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2.
HIV Med ; 13(10): 581-8, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22500780

RESUMO

BACKGROUND: Southern African countries have borne the brunt of the HIV/AIDS pandemic. Monitoring epidemiological dynamics is critical to identify the populations at greatest risk of infection and to guide control strategies. METHODS: A cross-sectional community-based study to determine age- and sex-specific HIV prevalence among individuals aged 18-47 years was carried out in Manhiça, southern Mozambique. Participants were randomly selected from the demographic surveillance system in place in the area and voluntary HIV counselling and testing were offered at home. In addition, HIV prevalence estimates from the antenatal clinic (ANC) were collected prospectively. RESULTS: A total of 839 individuals were invited to participate in the study. Of these, 722 were recruited (50.7% women). The overall HIV prevalence in the community was 39.9% [95% confidence interval (CI) 35.9-43.8%]. By age, the prevalence was 23.2% (95% CI 17.9-28.6%) in individuals aged 18-27 years, 41.2% (95% CI 35.6-48.3%) in those aged 28-37 years and 44.8% (95% CI 38.4-51.2%) in those aged 38-47 years. HIV prevalence was higher among women than men in all age groups. The overall HIV prevalence estimate for women in the community (43.1%; 95% CI 37.6-48.5%) was 1.4 times higher than that for those attending the ANC (29.4%; 95% CI 26.7-32.0%). CONCLUSIONS: The high HIV prevalence found in this region suggests that the epidemic is in a mature stable phase. The lower rates in the ANC than in the community suggest that ANC evaluations may underestimate community HIV prevalence. Resources to monitor HIV infection dynamics are needed to guide targeted control strategies in countries in which the epidemic exacts the greatest toll.


Assuntos
Soropositividade para HIV/epidemiologia , População Rural/estatística & dados numéricos , Vigilância de Evento Sentinela , Adolescente , Adulto , Distribuição por Idade , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Moçambique/epidemiologia , Prevalência , Fatores de Risco , Distribuição por Sexo , Adulto Jovem
3.
HIV Med ; 12(8): 500-5, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21794055

RESUMO

INTRODUCTION: The collection of incidence data on HIV infection is necessary to evaluate the status and dynamics of the epidemic and the effectiveness of intervention strategies. However, this is usually difficult in low-income countries. METHODS: Five yearly point HIV prevalence estimations (in 1999, 2003, 2004, 2005 and 2008) were obtained for women between 15 and 45 years of age participating in three studies carried out for other purposes at the Antenatal Clinic (ANC) in Manhiça, Mozambique. HIV incidence was estimated between prevalence points using a previously validated methodology. Two methods were used, one based on mortality rates for three HIV epidemic scenarios, and the other based on survival information after infection. The pattern over time was captured by fitting a log-regression model. RESULTS: The prevalence of HIV infection ranged from 12% in 1999 to 49% in 2008. The HIV incidence increased from approximately 3.5 cases per 100 person-years in 2001 to 14 per 100 person-years in 2004, with stabilization thereafter to levels of around 12 cases per 100 person-years. The incidence estimates were comparable for the two methods used. CONCLUSION: These findings indicate an increase in the prevalence and incidence of HIV infection among women of reproductive age over the 9 years of the analysis, with a plateau in the incidence of infection since 2005. However, the very high figures for both prevalence and incidence highlight the importance of the continuation of the prevention and treatment programmes that already exist, and suggest that implementation of preventive measures is needed in this area.


Assuntos
Infecções por HIV/epidemiologia , Adolescente , Adulto , Países em Desenvolvimento/estatística & dados numéricos , Feminino , Humanos , Incidência , Modelos Logísticos , Pessoa de Meia-Idade , Moçambique/epidemiologia , Gravidez , Prevalência , População Rural , Adulto Jovem
4.
Vaccine ; 28(30): 4851-7, 2010 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-20392430

RESUMO

Polysaccharide-protein conjugate vaccines against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae have proven efficacy against radiologically confirmed pneumonia. Measurement of pneumonia incidence provides a platform to estimate of the vaccine-preventable burden. Over 24 months, we conducted surveillance for radiologically confirmed severe pneumonia episodes among children <2 years of age admitted to a rural hospital in Manhiça, southern Mozambique. Study children were tested for HIV during the second year of surveillance. Severe pneumonia accounted for 15% of 5132 hospital admissions and 32% of in-hospital mortality among children <2 years of age. Also, 43% of chest radiographs were interpreted as radiologically confirmed pneumonia. HIV-infection was associated with 81% of fatal pneumonia episodes among children tested for HIV. The minimum incidence rate of radiologically confirmed pneumonia requiring hospitalization was 19 episodes/1000 child-years. Incidence rates among HIV-infected children were 9.3-19.0-fold higher than HIV-uninfected. Introduction of Hib and pneumococcal conjugate vaccines would have a substantial impact on pneumonia hospitalizations among African children if vaccine effects are similar to those observed in clinical trials.


Assuntos
Vacinas Anti-Haemophilus/uso terapêutico , Vacinas Pneumocócicas/uso terapêutico , Pneumonia Bacteriana/epidemiologia , Pneumonia Bacteriana/prevenção & controle , Efeitos Psicossociais da Doença , Interpretação Estatística de Dados , Determinação de Ponto Final , Infecções por HIV/epidemiologia , Haemophilus influenzae tipo b/imunologia , Hospitalização , Humanos , Lactente , Recém-Nascido , Moçambique/epidemiologia , Pneumonia Bacteriana/diagnóstico por imagem , Vigilância da População , Radiografia , Terminologia como Assunto , Vacinas Conjugadas
5.
Curr Top Microbiol Immunol ; 330: 151-71, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19203109

RESUMO

Measles is a highly contagious disease, which was responsible for high infant mortality before the advent of an effective vaccine in 1963. In immunocompetent individuals, measles virus (MV) infection triggers an effective immune response that starts with innate responses and then leads to successful adaptive immunity, including cell-mediated immunity and humoral immunity. The virus is cleared and lifelong protection is acquired. However, changing epidemiology of measles due to vaccination as well as severe immunodeficiency has created new pockets of individuals vulnerable to measles. This chapter reviews the knowledge on effective measles-specific immune responses induced by natural infection and vaccination and explores problems arising in specific cases of immunodeficiency, infant immunity, and ineffective vaccination against measles.


Assuntos
Vírus do Sarampo/imunologia , Sarampo/imunologia , Formação de Anticorpos , Feminino , Humanos , Imunidade Celular , Hospedeiro Imunocomprometido , Lactente , Masculino , Sarampo/epidemiologia , Sarampo/prevenção & controle , Sarampo/virologia , Vírus do Sarampo/fisiologia , Vacinação
6.
HIV Med ; 9(9): 757-64, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18651857

RESUMO

OBJECTIVES: Malaria infection may impact on mother-to-child transmission (MTCT) of HIV-1. Prevention of malaria in pregnancy could thus potentially affect MTCT of HIV. We studied the impact of intermittent preventive treatment during pregnancy (IPTp) on HIV-1 MTCT in southern Mozambique. METHODS: A total of 207 HIV-positive Mozambican pregnant women were enrolled in the study as part of a randomized placebo-controlled trial of two-dose sulfadoxine-pyrimethamine (SP) IPTp in women receiving single-dose nevirapine to prevent MTCT of HIV. HIV RNA viral load, maternal anaemia and peripheral and placental malaria were assessed at delivery. Infant HIV status was determined by DNA polymerase chain reaction (PCR) at 1 month of age. RESULTS: There were 19 transmissions of HIV in 153 mother-infant pairs. IPTp with SP did not have a significant impact on MTCT (11.8% in the SP group vs. 13.2% in the placebo group; P=0.784) or on maternal HIV RNA viral load [16 312 (interquartile range {IQR} 4076-69 296) HIV-1 RNA copies/mL in the SP group vs. 18 274 (IQR 5471-74 104) copies/mL in the placebo group; P=0.715]. In multivariate analysis, maternal HIV RNA viral load [adjusted odds ratio (AOR) 19.9; 95% confidence interval (CI) 2.3-172; P=0.006] and anaemia (haematocrit <33%; AOR 7.5; 95% CI 1.7-32.4; P=0.007) were independent risk factors for MTCT. Placental malaria was associated with a decrease in MTCT (AOR 0.23; 95% CI 0.06-0.89; P=0.034). CONCLUSIONS: IPTp with SP was not associated with a significant impact on MTCT of HIV. Maternal anaemia was an independent risk factor for MTCT.


Assuntos
Antimaláricos/uso terapêutico , Infecções por HIV/transmissão , HIV-1 , Malária Falciparum/tratamento farmacológico , Complicações Infecciosas na Gravidez/prevenção & controle , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêutico , Adulto , Anemia/parasitologia , Anemia/virologia , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Combinação de Medicamentos , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Recém-Nascido , Malária Falciparum/transmissão , Malária Falciparum/virologia , Moçambique , Nevirapina/uso terapêutico , Doenças Placentárias/parasitologia , Doenças Placentárias/virologia , Reação em Cadeia da Polimerase , Gravidez , Complicações Hematológicas na Gravidez/etiologia , RNA Viral , Carga Viral
7.
Cell Mol Life Sci ; 57(10): 1399-407, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11078019

RESUMO

Following infection, a virus must battle against the host's immune response. Viruses have developed many ways to escape immune surveillance and downregulate the host's immune response. Some viruses cause a generalized immunosuppression, thereby inhibiting or depressing the immune response towards themselves as well as towards unrelated pathogens. This review will focus on the mechanisms involved in the three main human viral infections causing immunosuppression: measles, human immunodeficiency virus and cytomegalovirus. We will also discuss what has been learned from the extensively studied mouse models of viral-induced immunosuppression: lymphocytic choriomeningitis virus and Rauscher leukemia virus. All of these viruses that induce generalized immunosuppression appear to do so by very similar mechanisms. They hinder antigen presentation to T cells and/or hematopoiesis. We will highlight the similarities in the viral targets as well as present evidence for alternate mechanisms.


Assuntos
Viroses/imunologia , Animais , Infecções por Citomegalovirus/imunologia , Infecções por HIV/imunologia , Humanos , Hospedeiro Imunocomprometido , Sarampo/imunologia
10.
J Virol ; 74(16): 7478-84, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10906201

RESUMO

Measles is a highly contagious disease currently responsible for over one million childhood deaths, particularly in the developing world. Since alpha/beta interferons (IFNs) are pivotal players both in nonspecific antiviral immunity and in specific cellular responses, their induction or suppression by measles virus (MV) could influence the outcome of a viral infection. In this study we compare the IFN induction and sensitivity of laboratory-passaged attenuated MV strains Edmonston and Moraten with those of recent wild-type viruses isolated and passaged solely on human peripheral blood mononuclear cells (PBMC) or on the B958 marmoset B-cell line. We report that two PBMC-grown wild-type measles isolates and two B958-grown strains of MV induce 10- to 80-fold-lower production of IFN by phytohemagglutinin-stimulated peripheral blood lymphocytes (PBL) compared to Edmonston and Moraten strains of measles. Preinfection of PBL with these non-IFN-inducing MV isolates prevents Edmonston-induced but not double-stranded-RNA-induced IFN production. This suggests that the wild-type viruses can actively inhibit Edmonston-induced IFN synthesis and that this is not occurring by double-stranded RNA. Furthermore, the wild-type MV is more sensitive than Edmonston MV to the effect of IFN. MV is thus able to suppress the synthesis of the earliest mediator of antiviral immunity, IFN-alpha/beta. This could have important implications in the virulence and spread of MV.


Assuntos
Interferon-alfa/biossíntese , Interferon beta/biossíntese , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Vírus do Sarampo/imunologia , Vírus do Sarampo/patogenicidade , Animais , Callithrix , Divisão Celular , Células Cultivadas , Humanos , Vacina contra Sarampo , Vírus do Sarampo/classificação , Vacinas Atenuadas , Vacinas Virais , Replicação Viral
11.
Cell ; 98(5): 629-40, 1999 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-10490102

RESUMO

Measles virus (MV) infects 40 million persons and kills one million per year primarily by suppressing the immune system and afflicting the central nervous system (CNS). The lack of a suitable small animal model has impeded progress of understanding how MV causes disease and the development of novel therapies and improved vaccines. We tested a transgenic mouse line in which expression of the MV receptor CD46 closely mimicked the location and amount of CD46 found in humans. Virus replicated in and was recovered from these animals' immune systems and was associated with suppression of humoral and cellular immune responses. Infectious virus was recovered from the CNS, replicated primarily in neurons, and spread to distal sites presumably by fast axonal transport. Thus, a small animal model is available for analysis of MV pathogenesis.


Assuntos
Encéfalo/virologia , Infecções do Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Terapia de Imunossupressão , Linfócitos/virologia , Vírus do Sarampo/isolamento & purificação , Sarampo/virologia , Animais , Antígenos CD/genética , Células Cultivadas , Cromossomos Artificiais de Levedura , Relação Dose-Resposta Imunológica , Citometria de Fluxo , Linfonodos/virologia , Proteína Cofatora de Membrana , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Microscopia Eletrônica , Neurônios/virologia , Baço/virologia , Fatores de Tempo , Distribuição Tecidual
12.
Virology ; 260(1): 136-47, 1999 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-10405365

RESUMO

Lymphotoxin beta (LTbeta), a member of the tumor necrosis factor family, plays an important role in lymphoid organogenesis. In order to determine whether LTbeta is involved in cellular immunity, we investigated the antiviral immune response of LTbeta-deficient (LTbeta -/-) mice to lymphocytic choriomeningitis virus (LCMV). Cytotoxic T lymphocyte (CTL) responses to LCMV were severely diminished, leading to viral persistence in brain and kidney. However, major functions of LTbeta-deficient T lymphocytes and dendritic cells were intact. Reconstitution of irradiated LTbeta +/+ mice with LTbeta -/- bone marrow induced a disorganized splenic structure, accompanied by impairment of the LCMV-specific CTL response. These data indicate that the absence of LTbeta does not affect the intrinsic function of T lymphocytes or of dendritic cells but that the structural integrity of the spleen is strongly associated with generation of antiviral immunity.


Assuntos
Vírus da Coriomeningite Linfocítica/imunologia , Linfotoxina-alfa/fisiologia , Proteínas de Membrana/fisiologia , Transferência Adotiva , Animais , Células da Medula Óssea/imunologia , Células Dendríticas/imunologia , Citometria de Fluxo , Linfotoxina-alfa/imunologia , Linfotoxina-beta , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Baço/imunologia , Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia
13.
J Virol ; 73(3): 1894-901, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9971768

RESUMO

One of the major mechanisms by which measles virus (MV) infection causes disease and death is suppression of the immune response. The nonresponsiveness of MV-infected human lymphocytes to mitogens and a partial block in the G0/G1 phase of the cell cycle observed in vitro is thought to reflect in vivo immunosuppression. In order to molecularly dissect MV-induced immunosuppression, we analyzed expression of surface activation markers and cell cycle-regulatory proteins in MV-infected human T lymphocytes. MV Edmonston (MV-Ed) could induce and maintain a high level of the early activation marker CD69 in the absence of proliferation. Expression of cyclins D3 and E, which positively control entry into S phase, was also significantly decreased. Analysis of inhibitors of progression into S phase showed that a high level of p27 was maintained in the G0/G1-blocked subpopulation of MV-Ed-infected cells compared to the proliferating MV-infected cells. Furthermore, cell cycle-related upregulation of retinoblastoma (Rb) protein synthesis did not occur in the MV-Ed-infected lymphocytes. Acridine orange staining, which distinguishes cells in G0 from cells in G1, showed that RNA levels were not upregulated following activation, which is consistent with cells remaining in a G0 state. Although expression of surface activation markers indicated entry into the cycle, intracellular Rb and RNA levels suggested a quiescent state. These results indicate that MV can uncouple activation of T lymphocytes from transition of G0 to G1.


Assuntos
Sarampo/imunologia , Proteínas Musculares , Fase de Repouso do Ciclo Celular , Proteína do Retinoblastoma/biossíntese , Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Ciclina D3 , Ciclinas/análise , Fase G1 , Humanos , Lectinas Tipo C , Ativação Linfocitária , Sarampo/metabolismo , Proteínas dos Microfilamentos/análise , RNA Ribossômico/biossíntese
14.
J Virol ; 72(5): 3512-9, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9557629

RESUMO

We investigated the relative importance of binding site occupancy and epitope specificity in antibody neutralization of human immunodeficiency virus (HIV) type 1 (HIV-1). The neutralization of a T-cell-line-adapted HIV-1 isolate (MN) was analyzed with a number of monovalent recombinant Fab fragments (Fabs) and monoclonal antibodies with a range of specificities covering all confirmed gp120-specific neutralization epitopes. Binding of Fabs to recombinant monomeric gp120 was determined by surface plasmon resonance, and binding of Fabs and whole antibodies to functional oligomeric gp120 was determined by indirect immunofluorescence and flow cytometry on HIV-infected cells. An excellent correlation between neutralization and oligomeric gp120 binding was observed, and a lack of correlation with monomeric gp120 binding was confirmed. A similar degree of correlation was observed between oligomeric gp120 binding and neutralization with a T-cell-line-adapted HIV-1 molecular clone (Hx10). The ratios of oligomer binding/neutralization titer fell, in general, within a relatively narrow range for antibodies to different neutralization epitopes. These results suggest that the occupancy of binding sites on HIV-1 virions is the major factor in determining neutralization, irrespective of epitope specificity. Models to account for these observations are proposed.


Assuntos
Epitopos de Linfócito B/imunologia , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , HIV-1/imunologia , Anticorpos Monoclonais/imunologia , Afinidade de Anticorpos , Especificidade de Anticorpos , Sítios de Ligação , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Imunoglobulina G/imunologia , Testes de Neutralização , Oligopeptídeos/imunologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Vírion/imunologia
15.
J Exp Med ; 183(2): 473-84, 1996 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-8627160

RESUMO

The spectrum of the anti-human immunodeficiency virus (HIV) neutralizing immune response has been analyzed by the production and characterization of monoclonal antibodies (mAbs) to the viral envelope glycoproteins, gp41 and gp120. Little is known, however, about the neutralization mechanism of these antibodies. Here we show that the binding of a group of neutralizing mAbs that react with regions of the gp120 molecule associated with and including the V2 and V3 loops, the C4 domain and supporting structures, induce the dissociation of gp120 from gp41 on cells infected with the T cell line-adapted HIV-1 molecular clone Hx10. Similar to soluble receptor-induced dissociation of gp120 from gp41, the antibody-induced dissociation is dose- and time-dependent. By contrast, mAbs binding to discontinuous epitopes overlapping the CD4 binding site do not induce gp120 dissociation, implying that mAb induced conformational changes in gp120 are epitope specific, and that HIV neutralization probably involves several mechanisms.


Assuntos
Anticorpos Antivirais/farmacologia , Glicoproteínas/imunologia , Proteína gp120 do Envelope de HIV/imunologia , HIV-1/imunologia , Sequência de Aminoácidos , Anticorpos Monoclonais/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Mapeamento de Epitopos , Citometria de Fluxo , Glicoproteínas/efeitos dos fármacos , Proteína gp41 do Envelope de HIV/imunologia , Dados de Sequência Molecular , Testes de Neutralização , Conformação Proteica/efeitos dos fármacos , Vírion/efeitos dos fármacos
16.
Vet Microbiol ; 44(2-4): 267-70, 1995 May.
Artigo em Inglês | MEDLINE | ID: mdl-8588321

RESUMO

The morbilliviruses have a restricted host range. This is probably dependent on the use of specific host cell receptors. In the present article, we have reviewed our approach to identify a host cell receptor for one of the morbilliviruses, measles virus and to elucidate the interaction between viral and cellular proteins during virus entry into the host cell.


Assuntos
Antígenos CD/metabolismo , Hemaglutininas Virais/metabolismo , Vírus do Sarampo/patogenicidade , Glicoproteínas de Membrana/metabolismo , Animais , Linhagem Celular , Haplorrinos , Células HeLa , Humanos , Vírus do Sarampo/metabolismo , Proteína Cofatora de Membrana , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Virais de Fusão/metabolismo
17.
J Virol ; 68(12): 7891-9, 1994 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-7966579

RESUMO

The CD46 molecule is a receptor for measles virus (MV), CD46, which protects autologous cells from complement-mediated damage, exists in several isoforms which are variably expressed in different human tissues. These isoforms differ in their cytoplasmic and transmembrane regions and in a small portion of their proximal extracytoplasmic regions. To examine the role of the cytoplasmic and transmembrane regions of CD46 in MV infection, mouse M12 B cells stably expressing a transmembrane or a chimeric glycosyl-phosphatidylinositol (GPI)-anchored form of CD46 (CD46-GPI) were used. Both the GPI-anchored and transmembrane CD46 forms were able to mediate MV binding. MV binding mediated by the GPI-anchored form but not that mediated by the transmembrane form was abolished after treatment with phosphatidylinositol phospholipase C. MV infection of both M12.CD46 and M12.CD46-GPI cells but not parental M12 cells resulted in MV replication. Expression of hemagglutinin induced cell surface down-regulation of both CD46 and CD46-GPI. Both M12.CD46 and M12.CD46-GPI cells were able to efficiently capture MV for presentation of viral antigens by major histocompatibility complex class II molecules to T cells. This presentation was blocked by chloroquine, indicating some virus endocytosis. These data imply that the extracytoplasmic region encompassing the four N-terminal invariable short consensus repeat regions of CD46 is sufficient to act as a receptor for MV and that the cytoplasmic and transmembrane regions of CD46 may not play a major role in the signal for the hemagglutinin-induced down-regulation of CD46 and/or endocytosis of MV.


Assuntos
Antígenos CD/fisiologia , Glicosilfosfatidilinositóis/fisiologia , Vírus do Sarampo/fisiologia , Glicoproteínas de Membrana/fisiologia , Receptores Virais/fisiologia , Replicação Viral , Animais , Antígenos CD/biossíntese , Antígenos CD/efeitos dos fármacos , Linfócitos B , Linhagem Celular , Regulação para Baixo , Citometria de Fluxo , Hemaglutininas/farmacologia , Humanos , Cinética , Proteína Cofatora de Membrana , Fusão de Membrana , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/efeitos dos fármacos , Camundongos , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/efeitos dos fármacos , Proteínas Recombinantes de Fusão/metabolismo , Transfecção
18.
J Virol ; 68(10): 6535-46, 1994 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7916060

RESUMO

It has been proposed recently that the cell surface peptidase CD26 acts in concert with CD4, the human immunodeficiency virus (HIV) primary receptor molecule, to mediate HIV entry into permissive cells. We have failed to detect significant levels of CD26 cell surface expression and enzymatic activity in a number of commonly propagated human CD4+ cell lines, although CD26 mRNA was present at very low levels, as detected by reverse transcription PCR. No relationship existed between the expression of CD26 and the ability of these cells to be infected with HIV or to fuse to form syncytia. We have tested two inhibitors of CD26 enzymatic activity and several anti-CD26 monoclonal antibodies and found that they inhibit neither HIV infection nor HIV-induced syncytium formation. NIH 3T3 cells stably transfected with the cDNAs for human CD4 and CD26 expressed these molecules at the cell surface and had CD26 enzymatic activity. Inoculation of the double transfectants with HIV did not result in virus entry above the background level, as verified by PCR amplification of viral DNA. We were unable to recover infectious virus from the HIV-inoculated NIH 3T3 double transfectants either by transfer of supernatants or by cocultivation with human CD4+ indicator cells. Moreover, the transfectants did not fuse with HIV-infected cells to form syncytia, nor were syncytia observed in HIV-inoculated cultures. These results are inconsistent with the CD26 molecule being a cofactor for entry of HIV in CD4+ cells.


Assuntos
Antígenos de Diferenciação de Linfócitos T/fisiologia , Antígenos CD4/fisiologia , HIV-1/fisiologia , Células 3T3 , Animais , Antígenos de Diferenciação de Linfócitos T/análise , Antígenos de Diferenciação de Linfócitos T/biossíntese , Sequência de Bases , Antígenos CD4/biossíntese , Linhagem Celular , Primers do DNA , DNA Viral/análise , DNA Viral/biossíntese , Dipeptidil Peptidase 4 , Células Gigantes/citologia , HIV-1/genética , Células HeLa , Humanos , Camundongos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Provírus/genética , Provírus/fisiologia , Linfócitos T , Transfecção , Células Tumorais Cultivadas , beta-Galactosidase/análise , beta-Galactosidase/biossíntese
19.
Cell Biol Int ; 18(5): 315-20, 1994 May.
Artigo em Inglês | MEDLINE | ID: mdl-8049676

RESUMO

The role of the measles virus (MV) receptor, human CD46, in the uptake of MV and antigen presentation by Major Histocompatibility Complex (MHC) class II molecules was investigated. Expression of CD46 in murine B cells resulted in cells highly efficient in capturing UV-inactivated MV particles and presenting both envelope hemagglutinin H and nucleoprotein N to specific T cell hybridomas. Although MV fuse with the plasma membrane of its target cells, presentation of both MV-H and -N was sensitive to inhibition by chloroquine but was not affected by a tripeptide which prevents virus-cell fusion. Whereas 50 microM of chloroquine was required to inhibit presentation of MV-H, purified H or soluble N, only a two-fold lower concentration was required to inhibit that of MV-N. This shows that some CD46-mediated captured MV particles are endocytosed, then disrupted and processed in an endosome/lysosome compartment.


Assuntos
Apresentação de Antígeno/imunologia , Antígenos CD/fisiologia , Antígenos de Histocompatibilidade Classe II/imunologia , Vírus do Sarampo/imunologia , Glicoproteínas de Membrana/fisiologia , Linfócitos T/imunologia , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Cloroquina/farmacologia , Endocitose/fisiologia , Hemaglutininas Virais/imunologia , Humanos , Ativação Linfocitária , Lisossomos/metabolismo , Vírus do Sarampo/efeitos dos fármacos , Vírus do Sarampo/efeitos da radiação , Proteína Cofatora de Membrana , Camundongos , Dados de Sequência Molecular , Proteínas do Nucleocapsídeo , Nucleoproteínas/imunologia , Oligopeptídeos/farmacologia , Células Tumorais Cultivadas , Raios Ultravioleta , Proteínas Virais/imunologia
20.
J Exp Med ; 179(1): 353-8, 1994 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-8270880

RESUMO

Measles virus after binding to its cell surface human CD46 receptor fuses with the plasma membrane. This fusion results in envelope hemagglutinin (H) and fusion glycoprotein (F) incorporated into the plasma membrane and injection of the nucleocapsid made of nucleoprotein (NP) into the cytosol. The influence of targeting measles virus (MV) to CD46 in the processing and presentation of MV H and NP to antigen specific MHC class II I-E(d)- and I-A(d)-restricted T cell hybridomas was explored using murine M12-CD46 B cell transfectants. Parent M12 cells, which lack any MV receptor, were unable to present any of these two viral proteins when incubated with MV particles. Incubating M12.CD46 cells with 200 ng and 10 micrograms of MV could strongly stimulate H-specific and NP-specific T cells, respectively. Neosynthesis of MV proteins was not necessary since the efficiency of antigen presentation was similar when using ultraviolet-inactivated MV. Similar enhancing effects (more than 1,000-fold) on antigen presentation were also observed when using purified native H soluble or incorporated into liposomes whereas denaturating H glycoprotein resulted in a poor efficiency in T cell stimulation, M12.CD46 being no more potent than the parental M12 counterpart. MV H and NP presentation efficiency did not depend on MV fusion with plasma membrane as revealed by the lack of effect of specific fusion inhibitors. Both MV H and NP presentations were sensitive to chloroquine inhibition indicating that antigens from CD46-mediated captured MV were likely processed in the endosome/lysosome compartment. Altogether these data indicate that (a) MV targeting via CD46 has a strong effect on the efficiency of antigen presentation by MHC class II, (b) the effect is mediated by the binding of H to CD46, and (c) though MV does fuse with plasma membrane, endocytosis, and processing of virus particles are also occurring. Since, in humans, CD46 is expressed in almost every tissue including professional antigen-presenting cells, such a targeting is likely to play a crucial role in the CD4+ T cell-mediated primary immune response against the pathogen in vivo.


Assuntos
Apresentação de Antígeno , Antígenos CD/imunologia , Linfócitos B/imunologia , Hemaglutininas Virais/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Vírus do Sarampo/imunologia , Glicoproteínas de Membrana/imunologia , Animais , Antígenos Virais/imunologia , Linhagem Celular , Humanos , Vírus do Sarampo/fisiologia , Proteína Cofatora de Membrana , Fusão de Membrana/imunologia , Camundongos , Proteínas do Envelope Viral/imunologia
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