RESUMO
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
Although the development of a fully protective HIV vaccine is the ultimate goal of HIV research, to date only one HIV vaccine trial, the RV144, has successfully induced a weakly protective response. The 31% protection from infection achieved in the RV144 trial was linked to the induction of nonneutralizing antibodies, able to mediate antibody-dependent cell-mediated cytotoxicity (ADCC), suggestive of an important role of Fc-mediated functions in protection. Similarly, Fc-mediated antiviral activity was recently shown to play a critical role in actively suppressing the viral reservoir, but the Fc effector mechanisms within tissues that provide protection from or after infection are largely unknown. Here we aimed to define the landscape of effector cells and Fc receptors present within vulnerable tissues. We found negligible Fc receptor-expressing natural killer cells in the female reproductive and gastrointestinal mucosa. Conversely, Fc receptor-expressing macrophages were highly enriched in most tissues, but neutrophils mediated superior antibody-mediated phagocytosis. Modifications in Fc domain of VRC01 antibody increased phagocytic responses in both phagocytes. These data suggest that non-ADCC-mediated mechanisms, such as phagocytosis and neutrophil activation, are more likely to play a role in preventative vaccine or reservoir-eliminating therapeutic approaches.
Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , HIV-1/imunologia , Fagocitose/imunologia , Receptores Fc/metabolismo , Adulto , Anticorpos Monoclonais/imunologia , Biomarcadores , Anticorpos Amplamente Neutralizantes , Citocinas/metabolismo , Feminino , Expressão Gênica , Anticorpos Anti-HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Humanos , Imunidade Inata , Mediadores da Inflamação/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Pessoa de Meia-Idade , Mucosa/imunologia , Mucosa/metabolismo , Mucosa/virologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptores Fc/genética , Adulto JovemRESUMO
Our objective was to evaluate valaciclovir for anogenital herpes in HIV-infected individuals using 2 controlled trials conducted before highly active antiretroviral therapy (HAART) was used. In Study 1, 1062 patients (CD4+ > or = 100 cells/mm(3)) received suppressive valaciclovir or aciclovir for one year and were assessed monthly. In Study 2, 467 patients were treated episodically for > or =5 days with valaciclovir or aciclovir and evaluated daily. Valaciclovir was as effective as aciclovir for suppression and episodic treatment of herpes. Hazard ratios [95% confidence interval (CI)] for time to recurrence for valaciclovir 500 mg twice daily and 1000 mg once daily vs aciclovir were 0.73[0.50, 1.06], P=0.10, and 1.31[0.94, 1.82], P=0.11. Valaciclovir 500 mg twice daily was superior to 1000 mg once daily, P=0.001. Valaciclovir 1000 mg twice daily was comparable to aciclovir on herpes episode duration (hazard ratio 0.92[0.75, 1.14]). Adverse events were similar among treatments. In conclusion, valaciclovir is a safe, effective, convenient alternative to aciclovir for HSV infection in HIV-infected individuals.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Aciclovir/análogos & derivados , Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Infecções por HIV/complicações , Herpes Genital/tratamento farmacológico , Herpes Genital/prevenção & controle , Simplexvirus , Valina/análogos & derivados , Valina/uso terapêutico , Aciclovir/administração & dosagem , Adulto , Idoso , Antivirais/administração & dosagem , Intervalos de Confiança , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Resultado do Tratamento , Valaciclovir , Valina/administração & dosagemRESUMO
The mechanisms underlying the massive gastrointestinal tract CD4 T-cell depletion in human immunodeficiency virus (HIV) infection are not well understood nor is it clear whether similar depletion is manifest at other mucosal surfaces. Studies of T-cell and virus dynamics in different anatomical sites have begun to illuminate the pathogenesis of HIV-associated disease. Here, we studied depletion and HIV infection frequencies of CD4 T cells from the gastrointestinal tract, bronchoalveolar lavage (BAL), and blood with the frequencies and functional profiles of HIV-specific T cells in these anatomically distinct sites in HIV-infected individuals. The major findings to emerge were as follows: (i) depletion of gastrointestinal CD4 T cells is associated with high frequencies of infected CD4 T cells; (ii) HIV-specific T cells are present at low frequencies in the gastrointestinal tract compared to blood; (iii) BAL CD4 T cells are not massively depleted during the chronic phase; (iv) infection frequencies of BAL CD4 T cells are similar to those in blood; (v) significantly higher frequencies and increased functionality of HIV-specific T cells were observed in BAL compared to blood. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might circumvent global depletion of mucosal CD4 T cells.
Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD4-Positivos/imunologia , HIV/imunologia , Mucosa Intestinal/imunologia , Síndrome da Imunodeficiência Adquirida/sangue , Lavagem Broncoalveolar , Contagem de Linfócito CD4 , Doença Crônica , Feminino , Humanos , Masculino , Especificidade de Órgãos/imunologiaRESUMO
BACKGROUND: The clinical events surrounding acute HIV-1 infection have been well described, but little is known about whether the virologic course of acute HIV-1 infection influences the subsequent progression of disease. OBJECTIVE: To define the virologic natural history of acute and very early HIV infection. DESIGN: Prospective, longitudinal cohort study. SETTING: University of Washington Research Clinic PARTICIPANTS: 74 adults enrolled soon after acquisition of HIV (mean, 69 days). MEASUREMENTS: Plasma HIV-1 RNA levels; quantitative cell cultures; CD4 cell counts; and detailed clinical assessments done at study entry, biweekly for 1 month, monthly for 2 months, and quarterly thereafter. RESULTS: In the first 30 days after acquisition of HIV, HIV-1 RNA levels varied greatly among participants (range, 27,200 to 1.6 x 10(6) copies per mL of plasma). Levels of HIV-1 RNA decreased by a mean of 6.5% per week for the first 120 days and then increased by a mean of 0.15% per week. CD4 cell counts decreased by a mean of 5.2 cells/mm3 per week for the first 160 days and by a mean of 1.9 cells/mm3 per week thereafter (P < 0.01). Disease progressed faster in participants who sought medical care for their acute seroconversion syndrome (P = 0.01) and those who had high plasma HIV-1 RNA levels 120 to 365 days after acquisition (P < 0.01). Peak levels in the first 120 days were not predictive of disease progression. CONCLUSIONS: The variability in viral RNA levels associated with acute HIV-1 infection is greater than previously appreciated. Within 120 days of acquisition, plasma HIV RNA levels rapidly decrease to an inflection point, after which they gradually increase. Virus-host interactions soon after acquisition seem to have a major influence on the long-term outcome of HIV-1 disease.
Assuntos
Soropositividade para HIV/virologia , HIV-1 , Adulto , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Progressão da Doença , Feminino , Seguimentos , Soropositividade para HIV/tratamento farmacológico , Humanos , Masculino , Estudos Prospectivos , RNA Viral/sangue , Carga ViralRESUMO
Bordetella bronchiseptica is a frequent cause of respiratory infections in animals but rarely causes disease in humans. We describe a patient with B. bronchiseptica pneumonia and bacteremia that developed following bone marrow transplantation. B. bronchiseptica infection persisted despite antimicrobial therapy and may have progressed because of the combined effects of the patient's underlying immunosuppression and the antimicrobial antagonism between doxycycline and ciprofloxacin.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Infecções por Bordetella/etiologia , Bordetella bronchiseptica/isolamento & purificação , Adulto , Bacteriemia/tratamento farmacológico , Bacteriemia/etiologia , Infecções por Bordetella/tratamento farmacológico , Ciprofloxacina/uso terapêutico , Doxiciclina/uso terapêutico , Antagonismo de Drogas , Feminino , Humanos , Pneumonia/tratamento farmacológico , Pneumonia/etiologiaRESUMO
Without potent antiretroviral therapy, most human immunodeficiency virus type 1 (HIV-1)-infected persons experience a progressive decline in CD4+ T cells and impairment in T helper function. It is unclear how soon after infection T cell dysfunction occurs. T helper responses were examined in blood and lymphoid tissue of 39 untreated patients with acute HIV-1 infection. Within the first 3 months, lymphoproliferative responses to mitogen, recall antigens, and HIV-1 antigens were impaired. After 6-9 months, responses to phytohemagglutinin and recall antigens improved. However, HIV-1-specific lymphoproliferation remained largely undetectable throughout 2 years of infection, and results were similar upon evaluation of lymphoid cells. Rare patients with HIV-1-specific responses had significantly lower plasma HIV-1 RNA levels than did nonresponders. These results indicate that T helper dysfunction occurs early after HIV-1 acquisition and that untreated individuals rarely recover HIV-specific helper responses; these findings lend support for early therapeutic intervention to prevent the destruction and further impairment of the T helper cells.
Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Linfonodos/imunologia , Ativação Linfocitária , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Candida/imunologia , Feminino , Proteína do Núcleo p24 do HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Linfonodos/citologia , Masculino , Fito-Hemaglutininas/imunologia , Proteínas Recombinantes/imunologia , Tétano/imunologiaRESUMO
Conventional antiretroviral therapy involves administration of standard fixed doses to adults and adolescents. This approach ignores interindividual variability in pharmacokinetics and results in substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and indinavir designed to achieve select target concentrations versus standard dose therapy. Twenty-four antiretroviral-naïve subjects completed the 24-week study; 13 received standard therapy, and 11 received concentration-controlled therapy. There were no differences in baseline characteristics. Oral clearance for all three drugs was not different between weeks 2 and 28; average ratios of week 2 oral clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for zidovudine, lamivudine, and indinavir, respectively, with 95% confidence intervals including 1. The selected target concentrations were average steady-state concentrations of 0.19 mg/liter for zidovudine and 0.44 mg/liter for lamivudine and a trough concentration of 0.15 mg/liter for indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter, respectively. Concentration-controlled therapy significantly reduced interpatient variability in zidovudine concentrations and significantly increased indinavir concentrations. There was no difference in adverse drug effects or adherence. This investigation has provided a pharmacologic basis for concentration-controlled therapy by demonstrating that it is feasible and has a safety profile no different from that of standard therapy. Additional studies to evaluate the virologic effect of the concentration-controlled approach to antiretroviral therapy are warranted.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Indinavir/uso terapêutico , Lamivudina/uso terapêutico , Zidovudina/uso terapêutico , Adulto , Algoritmos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Área Sob a Curva , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Meia-Vida , Humanos , Indinavir/administração & dosagem , Indinavir/farmacocinética , Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Zidovudina/administração & dosagem , Zidovudina/farmacocinéticaRESUMO
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.