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1.
Control Clin Trials ; 20(3): 253-66, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10357498

RESUMO

The results of multicenter clinical trials may differ across participating clinical sites. We present a diagnostic approach for evaluating this diversity that emphasizes the relationship between the observed event rates and treatment effects. We use as an example a trial of sequential strategies of Pneumocystis prophylaxis in human immunodeficiency virus infection with 842 patients randomly allocated to start prophylaxis with trimethoprim/sulfamethoxazole, dapsone, or pentamidine. Prophylaxis failure rates varied significantly across the 30 clinical sites (0-30.3%, p = 0.002 by Fisher's exact test) with prominent variability in the pentamidine arm (0-63.6%). Starting with oral regimens was better than starting with pentamidine in sites with high rates of events, whereas the three strategies had more similar efficacy in other sites. Sites enrolling fewer patients had lower event rates and had more patients who withdrew prematurely or were lost to follow-up. In a hierarchical regression model adjusting for random measurement error in the observed event rates, starting with trimethoprim/sulfamethoxazole was predicted to be increasingly better than starting with aerosolized pentamidine as the risk of prophylaxis failure increased (p = 0.01), reducing the risk of failure by 47% when the failure rate of pentamidine was 30%, whereas the two regimens were predicted to be equivalent when the failure rate was 17%. Differences in event rates could reflect a combination of heterogeneity in diagnosis, administration of treatments, and disease risk in patients across sites. The evaluation of clinical site differences with a systematic approach focusing on event rates may give further insight in the interpretation of the results of multicenter trials beyond an average treatment effect.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Anti-Infecciosos/uso terapêutico , Ensaios Clínicos Controlados como Assunto/estatística & dados numéricos , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Infecções por Pneumocystis/prevenção & controle , Dapsona/uso terapêutico , Humanos , Pentamidina/uso terapêutico , Probabilidade , Modelos de Riscos Proporcionais , Tamanho da Amostra , Falha de Tratamento , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
2.
AIDS ; 12(15): 1983-90, 1998 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-9814866

RESUMO

OBJECTIVES: To describe the methods and results of a standardized system for clinical endpoint determination for defining and reviewing endpoints in clinical trials for HIV-infected individuals. DESIGN: A system was developed utilizing standard definitions for the 24 diagnoses or clinical events that serve as trial endpoints and together define the combined endpoint 'progression of HIV disease. A common set of case report forms were used for all trials. Thus, an event of Pneumocystis carinii pneumonia (PCP), for example, for a subject co-enrolled in an antiretroviral trial and a PCP prophylaxis trial was only reported once. METHODS: A central committee was established to define clinical events and review endpoints across all studies. Events were classified according to established criteria for confirmed, probable and possible levels of certainty. RESULTS: This report describes the methods used to ascertain and review endpoints, and summarized 2299 clinical events for 8097 subjects enrolled in one or more of nine clinical trials. Data on the diagnostic certainty of events and agreement between site clinicians and the endpoint committee are presented. CONCLUSIONS: Uniform classification of endpoints across AIDS clinical trials can be accomplished by multicenter, multitrial organizations with standardized definitions and review of endpoint documentation. Our experience suggests that nurse coordinators reviewing all submitted endpoints for every trial are warranted and the need for external review by a clinical events committee may depend on the type of trial conducted.


Assuntos
Ensaios Clínicos como Assunto/normas , Infecções por HIV/tratamento farmacológico , Resultado do Tratamento , Infecções Oportunistas Relacionadas com a AIDS/classificação , Coleta de Dados/métodos , Progressão da Doença , Humanos
3.
J Infect Dis ; 178(1): 80-91, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9652426

RESUMO

A multicenter, double-blind, placebo-controlled trial randomized 28 patients with primary (acute) human immunodeficiency virus (HIV)-1 infection (PHI) to receive zidovudine, 1000 mg daily, or placebo for 24 weeks. At week 48, compared with placebo patients, zidovudine-treated patients had significantly higher CD4 cell counts (zidovudine, 666 cells/mm3; placebo, 362; P = .004) and lower peripheral blood mononuclear cell (PBMC) culture titers (zidovudine, 0.58 log infectious units per million cells; placebo, 1.68; P = .02) but no difference in plasma RNA (zidovudine, 3.93 log copies/mL; placebo, 4.00; P = .83). Serious adverse events and minor clinical events were infrequent and comparable in both arms. There were two deaths: 1 patient died of sepsis and renal disease (zidovudine arm), and 1 patient died of sepsis and tension pneumothorax (placebo arm). Six months of high-dose zidovudine initiated during PHI results in higher CD4 cell counts and lower PBMC culture titers but no difference in plasma HIV-1 RNA. Further studies with more potent antiretroviral combination therapies are warranted.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Zidovudina/uso terapêutico , Adolescente , Adulto , Western Blotting , Contagem de Linfócito CD4 , Método Duplo-Cego , Feminino , Seguimentos , Genótipo , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/fisiologia , Humanos , Masculino , Cooperação do Paciente , Fenótipo , Placebos , Carga Viral
4.
Nat Med ; 4(3): 341-5, 1998 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9500610

RESUMO

Evolutionary patterns of virus replication and distribution in lymphoid tissue during the early phases of HIV infection have not been delineated. Lymph node (LN) biopsies were excised from patients at different times after the estimated time of primary infection. Within 3 months of the acute viral syndrome, HIV was mostly present in individual virus-expressing cells in LNs; trapping of virions in the follicular dendritic cell (FDC) network was minimal or absent, but was the predominant form of HIV detected in LNs of subjects with chronic infection, either recent (4-20 months after primary infection) or long-term (>2-3 years after primary infection). Plasma viremia was significantly higher in patients during the first 3 months than in those recently infected; however, there were no significant differences in the number of virus-expressing cells per square millimeter of LN tissue in these two groups. Numbers of virus-expressing cells in lymphoid tissue were significantly lower in the subjects with long-term infection than in the other two groups. Therefore, during the transition from primary to chronic HIV infection, the level of HIV replication in lymphoid tissue remains elevated despite the fact that viremia is significantly downregulated. These findings have implications for therapeutic strategies in primary HIV infection and in recent seroconvertors.


Assuntos
Infecções por HIV/virologia , HIV/crescimento & desenvolvimento , Linfonodos/virologia , Doença Aguda , Biópsia , Doença Crônica , Células Dendríticas/virologia , Progressão da Doença , Infecções por HIV/terapia , Humanos , RNA Viral/sangue , Viremia , Replicação Viral
5.
AIDS Res Hum Retroviruses ; 13(10): 815-8, 1997 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-9197375

RESUMO

Critical advances in understanding the pathogenesis and treatment of HIV-1 infection have been made. These include the following: delineation of the replication kinetics of HIV in all stages of disease, underscoring the role of viral replication in disease pathogenesis; development of highly sensitive quantitative assays to determine viral load in infected individuals; and potent new antiretroviral drugs, the availability of which has provided a tool for the investigation of viral pathogenesis and immunopathogenesis, and has permitted the demonstration of the clinical efficacy of combination therapies. The results of studies of potent antiretroviral combination therapies presented at the Fourth Conference on Retroviruses and Opportunistic Infections (January 22-26, 1997, Washington, D.C.) demonstrate that such therapies are capable of at least partially restoring the immune system that is damaged by infection with HIV-1. This includes evidence for the ability of potent therapies to begin to reverse the abnormalities of maturation, activation, and function that are attributable directly or indirectly to the CD4+ helper T lymphocyte population.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Ensaios Clínicos como Assunto , Infecções por HIV/etiologia , Humanos , Sistema Imunitário/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia
7.
J Infect Dis ; 169(5): 981-9, 1994 May.
Artigo em Inglês | MEDLINE | ID: mdl-7909550

RESUMO

Interferon-alpha (IFN-alpha) can inhibit human immunodeficiency virus (HIV-1) replication and is effective in treating Kaposi's sarcoma; interleukin-2 (IL-2) can increase circulating lymphocytes in HIV-1-infected patients. The safety of combination treatment with recombinant (r)IFN-alpha 2b and IL-2 was evaluated in HIV-1-infected patients with > 200 CD4+ T cells/mm3. A maximal tolerated dose of rIFN-alpha 2b was determined for 17 patients; then they received in combination 3, 6, or 12 x 10(6) IU/day rIL-2, given intravenously over 21 days. Twelve patients ultimately received the combination, 9 for the full 21 days. Significant toxicities included flu-like symptoms, anemia, transaminemia, and depression. Transient increases in CD4+ T cell percentages and spontaneous lymphocyte blast transformation were observed. Quantitative microcultures demonstrate a decline in HIV titers in patients receiving rIFN-alpha 2b (5/9) with a further decline on addition of rIL-2 (7/9). In summary, continuous rIL-2 at 6 x 10(6) IU/day in combination with rIFN-alpha 2b was reasonably tolerated and provided preliminary evidence of immunomodulatory and antiviral activity.


Assuntos
Infecções por HIV/terapia , HIV-1 , Interferon-alfa/uso terapêutico , Interleucina-2/uso terapêutico , Adolescente , Adulto , Linfócitos T CD4-Positivos , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Interferon-alfa/efeitos adversos , Interleucina-2/efeitos adversos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/toxicidade , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/terapia
8.
Eur J Immunol ; 24(3): 531-6, 1994 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-7907291

RESUMO

In the present study the requirements for in vitro infection of antigen-specific CD8+ cytotoxic T lymphocytes (CTL) with human immunodeficiency virus -1(HIV-1) were investigated. CD3+CD8+CD4- HIV-1 nef-specific CTL become infected with HIV-1 after short-term co-culture with HLA-matched HIV-1-infected CD20+ B lymphoblastoid cells (B-LCL) which are specifically killed. Similar results were observed with an allospecific CD8+ CTL population. In addition, co-culture experiments showed that once infected with HIV-1, these CD8+ CTL could spread the infection further to uninfected CD4+ lymphocytes. In contrast, CD8+ CTL did not become infected with HIV-1 when co-cultured with HLA-mismatched HIV-1-infected B-LCL which are not killed. These observations in vitro could have relevance in peripheral lymphoid organs contributing to the progressive decrease of HIV-specific CD8+ CTL activity that is associated with the progression to AIDS.


Assuntos
Infecções por HIV/microbiologia , Subpopulações de Linfócitos T/microbiologia , Linfócitos T Citotóxicos/microbiologia , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8/análise , Células Cultivadas , Citotoxicidade Imunológica , DNA Viral/análise , Produtos do Gene nef/imunologia , Infecções por HIV/transmissão , HIV-1/crescimento & desenvolvimento , Humanos , Imunidade Celular , Técnicas In Vitro , Linfoma de Células B/microbiologia , Células Tumorais Cultivadas , Produtos do Gene nef do Vírus da Imunodeficiência Humana
9.
Adv Intern Med ; 39: 305-55, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-8140958

RESUMO

Research progress in the understanding of HIV and its effects on the human immune system continues at a rapid pace. Such research is yielding new ideas for chemotherapeutic agents, immunologic stimulators and modifiers, and potential vaccines. Clinical trials to test these approaches are under way. Despite the accomplishments, the epidemic progresses unchecked, resulting in continued suffering and death and enormous demands on the health care system of many nations. Clinicians have had to deal with new and difficult opportunistic infections. Yet advances in the treatment and prevention of these illnesses have benefited many AIDS victims. In the United States, the AIDS epidemic is now concentrating in the inner cities, involving injection drug users, minorities, heterosexuals, women and their offspring. In the developing world, AIDS continues to be predominantly a heterosexually transmitted disease, where more than one third of prostitutes in central African cities are infected. The major burden of the AIDS epidemic in the remainder of this and the next century will be in India and Southeast Asia, again predominantly via heterosexual spread. A great deal is now understood concerning the life cycle of HIV. More light has been shed on the interaction of HIV and CD4+ T cells, the cellular and viral factors involved in viral expression vs. latency, the function of the viral regulatory and structural proteins and the role of cytokines in regulation of HIV expression. Our understanding of the precise mechanisms whereby HIV causes a loss of CD4+ T cells remains incomplete. The direct infection and cell killing of CD4+ T cells is important and is supported by recent evidence demonstrating a high viral burden in these cells in the lymphoid tissue of patients. Over the last 1 to 2 years, there has been new evidence for indirect mechanisms of CD4+ T-cell depletion and/or dysfunction including: autoimmune reactions, perturbations of specific V beta T-cell receptor populations, infection of T-cell precursors in bone marrow and thymus, immunosuppression and dysregulation by viral proteins, possible super-antigen effects, and antigen-induced apoptosis or programmed cell death. New information has come forth in our understanding of B-cell abnormalities in HIV pathogenesis, including the putative role of IL-6 in B-cell activation and the identification of EBV in B-cell lymphomas in the CNS of patients with AIDS. It is expected that these and future discoveries concerning immunopathogenesis of HIV infection will help steer the therapeutic effort. Major strides continue to be made in the therapeutic arena for HIV infection and its complications.(ABSTRACT TRUNCATED AT 400 WORDS)


Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , HIV-1 , Vacinas contra a AIDS , Infecções Oportunistas Relacionadas com a AIDS/terapia , Síndrome da Imunodeficiência Adquirida/epidemiologia , Síndrome da Imunodeficiência Adquirida/terapia , Feminino , Terapia Genética , Infecções por HIV/epidemiologia , Infecções por HIV/terapia , Humanos , Masculino , Vacinas Virais , Zidovudina/uso terapêutico
10.
J Infect Dis ; 168(6): 1490-501, 1993 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8245534

RESUMO

Primary human immunodeficiency virus type 1 (HIV-1) infection can present clinically as the abrupt onset of a febrile illness resembling acute mononucleosis. The symptoms coincide with high titers of culturable plasma viremia, cell-associated virus, and antigenemia, which rapidly decrease coincident with the emergence of detectable HIV-specific antibody and HIV-specific cytotoxic T lymphocytes. This article reviews the human and animal model data on the virologic and immunologic events that occur during primary HIV-1 and animal retrovirus infections, evaluates the prophylactic treatment experience of retrovirus infections in the animal model, and provides a plausible rationale for treatment intervention of primary HIV-1 infection in humans. Recent work delineating the pathogenesis of primary HIV-1 infection provides insight into the major mechanisms of viral dissemination and host immune response. The results from retrovirus-infected animal models treated with antiviral agents suggests that therapy at the time of viral dissemination may be an effective strategy that may modify disease progression. Clinical trials to evaluate this approach are in progress.


Assuntos
Infecções por HIV , HIV-1 , Animais , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/microbiologia , Humanos , Infecções por Retroviridae/imunologia , Infecções por Retroviridae/microbiologia
12.
Clin Infect Dis ; 17(4): 749-71, 1993 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8268360

RESUMO

The primary approach to therapy for infection with human immunodeficiency virus (HIV) continues to be centered around antiretroviral agents that have conferred significant clinical benefits. The considerable degree of immunologic dysfunction in HIV infection, however, has led to intense interest in methods of immune stimulation and reconstitution. Immunomodulatory intervention in HIV infection is highly controversial. Over the years a number of immunomodulatory agents--many with only a poor rationale for their clinical use--have been evaluated. In this review we concentrate on immunomodulatory approaches that are currently being investigated. We group these interventions, reviewing the rationale and clinical data for each category: passive immunity (administration of immunoglobulins and use of apheresis), thymic hormone treatment, cytokine treatment (administration of interleukins, tumor necrosis factor, and interferons), adoptive cellular immunity, and therapeutic vaccination. At present, the only interventions supported by data from well-controlled studies are the parenteral administration of interferon alpha to patients with HIV-associated Kaposi's sarcoma and the administration of pooled immunoglobulin (to decrease the rate of bacterial infections) to children who cannot take trimethoprim-sulfamethoxazole. However, several other approaches under development show promise in reversing some of the immune deficits of HIV infection. Clinical evaluation of these approaches should yield valuable insights into the immunopathogenesis of HIV infection, and these insights should facilitate the formulation of new modalities of treatment.


Assuntos
Infecções por HIV/terapia , HIV-1 , Imunoterapia/métodos , Vacinas contra a AIDS/farmacologia , Vacinas contra a AIDS/uso terapêutico , Adulto , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Remoção de Componentes Sanguíneos , Criança , Pré-Escolar , Citocinas/farmacologia , Citocinas/uso terapêutico , HIV-1/imunologia , Humanos , Imunoglobulinas Intravenosas/farmacologia , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Recém-Nascido , Hormônios do Timo/farmacologia , Hormônios do Timo/uso terapêutico
13.
Infect Agents Dis ; 2(5): 291-303, 1993 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8173814

RESUMO

Viral infections such as with the human immunodeficiency virus (HIV) present difficult challenges for the development of effective antiviral therapies. These viruses depend on the host cell machinery for their existence, and interference with these processes typically interferes with other important host physiology. HIV presents other challenges as well because of its inherent pathogenic destruction of the immune system. It is the goal of HIV therapeutics to attempt to cure HIV infection, or if that is not possible, to stop HIV disease progression while preserving a high quality of life for HIV-infected individuals. This may be achieved through an effective combination of interference with the viral life cycle and the pathogenic processes, and by slowing or reversing the immunologic dysfunction that leads to the complications of HIV infection. Unprecedented progress has been made in understanding the virus and HIV disease pathogenesis. This knowledge has led to the identification of viral features that have become targets for therapeutic intervention. This article reviews the most important priorities of HIV treatment research for adult HIV-infected patients for the immediate future. These priorities include the following: development of new antiretroviral compounds and their application as both monotherapies and in combination therapy approaches; immune-based therapeutic approaches; and research and treatment for acute or primary HIV infections.


Assuntos
Infecções por HIV/terapia , Antivirais/uso terapêutico , Quimioterapia Combinada , HIV-1 , Humanos , Imunoterapia
14.
AIDS Res Hum Retroviruses ; 9(9): 913-24, 1993 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-7903045

RESUMO

A Workshop on primary human immunodeficiency virus type 1 (HIV-1) infection sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and the Office of AIDS Research (OAR) of the National Institutes of Health (NIH) was held February 25-26, 1993 in Bethesda, Maryland. The major goals of this scientific meeting were to bring together researchers and infectious disease specialists who have expertise in primary HIV-1 infection (PHI) to review the pathogenesis of PHI, the treatment experience of PHI in humans and of early retroviral infection in animal models, and to devise theoretical and operational strategies for future clinical trials relating to therapeutic intervention of PHI. The proceedings of this workshop are timely and serve to further the development of innovative strategies for the treatment of HIV-1 infection.


Assuntos
Infecções por HIV , HIV-1 , Animais , Antivirais/uso terapêutico , Criança , Ensaios Clínicos como Assunto , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/microbiologia , Infecções por HIV/patologia , Humanos , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia
15.
Clin Infect Dis ; 15(1): 134-57, 1992 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-1617054

RESUMO

Opportunistic infections are a major cause of morbidity and death among patients infected with the human immunodeficiency virus (HIV), particularly late in the disease, when immunosuppression is severe. Some pathogens, such as Pneumocystis carinii and Toxoplasma gondii, are extremely common in this population and are readily recognized by clinicians caring for these patients. However, many other organisms occasionally cause conditions that clinically mimic the more commonly encountered pathogens. Clinicians must be alert to the threat posed by these less frequently occurring organisms and of the broader differential diagnosis that must be considered for infections in patients with HIV infection.


Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Infecções Oportunistas/microbiologia , Infecções Oportunistas/parasitologia , Gastroenteropatias/microbiologia , Gastroenteropatias/parasitologia , Cardiopatias/microbiologia , Cardiopatias/parasitologia , Humanos , Artropatias/microbiologia , Artropatias/parasitologia , Pneumopatias/microbiologia , Pneumopatias/parasitologia , Doenças do Sistema Nervoso/microbiologia , Doenças do Sistema Nervoso/parasitologia , Infecções Oportunistas/complicações , Dermatopatias Infecciosas/complicações
16.
J Immunol ; 149(2): 689-97, 1992 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-1378076

RESUMO

Individuals infected with HIV frequently develop cytopenias and suppressed hematopoiesis. The role of direct HIV infection of hematopoietic progenitor cells in this process has not been defined. In this study, purified CD34+ bone marrow progenitor cells from 74 Zairian and American patients were studied by both coculture viral isolation and polymerase chain reaction for evidence of HIV infection. A total of 36.5% of Zairian and 14% of American patients had HIV infection of the CD34+ cell subset, with as many as 1 in 500 CD34+ cells infected. Most of the Zairian patients in this study had advanced HIV infection and markedly decreased CD4/CD8 T lymphocyte ratios (mean 0.160 +/- 0.08), and no laboratory value predicted the presence of infection in the CD34+ subset of a given Zairian individual. In contrast, American patients with CD34+ cell infection had total CD4 cells less than 20/mm3 and a greater decrease of the CD4/CD8 T lymphocyte ratio compared to seropositive Americans without CD34+ cell infection (p = 0.003). Hematopoiesis, studied by methylcellulose colony assays, was depressed in all seropositive patients studied with no significant further suppression when CD34+ cells were infected. Thus, CD34+ bone marrow progenitor cells are infected in vivo in a subset of seropositive individuals and may serve as an additional reservoir of virus in HIV-infected individuals.


Assuntos
Antígenos CD/análise , Medula Óssea/microbiologia , Soropositividade para HIV/microbiologia , HIV/isolamento & purificação , Células-Tronco Hematopoéticas/microbiologia , Adulto , Idoso , Antígenos CD34 , Medula Óssea/imunologia , Células da Medula Óssea , Antígenos CD4/análise , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Separação Celular , Feminino , Células-Tronco Hematopoéticas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase
17.
Proc Natl Acad Sci U S A ; 88(21): 9838-42, 1991 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-1682922

RESUMO

The total number of human immunodeficiency virus type 1 (HIV-1)-infected circulating CD4+ T lymphocytes is considered to be a reflection of the HIV burden at any given time during the course of HIV infection. However, the low frequency of HIV-infected circulating CD4+ T lymphocytes and the low level or absence of plasma viremia in the early stages of infection do not correlate with the progressive immune dysfunction characteristic of HIV infection. In this study, we have determined whether HIV-infected circulating CD4+ T lymphocytes are a correct reflection of the total pool of HIV-infected CD4+ T cells (i.e., HIV burden). To this end, HIV burden has been comparatively analyzed in peripheral blood and lymphoid tissues (lymph nodes, adenoids, and tonsils) from the same patients. The presence of HIV-1 DNA in mononuclear cells isolated simultaneously from peripheral blood and lymphoid tissues of the same patients was determined by polymerase chain reaction amplification. We found that the frequency of HIV-1-infected cells in unfractionated or sorted CD4+ cell populations isolated from lymphoid tissues was significantly higher (0.5-1 log10 unit) than the frequency in peripheral blood. Comparable results were obtained in five HIV seropositive patients in the early stages of disease and in one patient with AIDS. These results demonstrate that a heavy viral load does reside in the lymphoid organs, indicating that they may function as major reservoirs for HIV. In addition, the finding of a heavy viral load in the lymphoid organs of patients in the early stages of disease may explain the progressive depletion of CD4+ T lymphocytes and the immune dysfunction associated with the early stages of HIV infection.


Assuntos
Síndrome da Imunodeficiência Adquirida/microbiologia , Soropositividade para HIV/microbiologia , Tecido Linfoide/microbiologia , Adulto , Linfócitos T CD4-Positivos/microbiologia , Pré-Escolar , DNA Viral/análise , Feminino , Proteína do Núcleo p24 do HIV/sangue , Humanos , Linfonodos/microbiologia , Masculino , Reação em Cadeia da Polimerase
18.
J Immunol ; 147(8): 2553-8, 1991 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-1918977

RESUMO

The hallmark of infection with HIV-1 is progressive depletion and qualitative dysfunction of the CD4+ Th cell population in infected individuals. Clinical trials of antiretroviral agents have shown that, despite suppression of virus replication, regeneration of the T cell pool does not occur. One proposed explanation for the defective regenerative capacity of the CD4+ T cell pool is infection of early T lymphocyte progenitors or stem cells. An additional explanation could be failure of cells of the intrathymic microenvironment (thymic epithelial (TE) cells) to carry out critical nurturing functions for developing thymocytes, i.e., secretion of thymocyte-trophic cytokines and expression of adhesion molecules. This study examines the effect of HIV on cultured TE cells and determines the role of TE cells in the regulation of viral expression in chronically HIV-infected cells. We found no evidence of infection of TE cells after exposure to HIV-1. However, normal human serum induced secretion of IL-6 by TE cells; induction of TE IL-6 was partially blocked by anti-IFN-gamma antibodies. Moreover, supernatants from TE cells maintained in normal human serum up-regulated HIV replication in chronically HIV-1-infected cells. Because intrathymic T cell precursors can be infected with HIV and T cell precursors come into close contact with TE cells in the thymus, IL-6 secreted by TE cells during normal intrathymic development may induce HIV expression in infected thymocytes in vivo and promote the intrathymic spread of HIV.


Assuntos
HIV/fisiologia , Interleucina-6/metabolismo , Timo/microbiologia , Comunicação Celular , Células Cultivadas , Criança , Epitélio/metabolismo , Epitélio/microbiologia , Humanos , Interferon gama/fisiologia , Timo/metabolismo , Regulação para Cima , Replicação Viral
19.
J Immunol ; 146(10): 3396-404, 1991 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-2026871

RESUMO

Several reports implicate Langerhans cells of skin as susceptible targets, reservoirs, and vectors for transmission of HIV: 1) numbers of Langerhans cells in skin of HIV-infected patients were decreased about 50% of that in control skin; 2) as many as 30% of Langerhans cells in the skin of HIV-infected patients were morphologically abnormal; 3) viral particles typical for HIV were identified in or around 2 to 5% of these cells; and 4) infectious HIV was isolated from skin biopsies of infected patients. These results were consistent with similar observations of HIV-infected macrophages in such tissues as brain, lung, and lymph node. Despite these findings, other investigators find no evidence for virus infection in the epidermis of HIV-infected patients by any of several immunohistochemical or ultrastructural criteria. To address this controversy, we obtained skin from 28 HIV-seropositive subjects at various clinical stages by full thickness biopsy or suction blister. Samples were analyzed by transmission electron microscopy for presence of HIV virions, by immunofluorescent staining for viral proteins, by in situ hybridization for HIV-specific mRNA, by polymerase chain reaction amplification of virus-specific DNA, and by direct virus isolation by coculture of epidermis onto monocyte target cells. By any of these techniques, demonstration of HIV in the epidermis of infected patients was equivocal and even then, infrequent. In contrast, viral DNA was detected from the dermis of the same skin samples (26 of 28 samples). Moreover, the number and morphology of Langerhans cells in skin of infected patients were within normal limits, regardless of stage of disease. These studies in toto suggest that a role for Langerhans cells as a principal viral reservoir or vector of transmission is highly unlikely.


Assuntos
Infecções por HIV/microbiologia , HIV/isolamento & purificação , Células de Langerhans/microbiologia , Idoso , Contagem de Células , Células Cultivadas , DNA Viral/análise , Humanos , Células de Langerhans/fisiologia , Monócitos/microbiologia , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , RNA Viral/análise , Proteínas Virais/análise
20.
J Immunol ; 146(7): 2220-6, 1991 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-1706390

RESUMO

In this study, we have investigated the basic requirements for HIV-1 infection of CD8+ lymphocytes in vitro. Unfractionated PBL obtained from healthy HIV-1 seronegative donors were activated with PHA and infected in vitro with HIV-1LAV. Based on immunofluorescent labeling, the vast majority of cells (85 to 97%) surviving peak virus replication belonged to the CD8+ subset and only a small percentage (0.5 to 1.5%) were CD4+. Amplification of HIV-1 proviral sequences by polymerase chain reaction performed on the sorted surviving CD8+ cells demonstrated that CD8+ cells harbored HIV-1 proviral DNA. In addition, stimulation of these HIV-1-infected, CD8(+)-sorted cells either with PHA or anti-CD2 mAb resulted in induction of virus replication, as measured by reverse transcriptase activity. Electron microscopic analysis of CD8+ cells chronically infected with HIV-1 and stimulated with PHA showed typical virions budding from, and associated with, the surface of cells immunolabeled with gold beads directed toward the CD8 molecule. Infection of CD8+ cells with HIV-1 occurred only when CD4+ cells were present in the PHA-activated lymphocyte population exposed to HIV-1 at the beginning of the culture or when sorted CD8+CD4- lymphocytes were cocultured with autologous sorted CD8-CD4+ cells that had been previously infected with HIV-1. Coculture of these cells with PHA-blasts and incubation of their supernatants with a CD4+ cell line showed that these chronically infected CD8+ cells could spread HIV-1 infection to uninfected CD4+ cells after stimulation with PHA or anti-CD2 mAb. Therefore, these results suggest that the minimal requirement for in vitro infection of CD3+CD8+CD4- lymphocytes is the presence of infected CD4+ cells and that infected CD8+ T lymphocytes can further spread the infection to CD4+ cells.


Assuntos
Antígenos de Diferenciação de Linfócitos T/análise , Linfócitos T CD4-Positivos/microbiologia , Infecções por HIV/microbiologia , HIV-1/crescimento & desenvolvimento , Subpopulações de Linfócitos T/microbiologia , Antígenos CD/análise , Complexo CD3 , Antígenos CD8 , Células Cultivadas , DNA Viral/análise , Citometria de Fluxo , Humanos , Técnicas In Vitro , Microscopia Eletrônica , Reação em Cadeia da Polimerase , DNA Polimerase Dirigida por RNA/análise , Receptores de Antígenos de Linfócitos T/análise , Replicação Viral
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