 1 in 8 children, by the age of 18 years, annually. Paediatricians may encounter a variety of forms of maltreatment such as neglect, emotional, physical and sexual abuse. These aspects should be recognised, examined and evaluated by employing a systematic approach and focusing on basic needs of children that may not be met. Child maltreatment is a global problem with serious life-long physical and psychological or psychiatric outcomes. It is associated with important economic and social costs (such as physical and mental health, productivity losses, child welfare, criminal justice and special education costs) due to its high prevalence and its long-term and short-term consequences. In the United States, the average cost of nonfatal maltreatment is $210,012 per children and the cost of fatal maltreatment is $1,272,900. General Practitioners are quite prepared to face the problem of child maltreatment: since they have the opportunity to meet several members of the same family, they can detect stressors that put children at risk of maltreatment. All health professionals have the responsibility to protect children from abuse and neglect.
Assuntos
Maus-Tratos Infantis , Saúde Mental , Transtornos do Neurodesenvolvimento/etiologia , Cuidadores , Criança , Feminino , Humanos , Masculino , Transtornos do Neurodesenvolvimento/epidemiologia , Prevalência , Estados UnidosRESUMO
The risk of infection by HIV-1 through transfusion of contaminated blood products has been markedly decreased but not eliminated by serological screening of donors. Methods are required to further minimize or eliminate the risk of infection of blood product recipients. We therefore examined the capacity of alkylureas to inhibit infectivity of HIV-1. Incubation of free HIV-1 virions with alkylureas suppressed their infectivity, and the minimal inhibitory concentration of the alkylureas was related to the length of the alkyl chain. Butylurea, the most potent inhibitor of HIV-1, inhibited the infectivity of 10(5) median tissue culture infective dose (TCID)50 of HIV-1, chronically HIV-1-infected H9 cells and mononuclear cells from two HIV-1-infected patients. Size fractionation of HIV-1 following incubation with butylurea indicated that the structure of the virus was disrupted by butylurea. This study demonstrates that butylurea, at a concentration that has been shown not to affect red blood cell function, can inhibit infectivity of extracellular and intracellular HIV-1. Since the HIV-1 inhibitory capacity of the alkylureas increases with the length of the alkyl side chain, it is likely that hydrophobic interactions between the alkylureas and HIV-1 are responsible for the observed effect.
Assuntos
HIV-1/efeitos dos fármacos , Ureia/análogos & derivados , Linhagem Celular , Cromatografia , Ensaio de Imunoadsorção Enzimática , Proteína do Núcleo p24 do HIV/análise , Transcriptase Reversa do HIV , Humanos , DNA Polimerase Dirigida por RNA/metabolismo , Ureia/farmacologiaRESUMO
OBJECTIVES: To develop a peptide-based model for a preventive vaccine for HIV-1 infection. DESIGN: Phase I trial in HIV-1-seronegative volunteers. PARTICIPANTS: Adult healthy subjects HIV-1-antibody-seronegative in an enzyme-linked immunosorbent assay, screened for tuberculin [purified protein derivative (PPD)] reactivity with 2 tuberculin units PPD-administered intradermally. INTERVENTIONS: Submicrogram doses of a PPD conjugate with a peptide of the primary neutralizing domain (PND) of HIV-1MN (PPD-MN-PND) were administered intradermally to tuberculin skin-test-positive and -negative volunteers. RESULTS: Antibodies to the MN-PND were measured after two immunizations in 10 out of 11 PPD skin-test-positive volunteers. After the fourth immunization high-affinity antibodies were detected, which persisted for over 1 year. High titers of MN-PND-specific immunoglobulin (Ig) G and IgA were detected in the serum and saliva of all volunteers tested. Serum antibodies were cross-reactive with PND peptide from some other HIV-1 strains but neutralized only the HIV-1MN prototype. Human leukocyte antigen (HLA)-B7-restricted MN-PND-specific cytotoxic T lymphocytes (CTL) were also detected. CONCLUSIONS: The PPD-MN-PND vaccine at submicrogram doses is safe and immunogenic in PPD skin-test-positive healthy adult volunteers. Long lasting humoral immune responses in the serum and saliva were possibly accompanied by HLA-B7-restricted CTL responses. This is a vaccine prototype that can be rapidly and inexpensively modified to include other peptide epitopes. It is especially suitable for use in a worldwide multibillion Bacillus Calmette-Guérin (BCG)-primed or tuberculosis-exposed population at risk for HIV-1 infection.
Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Anti-HIV/análise , Proteína gp120 do Envelope de HIV/imunologia , Soronegatividade para HIV/imunologia , HIV-1/imunologia , Fragmentos de Peptídeos/imunologia , Tuberculina/química , Adulto , Sequência de Aminoácidos , Afinidade de Anticorpos , Reações Cruzadas , Anticorpos Anti-HIV/sangue , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/química , Humanos , Imunoglobulina A/análise , Imunoglobulina A/sangue , Imunoglobulina G/análise , Imunoglobulina G/sangue , Dados de Sequência Molecular , Testes de Neutralização , Fragmentos de Peptídeos/química , Saliva/imunologia , Linfócitos T Citotóxicos/imunologia , Tuberculina/imunologia , Teste Tuberculínico , Vacinação , Vacinas Conjugadas/imunologiaRESUMO
High concentrations of the cryptococcal capsular polysaccharide (CCP) are present in the serum, cerebrospinal fluid or both in the majority of AIDS patients infected with Cryptococcus neoformans. Because the prognosis of AIDS patients infected with cryptococcus is poor, we investigated whether the presence of CCP enhanced HIV-1 infection. The presence of CCP markedly increased the infectivity of HIV-1-infected H9 cells and subsequent production of infectious HIV-1 and formation of syncytia. In addition to enhancing the infectivity of H9 cells infected with laboratory isolates of HIV-1, the presence of CCP also increased the infectivity of peripheral blood mononuclear cells (PBMCs) infected with primary field strains of HIV-1. The in vitro infectivity of PBMCs from 20 of 44 HIV-1-infected individuals was significantly increased when cultured with CCP. Furthermore, HIV-1 was isolated from the PBMCs of three of these individuals only when cultured in the presence of CCP. CCP increased the binding of HIV-1 and recombinant gp120 to H9 cells and recombinant CD4, respectively. Thus, it is possible that the enhancement of HIV-1 infectivity by CCP is due to its capacity to increase the adherence of HIV-1 to target cells. Whereas the capsular polysaccharide of Haemophilus influenzae also markedly enhanced the infectivity of HIV-1, the capsular polysaccharides of C. freundii or S. flexneri had minimal effects on the infectivity of HIV-1. This indicated that the capacity to enhance HIV-1 infectivity was a property of polysaccharides from some pathogens and not others.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Cryptococcus neoformans/imunologia , HIV-1/fisiologia , Haemophilus influenzae/imunologia , Linfócitos/virologia , Polissacarídeos Bacterianos/farmacologia , Polissacarídeos/farmacologia , Infecções Oportunistas Relacionadas com a AIDS/sangue , Infecções Oportunistas Relacionadas com a AIDS/líquido cefalorraquidiano , Síndrome da Imunodeficiência Adquirida/sangue , Síndrome da Imunodeficiência Adquirida/líquido cefalorraquidiano , Linhagem Celular , Células Cultivadas , Criptococose/sangue , Criptococose/líquido cefalorraquidiano , Células Gigantes , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/imunologia , Humanos , Polissacarídeos Bacterianos/sangue , Polissacarídeos Bacterianos/líquido cefalorraquidiano , Proteínas Recombinantes/metabolismoRESUMO
Activity of the distal region of the human immunodeficiency virus (HIV-1) long terminal repeat (LTR), which contains binding sites for the Ets-1 and USF-1 proteins, is integral for HIV-1 replication. The Ets-1 and USF-1 proteins play a critical role in the activity of the HIV-1 LTR distal enhancer region, as indicated by the potent dominant negative effect of a mutant Ets-1 lacking trans-activation domains on the transcriptional activity of the LTR. To determine the biological relevance of the Ets-1 and USF-1 proteins in HIV-1 replication, we examined the effect of expression of the dominant-negative mutant of Ets-1 (dnEts-1) on HIV-1 infection of T cells. We demonstrated that expression of dnEts markedly suppressed HIV-1 infection of a T cell line. This finding indicates that formation of a transcriptionaly active USF-1/Ets-1 complex is important in the productive infection of cells by HIV-1, and suggests that inhibition of the interaction between USF-1 and Ets-1 with the HIV-1 LTR may provide a new target for anti-HIV-1 gene therapy.
Assuntos
Proteínas de Ligação a DNA , HIV-1/fisiologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Linfócitos T/virologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Divisão Celular , Linhagem Celular , Vetores Genéticos , Repetição Terminal Longa de HIV , HIV-1/patogenicidade , Humanos , Mutação , Proteína Proto-Oncogênica c-ets-1 , Proteínas Proto-Oncogênicas c-ets , Retroviridae/genética , Linfócitos T/citologia , Transdução Genética , Transfecção , Fatores Estimuladores Upstream , Replicação ViralRESUMO
To investigate the mechanism of HIV-1-induced hematopoietic abnormalities, we examined the effect of HIV-1 infection on the in vitro and in vivo behavior of precursor cells obtained from human fetal bone marrow (HFBM). After infection with the monocyte-tropic isolate HIV-1(ADA), HFBM cells displayed a significant decrease in their subsequent in vitro production of precursor cell colonies and a marked impairment in their engraftment of the bone marrow of irradiated SCID mice. By injecting retrovirally tagged, purified human CD34+ cells into HIV-1(ADA)-infected or uninfected human thymic tissue implanted in SCID mice, we demonstrated that HIV-1 infection also inhibited the in vivo differentiation of CD34+ cells into T cells. To determine the mechanism by which HIV-1 suppressed hematopoietic activity, we investigated whether HIV-1 infection induced apoptotic cell death in hematopoietic cells. Multiparameter flow cytometry with FITC-labeled annexin V and propidium iodide demonstrated that infection of the HFBM with monocyte-tropic, but not T cell line-tropic HIV-1, stimulated apoptosis in the CD34+ hematopoietic precursor population. The presence of a TNF-alpha inhibitor during exposure of the HFBM cells to HIV-1 substantially reduced the level of apoptosis of CD34+ cells and significantly decreased the repression of in vitro colony formation induced by HIV-1. However, inhibition of TNF-alpha during HFBM cell culture with HIV-1 did not restore their capacity to engraft SCID mice. Taken together, these results indicated that HIV-1 suppression of human hematopoietic cell maturation is a multifactoral phenomenon, a crucial element of which may be HIV-1-induced apoptosis of precursor cells mediated by TNF-alpha production.
Assuntos
Apoptose , Medula Óssea/embriologia , HIV-1/fisiologia , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/virologia , Animais , Diferenciação Celular , Linhagem da Célula , Transplante de Tecido Fetal , Sobrevivência de Enxerto , Fatores de Crescimento de Células Hematopoéticas/farmacologia , Células-Tronco Hematopoéticas/citologia , Humanos , Camundongos , Camundongos SCID , Quimera por Radiação , Timo/transplante , Transplante Heterólogo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Mucosal transmission is a major route by which individuals become infected with HIV. Investigation into the mechanism by which mucosal transmission of HIV occurs would be greatly facilitated by the development of a small animal model infectible with HIV by the mucosal route. We have previously described a SCID-hu mouse model, in which human thymic and liver tissues are implanted under both kidney capsules (thy/liv-SCID-hu mice), which are populated in the periphery with high numbers of human T cells and that develop disseminated HIV-1 infection after intraperitoneal injection. To expand further the usefulness of the thy/liv-SCID-hu mouse as a model for studying mucosal transmission of HIV, thy/liv-SCID-hu mice were subcutaneously implanted with human intestinal tissue in a manner that maintained the lumen. Four months later, the histological appearance of the implanted intestine resembled that of normal human bowel tissue and the lamina propria was populated with human T cells. Six weeks after introduction of HIV into the lumen of the intestinal implant, the mice developed disseminated HIV infection. Scattered HIV-infected cells were detected in the lamina propria of the implant, indicating that HIV infection in these mice was mediated by transmission of the virus across the mucosa of the human intestinal implant. Thus, our modified thy/liv-SCID-hu mice transplanted with human bowel tissue should provide a novel model for investigating mucosal transmission of HIV.
Assuntos
Infecções por HIV/transmissão , Intestinos/virologia , Animais , HIV-1 , Humanos , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/virologia , Intestinos/imunologia , Intestinos/transplante , Camundongos , Camundongos SCID , Modelos Biológicos , Cavidade Peritoneal , Linfócitos T/citologia , Transplante HeterólogoRESUMO
To generate an in vivo system for investigating the postintegration phase of HIV-1 replication, mouse lines transgenic for a full-length infectious proviral clone of a monocyte-tropic HIV-1 isolate, HIV-1JR-CSF, were constructed. Leukocytes from two independent JR-CSF transgenic mouse lines produced HIV-1 that infected human PBMCs. Plasma viremia was detected in these mice at levels (mean, >60,000 HIV RNA copies/ml) comparable to those reported for HIV-1-infected individuals. The levels of HIV RNA in these mice increased several-fold after either treatment with the superantigen Staphylococcus enterotoxin B or infection with Mycobacterium tuberculosis. Thus, a provirus encoding a monocyte-tropic HIV-1 strain under the control of its LTR expressed as a transgene in mice can proceed through the postintegration replication phase and produce infectious virus. In addition, the presence of plasma viremia that can be monitored by measuring plasma HIV-1 RNA levels permits these mice to be used to study the impact of different interventions on modulating in vivo HIV-1 production. Therefore, these mice provide a novel manipulable system to investigate the in vivo regulation of HIV-1 production by factors that activate the immune system. Furthermore, this murine system should be useful in delineating the role of human-specific factors in modulating HIV-1 replication and investigating the in vivo therapeutic efficacy of agents that target the postintegration stages of HIV-1 replication.
Assuntos
Infecções por HIV/virologia , HIV-1/genética , Camundongos Transgênicos/virologia , Provírus/genética , Replicação Viral/genética , Animais , Técnicas de Cocultura , Enterotoxinas/imunologia , Infecções por HIV/imunologia , HIV-1/patogenicidade , Humanos , Hibridização In Situ , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos/sangue , Camundongos Transgênicos/imunologia , Dados de Sequência Molecular , Monócitos/virologia , Mycobacterium tuberculosis/imunologia , Reação em Cadeia da Polimerase , RNA Viral/análise , Staphylococcus/imunologia , Vacinação , Viremia/virologiaRESUMO
Little information is available on asymptomatic carriage of Cryptosporidium in immunocompetent and immunodeficient children. We prospectively studied a group of asymptomatic children, 78 immunocompetent and 50 immunodeficient, to document the incidence of asymptomatic carriage of cryptosporidiosis in such a population. We also investigated whether the treatment of children who carried asymptomatic cryptosporidiosis could help in reducing their risk of gastrointestinal symptoms as well as the shedding of infectious oocysts. The occurrence of multiple infections with common intestinal pathogens including Giardia lamblia was also investigated. Asymptomatic cryptosporidiosis was documented in 6.4% of immunocompetent and 22% of immunodeficient children. In a control symptomatic population Cryptosporidium was found in 4.4% of immunocompetent and 4.8% of immunodeficient children. Asymptomatic carriage of Cryptosporidium was documented in 2 human immunodeficiency virus-infected children, one of whom also carried Giardia asymptomatically. Treatment with spiramycin (100 mg/kg daily for 14 days) reduced significantly the duration of the shedding of potentially infectious oocysts. Finally no gastrointestinal symptoms developed in children treated for asymptomatic infection with Cryptosporidium, whereas children who were not treated developed gastrointestinal symptoms.
Assuntos
Portador Sadio/parasitologia , Criptosporidiose/etiologia , Cryptosporidium/isolamento & purificação , Fezes/parasitologia , Giardia lamblia/isolamento & purificação , Imunocompetência , Síndromes de Imunodeficiência/parasitologia , Adolescente , Animais , Antibacterianos/uso terapêutico , Portador Sadio/tratamento farmacológico , Criança , Pré-Escolar , Criptosporidiose/tratamento farmacológico , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Lactente , Estudos Prospectivos , Espiramicina/uso terapêuticoRESUMO
Mismanaged protein trafficking by the proteostasis network contributes to several conformational diseases, including cystic fibrosis, the most frequent lethal inherited disease in Caucasians. Proteostasis regulators, as cystamine, enable the beneficial action of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators in ΔF508-CFTR airways beyond drug washout. Here we tested the hypothesis that functional CFTR protein can sustain its own plasma membrane (PM) stability. Depletion or inhibition of wild-type CFTR present in bronchial epithelial cells reduced the availability of the small GTPase Rab5 by causing Rab5 sequestration within the detergent-insoluble protein fraction together with its accumulation in aggresomes. CFTR depletion decreased the recruitment of the Rab5 effector early endosome antigen 1 to endosomes, thus reducing the local generation of phosphatidylinositol-3-phosphate. This diverts recycling of surface proteins, including transferrin receptor and CFTR itself. Inhibiting CFTR function also resulted in its ubiquitination and interaction with SQSTM1/p62 at the PM, favoring its disposal. Addition of cystamine prevented the recycling defect of CFTR by enhancing BECN1 expression and reducing SQSTM1 accumulation. Our results unravel an unexpected link between CFTR protein and function, the latter regulating the levels of CFTR surface expression in a positive feed-forward loop, and highlight CFTR as a pivot of proteostasis in bronchial epithelial cells.
Assuntos
Brônquios/fisiopatologia , Membrana Celular/fisiologia , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Fibrose Cística/fisiopatologia , Células Epiteliais/fisiologia , Deficiências na Proteostase/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Proteína Beclina-1 , Brônquios/patologia , Linhagem Celular , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Células Epiteliais/patologia , Humanos , Proteínas de Membrana/fisiologia , Mutação/genética , Monoéster Fosfórico Hidrolases/fisiologia , Receptores da Transferrina/fisiologia , Proteína Sequestossoma-1 , Proteínas rab5 de Ligação ao GTP/fisiologiaAssuntos
Vacinas contra a AIDS/farmacologia , Proteína gp120 do Envelope de HIV/imunologia , HIV-1/imunologia , Fragmentos de Peptídeos/imunologia , Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Sequência de Aminoácidos , Reações Cruzadas , Anticorpos Anti-HIV/sangue , Antígenos HIV/genética , Proteína gp120 do Envelope de HIV/genética , HIV-1/genética , Humanos , Esquemas de Imunização , Imunoglobulina G/sangue , Imunoglobulina G/classificação , Dados de Sequência Molecular , Testes de Neutralização , Fragmentos de Peptídeos/genética , Segurança , Linfócitos T Citotóxicos/imunologia , Tuberculina/administração & dosagem , Tuberculina/efeitos adversos , Tuberculina/imunologia , Teste Tuberculínico , Vacinas Conjugadas/efeitos adversos , Vacinas Conjugadas/imunologia , Vacinas Conjugadas/farmacologiaAssuntos
Síndrome da Imunodeficiência Adquirida/microbiologia , Cryptococcus neoformans/fisiologia , HIV-1/fisiologia , Polissacarídeos/fisiologia , Linhagem Celular , Criança , Pré-Escolar , Proteína do Núcleo p24 do HIV/sangue , Infecções por HIV/microbiologia , Humanos , Lactente , Leucócitos Mononucleares/microbiologia , Replicação ViralAssuntos
Aleitamento Materno , Cárie Dentária/epidemiologia , Alimentação com Mamadeira , Criança , Pré-Escolar , Estudos Transversais , Índice CPO , Feminino , Humanos , Itália , Masculino , Saúde BucalRESUMO
OBJECTIVE: Individuals homozygous for a deletion in the CCR5 gene (CCR5delta32/CCR5delta32) are resistant to HIV infection, indicating that this particular chemokine receptor plays a crucial role in the initiation of in vivo HIV infection. We investigated the effect of the heterozygote genotype (CCR5/CCR5delta32) on susceptibility of peripheral blood mononuclear cells (PBMC) to HIV infection. DESIGN: Sensitivity to HIV infection of PBMC from volunteers with either the CCR5/CCR5, CCR5/CCR5delta32, or CCR5delta32/CCR5delta32 genotypes was examined by challenging their PBMCs with serial titers of HIV isolates with different cellular tropisms. The genotype of the PBMCs was correlated with the lowest viral inoculum required to initiate productive infection with either three M-tropic HIV-1 isolates, (92RW009A, HIV-1ada, and HIV-1(59)), one dual-tropic HIV-1 isolate (92BR021), or two T-tropic HIV-1 isolates (92UG021 and 92UG029). RESULTS: PBMCs from the CCR5/CCR5delta32 group required a significantly higher inoculum (p value from .036 to .003) to become infected with these three M-tropic HIV-1 isolates than did PBMC from the CCR5/CCR5 group, but became infected after exposure to an inoculum of T-tropic HIV-1 isolates that was comparable to that which infected PBMCs from the CCR5/CCR5 individuals. CONCLUSIONS: The decreased susceptibility of PBMCs from individuals heterozygous for the CCR5 deletion to HIV infection by M-tropic HIV-1 isolates may provide a mechanistic explanation for the delayed progression of disease in some CCR5/CCR5delta32 individuals.
Assuntos
Infecções por HIV/genética , HIV-1/imunologia , Heterozigoto , Leucócitos Mononucleares/imunologia , Receptores CCR5/genética , Alelos , Células Cultivadas , Progressão da Doença , Deleção de Genes , Genótipo , Infecções por HIV/imunologia , Humanos , Imunidade Inata , Lactente , Leucócitos Mononucleares/virologiaRESUMO
Highly active antiretroviral therapy (HAART), which combines multiple inhibitors of essential human immunodeficiency virus type 1 (HIV-1) enzymes, induces dramatic and sustained viral load reductions in many people infected with HIV-1. However, reservoirs of infected cells capable of producing replication-competent virus persist even after years of HAART, preventing elimination of infection. CD4-PE40 and 3B3(Fv)-PE38, chimeric toxins designed to target the HIV envelope (Env), represent a complementary class of agents that selectively kill productively infected cells. To investigate whether these Env-targeted toxins might serve as adjuncts to HAART for the elimination of infected cells, we tested their ability to augment HAART efficacy in vivo by using a thy/liv SCID-hu mouse model. CD4-PE40 and 3B3(Fv)-PE38 markedly enhanced the capacity of HAART to suppress acute HIV-1 infection and improved HAART-mediated viral load reduction in mice with established HIV-1 infection. These results represent the first demonstration of in vivo anti-HIV-1 efficacy for Env-targeted toxins and support their potential therapeutic utility in combination with HAART.
Assuntos
Fármacos Anti-HIV/uso terapêutico , HIV-1 , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas do Envelope Viral/antagonistas & inibidores , Animais , Quimioterapia Combinada , Humanos , Fígado/imunologia , Camundongos , Camundongos SCID , Timo/imunologiaRESUMO
An investigation was carried out on 61 children suffering from symptomatic giardiasis with the object of verifying the incidence and entity of lactose malabsorption. Furthermore, the possibility of a substitutive yogurt diet was verified in the lactose malabsorbers. The subjects, all children older than 1 year, were studied according to a schedule that included a lactose hydrogen breath test (BT) performed prior to therapy and a further BT 60 days following therapy. The subjects were divided in two groups: group A, 40 children, received a dose of 250 ml of cow's milk; group B, 21 children, received a stress dose of 2 g/kg lactose (max 50 g). Those subjects who were lactose malabsorbers at the 60 day follow-up were also given a BT at 75 days, and in the case of persistent malabsorption, a further BT was performed after 24 h with the administration of yogurt (450 g containing 12.1 g of lactose). Furthermore, 40 subjects matched for age and sex but without any GI complaints served as controls. The results showed lactose malabsorption to be frequent in children with Giardia lamblia symptomatic infection. According to the BT with a standard lactose load, all patients were malabsorbers; when testing lactose absorption with 250 ml of cow's milk, 45% of patients were found to be malabsorbers. In the latter subjects, the oral load of yogurt was uniformly well tolerated and gave rise to no H2 increment on the BT. We conclude that the occurrence of lactose malabsorption of nutritional relevance is common in children suffering or having suffered from giardiasis.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Laticínios , Giardíase/complicações , Intolerância à Lactose/parasitologia , Iogurte , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Absorção Intestinal , Intolerância à Lactose/dietoterapia , MasculinoRESUMO
In an ophthalmologic study of 90 children with symptomatic giardiasis, ocular alterations were found in 10. Eight of these subjects presented an extensive "salt and pepper" degeneration of the pigmented epithelium involving 360 degrees of the midperiphery of both eyes. In one of the eight children, the pigmented epithelium showed atrophic areas, and in another there was a small hard exudate in the left eye. Of 2 remaining of the 10 children with ocular alterations, 1 presented with slight decoloration of the temporal half of the optic disc, and the other was affected by chorioretinitis. After single-dose antiprotozoic therapy (tinidazole 50 mg/kg), parasitologic tests were negative in all subjects and remained so throughout a 1-year follow-up. However, the characteristic epithelial lesion remained unaltered in all eight children for the entire follow-up period, as well as the optic disc decoloration in the only observed case. The child affected by chorioretinitis recovered after 3 weeks of combined treatment with bethametasone plus deflazacort. In two control groups, 1 of 200 healthy children and 1 of 200 children with gastrointestinal symptoms but without giardiasis, no case of "salt and pepper" degeneration of the pigmented epithelium or other significant ocular alterations was found.
Assuntos
Oftalmopatias/complicações , Giardíase/complicações , Enteropatias Parasitárias/complicações , Criança , Pré-Escolar , Coriorretinite/complicações , Coriorretinite/diagnóstico , Oftalmopatias/diagnóstico , Oftalmopatias/patologia , Feminino , Giardíase/diagnóstico , Humanos , Enteropatias Parasitárias/diagnóstico , Masculino , Epitélio Pigmentado Ocular/patologia , Degeneração Retiniana/complicações , Degeneração Retiniana/patologiaRESUMO
Patients with AIDS who become infected with Cryptococcus neoformans have a poor prognosis. We speculated that the presence of cryptococcal capsular polysaccharide may enhance HIV-1 infection. In an in-vitro study, the presence of cryptococcal polysaccharide significantly increased (p less than 0.05) production of p24 antigen after infection of H9 cells with HIV-1-infected H9 cells. We also found similar results when lymphocytes from an HIV-1-infected patient were co-cultured with mononuclear cells from an uninfected individual. Our findings suggest a new pathogenic role for the capsular polysaccharide--namely, the capacity to enhance HIV-1 infectivity.