RESUMO
Tracking human immunodeficiency virus-type 1 (HIV-1) infection at the cellular level in tissue reservoirs provides opportunities to better understand the pathogenesis of infection and to rationally design and monitor therapy. A quantitative technique was developed to determine viral burden in two important cellular compartments in lymphoid tissues. Image analysis and in situ hybridization were combined to show that in the presymptomatic stages of infection there is a large, relatively stable pool of virions on the surfaces of follicular dendritic cells and a smaller pool of productively infected cells. Despite evidence of constraints on HIV-1 replication in the infected cell population in lymphoid tissues, estimates of the numbers of these cells and the virus they could produce are consistent with the quantities of virus that have been detected in the bloodstream. The cellular sources of virus production and storage in lymphoid tissues can now be studied with this approach over the course of infection and treatment.
Assuntos
Células Dendríticas/virologia , Infecções por HIV/virologia , HIV-1/fisiologia , Leucócitos Mononucleares/virologia , Tecido Linfoide/virologia , Carga Viral , Adulto , Elementos Antissenso (Genética) , Autorradiografia , Contagem de Linfócito CD4 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Processamento de Imagem Assistida por Computador , Hibridização In Situ , Linfonodos/virologia , Tonsila Palatina/virologia , Sondas RNA , RNA Viral/análise , RNA Viral/sangue , Sensibilidade e Especificidade , Baço/virologiaRESUMO
In lymphoid tissue, where human immunodeficiency virus-type 1 (HIV-1) is produced and stored, three-drug treatment with viral protease and reverse transcriptase inhibitors markedly reduced viral burden. This was shown by in situ hybridization and computerized quantitative analysis of serial tonsil biopsies from previously untreated adults. The frequency of productive mononuclear cells (MNCs) initially diminished with a half-life of about 1 day. Surprisingly, the amount of HIV-1 RNA in virus trapped on follicular dendritic cells (FDCs) decreased almost as quickly. After 24 weeks, MNCs with very few copies of HIV-1 RNA per cell were still detectable, as was proviral DNA; however, the amount of FDC-associated virus decreased by >/=3.4 log units. Thus, 6 months of potent therapy controlled active replication and cleared >99.9 percent of virus from the secondary lymphoid tissue reservoir.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Células Dendríticas/virologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Tonsila Palatina/virologia , Adulto , Linfócitos T CD4-Positivos/virologia , DNA Viral/análise , Células Dendríticas/citologia , Quimioterapia Combinada , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/isolamento & purificação , HIV-1/fisiologia , Humanos , Processamento de Imagem Assistida por Computador , Hibridização In Situ , Cinética , Lamivudina/uso terapêutico , Leucócitos Mononucleares/citologia , Macrófagos/virologia , Provírus/genética , RNA Viral/análise , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/uso terapêutico , Carga Viral , Replicação Viral/efeitos dos fármacos , Zidovudina/uso terapêuticoRESUMO
In sexual transmission of simian immunodeficiency virus, and early and later stages of human immunodeficiency virus-type 1 (HIV-1) infection, both viruses were found to replicate predominantly in CD4(+) T cells at the portal of entry and in lymphoid tissues. Infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells. The infected proliferating cells correspond to the short-lived population that produces the bulk of HIV-1. Most of the HIV-1-infected resting T cells persisted after antiretroviral therapy. Latently and chronically infected cells that may be derived from this population pose challenges to eradicating infection and developing an effective vaccine.
Assuntos
Linfócitos T CD4-Positivos/virologia , Infecções por HIV/transmissão , HIV-1/fisiologia , Ativação Linfocitária , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/fisiologia , Animais , Fármacos Anti-HIV/uso terapêutico , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Ciclo Celular , Colo do Útero/virologia , Células Epiteliais/virologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Linfonodos/virologia , Macaca mulatta , RNA Viral/análise , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Fatores de Tempo , Replicação ViralRESUMO
Malassezia furfur is a yeast that can cause a variety of infections, most commonly in normal hosts, and also in immunocompromised hosts. This yeast typically colonizes the skin, and is the causative agent of tinea versicolor. However, in immunocompromised hosts, it can more commonly cause catheter-related fungemia or folliculitis. Pulmonary infections from Malassezia have not been commonly recognized. Unlike many other common opportunistic fungal infections in immunocompromised hosts, neutropenia and the use of broad-spectrum antibiotics do not appear to be significant risk factors for Malassezia infections in the stem cell transplant (SCT) population. Additionally, disseminated infection, despite fungemia, is uncommon. A series of patients who underwent SCT at the University of Minnesota between 2004 and 2006 were reviewed for the occurrence of suspected Malassezia infections in the post-transplant period. Four cases of possible pulmonary M. furfur infection were identified in our SCT recipients. The clinical characteristics of these patients, the infections, treatment, and outcome are described. In addition, we discuss the possible pathogenicity of this yeast in the pulmonary setting.
Assuntos
Pneumopatias Fúngicas , Malassezia/patogenicidade , Transplante de Células-Tronco/efeitos adversos , Centros Médicos Acadêmicos , Adulto , Idoso , Criança , Feminino , Humanos , Pneumopatias Fúngicas/diagnóstico , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/mortalidade , Malassezia/classificação , Malassezia/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Minnesota , Micoses/diagnóstico , Micoses/microbiologia , Micoses/mortalidade , Escarro/microbiologiaRESUMO
OBJECTIVES: Triple combination treatment of HIV-1 infection using two reverse transcriptase inhibitors and a protease inhibitor can result in significant and sustained decreases in the quantity of viral RNA in peripheral blood. Lymphoid tissue, however, constitutes the major reservoir of HIV in infected patients. Study of the viral burden in these tissues has provided additional insight in the efficacy of antiretroviral treatment. DESIGN: Patients were randomized into two groups in order to study differences in the development of resistance to reverse transcriptase inhibitors. Group I started treatment with all three drugs simultaneously. Group II started with ritonavir monotherapy, aiming at initial reduction in virus production before the addition of lamivudine and zidovudine 3 weeks later. METHODS: Changes in the amount of HIV in plasma and tonsillar lymphoid tissue during 24 weeks of treatment with ritonavir, lamivudine and zidovudine were studied by reverse transcriptase polymerase chain reaction. RESULTS: Thirty-three antiretroviral-naive HIV-infected patients were included for analysis. After 24 weeks, median CD4+ cell count increased by 152 x 10(6)/l and median plasma viral RNA levels decreased by at least 2.87 log10 copies/ml. In 88% of the patients remaining on treatment, plasma RNA levels were below the quantification limit of the assay used (mean, 2.4 log10 copies/ml). The lymphoid tissue viral burden, ranging from 9.16 to 8.52 log10 copies/g at baseline, was markedly reduced with at least 2.1 log10 copies/g by week 24 in the five patients analysed. Eight patients (24%) withdrew because of side-effects. In one patient in group II, ritonavir and lamivudine resistance-associated mutations developed. CONCLUSIONS: Treatment with this triple antiretroviral drug combination produced a durable and strong decrease of HIV-1 RNA burden in both plasma and lymphoid tissue.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Tecido Linfoide/virologia , RNA Viral/análise , Adulto , Resistência Microbiana a Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Lamivudina/uso terapêutico , Tecido Linfoide/química , Masculino , Tonsila Palatina/química , Tonsila Palatina/virologia , Reação em Cadeia da Polimerase , RNA Viral/sangue , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/uso terapêutico , Resultado do Tratamento , Carga Viral , Zidovudina/uso terapêuticoAssuntos
Infecções por HIV , HIV-1 , Bancos de Tecidos , Fármacos Anti-HIV/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , National Institutes of Health (U.S.) , Linfócitos T/imunologia , Estados UnidosRESUMO
A number of the herpesviruses as well as representatives of other viral genera can produce serious opportunistic infections in persons infected with HIV. Although some, such as JC virus, HHV-6, and HHV-8, remain essentially untreatable at this time, others are readily treatable or can be retarded with chemoprophylaxis. Further therapeutic advances for some of these viral superinfections, particularly CMV, HSV, VZV, HHV-8, and human genital papillomavirus, will considerably improve the longevity and quality of life of persons with AIDS.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/virologia , Infecções por HIV/complicações , Herpesviridae , Viroses/virologia , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/terapia , Humanos , Viroses/diagnóstico , Viroses/terapiaRESUMO
New highly active antiretroviral therapies are boosting the blood absolute CD4+ counts of many patients with AIDS and are decreasing the prevalence of AIDS-related opportunistic infections. Nevertheless, the prevention, diagnosis, and treatment of opportunistic infections remain important features of management of HIV infection. In recent years, significant advances have been made in the prevention and treatment of opportunistic diseases such as Pneumocystis carinii pneumonia, Cytomegalovirus retinitis, disseminated Mycobacterium avium-intracellulare infection, and mucosal candidiasis. Tuberculosis, cryptococcal meningitis, herpes simplex virus infection, shingles, and infectious enteritis also continue to be troublesome. Kaposi's sarcoma may be the newest AIDS-related opportunistic infection to be identified. The immune system effects of highly active antiretroviral therapy are as yet poorly understood. Therefore, an aggressive approach to diagnosis and treatment of opportunistic infections remains mandatory, and patients receiving antiretroviral therapy should continue to adhere to recommendations for prophylaxis against such infections.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Fármacos Anti-HIV/uso terapêutico , Anti-Infecciosos/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Humanos , Pneumonia por Pneumocystis/tratamento farmacológicoRESUMO
The National NeuroAIDS Tissue Consortium (NNTC) was founded in 1998, in response to the scientific need for well-characterized central nervous system (CNS) and peripheral nervous system (PNS) tissues and fluids from HIV-infected individuals. In addition to performing the routine functions of non-transplant anatomic tissue banks, the Consortium offers a unique model for the integration of independent research entities in order to provide well-characterized tissues and fluids for the international research community. Herein, we describe the structure of the Consortium, pointing out the inherent strengths of linking together multiple independent sites for the purpose of banking HIV-infected nervous system tissues. We describe the neuropathology protocol that was adopted and successfully implemented at the four participating banks of the Consortium.
Assuntos
Complexo AIDS Demência/patologia , Infecções do Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso Periférico/patologia , Bancos de Tecidos/organização & administração , Bancos de Tecidos/normas , Sistema Nervoso Central/patologia , Humanos , Relações Interinstitucionais , Músculo Esquelético/patologia , Sistema Nervoso Periférico/patologia , Hipófise/patologia , Avaliação de Programas e Projetos de Saúde , Controle de Qualidade , Gânglio Trigeminal/patologiaRESUMO
OBJECTIVES: Widespread dendritic injury may be one mechanism involved in the neurologic impairment that occurs in HIV-1 infection. The objectives of this study were to quantitate the extent of dendritic injury in a primate model of central nervous system (CNS) infection, investigate the role of nitric oxide (NO) as a mediator of neuropathologic changes, and evaluate the relation of these changes to cognitive and motor function. STUDY DESIGN/METHODS: Cognitive and motor function was assessed in rhesus macaque monkeys infected with simian immunodeficiency virus (SIV). In situ hybridization, immunohistochemistry, and quantitative image analysis were employed to assess the relations among productive infection, NO synthase (iNOS), and dendritic injury. RESULTS: Productive infection of cells of the macrophage lineage in CNS is associated with inflammation, increased expression of iNOS, and dendritic injury. The tests of cognitive and motor function employed were abnormal in both animals that had evidence of productive infection and those that did not. CONCLUSIONS: Increased NO accompanying productive infection and encephalitis may be one cause of neuronal injury in lentivirus infections of the CNS. Extension of tests of cognitive and motor function to late-stage AIDS in rhesus monkeys is needed to assess the potential role of NO-induced dendritic damage in lentiviral encephalopathy/AIDS dementia complex.
Assuntos
Dendritos/patologia , Encefalite Viral/enzimologia , Óxido Nítrico Sintase/biossíntese , Síndrome de Imunodeficiência Adquirida dos Símios/enzimologia , Vírus da Imunodeficiência Símia , Animais , Sistema Nervoso Central/virologia , Transtornos Cognitivos , Encefalite Viral/patologia , Macaca mulatta , Atividade Motora , Neurônios , Óxido Nítrico Sintase Tipo II , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Replicação ViralRESUMO
Over the course of HIV-1 infection, the lymphoid follicles where the humoral immune response is generated initially increase in size and number and then progressively involute. In advanced disease, the network of the processes of follicular dendritic cells (FDCs) that serve as antigen repositories and anatomical substrate for B and T cells and antigen to interact is destroyed, contributing to the breakdown of the immune system. Because destruction of FDCs is associated with deposition of HIV-1, and much of the virus can be cleared from the network with antiretroviral therapy, we investigated the reversibility of damage. We measured the immunohistochemically stainable FDC compartment by quantitative image analysis, and we documented changes in this compartment at different stages of disease. We show that treatment, initiated even at advanced stages of HIV-1 disease, can slowly reverse pathological changes in the FDC network.
Assuntos
Células Dendríticas/patologia , Infecções por HIV/patologia , HIV-1/isolamento & purificação , Tecido Linfoide/patologia , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Tecido Linfoide/efeitos dos fármacosRESUMO
Potent combinations of antiretroviral drugs diminish the turnover of CD4+ T lymphocytes productively infected with HIV-1 and reduce the large pool of virions deposited in lymphoid tissue (LT). To determine to what extent suppression of viral replication and reduction in viral antigens in LT might lead correspondingly to repopulation of the immune system, we characterized CD4+ T lymphocyte populations in LT in which we previously had quantitated viral load and turnover of infected cells before and after treatment. We directly measured by quantitative image analysis changes in total CD4+ T cell counts, the CD45RA+ subset, and fractions of proliferating or apoptotic CD4+ T cells. Compared with normal controls, we documented decreased numbers of CD4+ T cells and increased proliferation and apoptosis. After treatment, proliferation returned to normal levels, and total CD4+ T and CD45RA+ cells increased. We discuss the effects of HIV-1 on this subset based on the concept that renewal mechanisms in the adult are operating at full capacity before infection and cannot meet the additional demand imposed by the loss of productively infected cells. The slow increases in the CD45RA+ CD4+ T cells are consistent with the optimistic conclusions that (i) renewal mechanisms have not been damaged irreparably even at relatively advanced stages of infection and (ii) CD4+ T cell populations can be partially restored by control of active replication without eradication of HIV-1.