RESUMO
Allograft inflammatory factor 1 (AIF1) is a commonly used marker for microglia in the brains of humans and some animal models but has had limited applications elsewhere. We sought to determine whether AIF1 can be used as a macrophage marker across common laboratory animal species and tissues. We studied tissues (that is, spleen, liver, and lung) with defined macrophage populations by using an AIF1 immunostaining technique previously validated in human tissue. Tissues were collected from various mouse strains (n = 20), rat strains (n = 15), pigs (n = 4), ferrets (n = 4), and humans (n = 4, lung only). All samples of liver had scattered immunostaining in interstitial cells, consistent with resident tissue macrophages (Kupffer cells). Spleen samples had cellular immunostaining of macrophages in both the red and white pulp compartments, but the red pulp had more immunostained cellular aggregates and, in some species, increased immunostaining intensity compared with white pulp. In lung, alveolar macrophages had weak to moderate staining, whereas interstitial and perivascular macrophages demonstrated moderate to robust staining. Incidental lesions and tissue changes were detected in some sections, including a tumor, inducible bronchus-associated lymphoid tissue, and inflammatory lesions that demonstrated AIF1 immunostaining of macrophages. Finally, we compared AIF1 immunostaining of alveolar macrophages between a hypertensive rat model (SHR strain) and a normotensive model (WKY strain). SHR lungs had altered intensity and distribution of immunostaining in activated macrophages compared with macrophages of WKY lungs. Overall, AIF1 immunostaining demonstrated reproducible macrophage staining across multiple species and tissue types. Given the increasing breadth of model species used to study human disease, the use of cross-species markers and techniques can reduce some of the inherent variability within translational research.
Assuntos
Proteínas de Ligação ao Cálcio/análise , Proteínas de Ligação a DNA/análise , Macrófagos/metabolismo , Proteínas dos Microfilamentos/análise , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação a DNA/metabolismo , Furões , Humanos , Imuno-Histoquímica , Macrófagos/citologia , Camundongos , Proteínas dos Microfilamentos/metabolismo , Ratos , Especificidade da Espécie , SuínosRESUMO
BACKGROUND: We evaluated the changes in the levels of soluble biomarkers of inflammation and coagulation and T-cell activation among participants of AIDS Clinical Trials Group Study A5217 who were started on antiretroviral therapy (ART) within the first 6 months of HIV infection. METHODS: Cryopreserved specimens were obtained pre-ART (week 0), at the time of virologic suppression (week 36), and at 36 weeks after treatment interruption (week 72). Levels of D-dimer, C-reactive protein (CRP), and soluble CD14 (sCD14) were measured in plasma, whereas T-cell activation levels, defined as the frequencies of CD4 and CD8 T cells coexpressing HLA-DR and CD38, were measured in peripheral blood mononuclear cells. RESULTS: D-dimer levels were significantly lower at viral suppression (P = 0.031), whereas CRP and sCD14 levels remained similar to pre-ART levels. At viral suppression, levels of the soluble markers did not correlate with each other. CD4 T-cell counts pre-ART tended to modestly correlate with levels of D-dimer (r = 0.35; P = 0.058) and CRP (r = 0.33; P = 0.078). At 36 weeks after treatment interruption (week 72), D-dimer levels returned back to pre-ART levels. However, CD8 T-cell activation was significantly lower than pre-ART levels (35.8% at week 0 vs 28.9% at week 72; P = 0.004). CONCLUSIONS: Among the A5217 participants who started ART within the first 6 months of HIV infection, high levels of sCD14 and CRP remain similar to pre-ART levels, suggesting that immune damage occurring in the initial stages of infection persists despite short-term virologic suppression.
Assuntos
Antirretrovirais/uso terapêutico , Biomarcadores/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Inflamação/patologia , ADP-Ribosil Ciclase 1/análise , Adulto , Coagulação Sanguínea , Proteína C-Reativa/análise , Linfócitos T CD4-Positivos/química , Linfócitos T CD8-Positivos/química , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Antígenos HLA-DR/análise , Humanos , Receptores de Lipopolissacarídeos/sangue , Ativação Linfocitária , Masculino , Glicoproteínas de Membrana/análise , Plasma/química , Resultado do TratamentoRESUMO
Palliative care seeks to improve the quality of life for patients suffering from the impact of life-limiting illnesses. Palliative care encompasses but is more than end-of-life care, which is defined as care during the final hours/days/weeks of life. Although palliative care policies increasingly require all healthcare professionals to have at least basic or non-specialist skills in palliative care, international evidence suggests there are difficulties in realising such policies. This study reports on an action research project aimed at developing respiratory nursing practice to address the palliative care needs of patients with advanced chronic obstructive pulmonary disease (COPD). The findings suggest that interlevel dynamics at individual, team, interdepartmental and organisational levels are an important factor in the capacity of respiratory nurses to embed non-specialist palliative care in their practice. At best, current efforts to embed palliative care in everyday practice may improve end-of-life care in the final hours/days/weeks of life. However, embedding palliative care in everyday practice requires a more fundamental shift in the organisation of care.
Assuntos
Cuidados Paliativos/métodos , Doença Pulmonar Obstrutiva Crônica/enfermagem , Idoso , Pesquisa sobre Serviços de Saúde , Humanos , Pessoa de Meia-Idade , Cuidados de Enfermagem/psicologia , Cultura Organizacional , Cuidados Paliativos/psicologia , Qualidade de Vida , Assistência Terminal/métodosRESUMO
BACKGROUND: The benefits of antiretroviral therapy during early human immunodeficiency virus type 1 (HIV-1) infection remain unproved. METHODS: A5217 study team randomized patients within 6 months of HIV-1 seroconversion to receive either 36 weeks of antiretrovirals (immediate treatment [IT]) or no treatment (deferred treatment [DT]). Patients were to start or restart antiretroviral therapy if they met predefined criteria. The primary end point was a composite of requiring treatment or retreatment and the log(10) HIV-1 RNA level at week 72 (both groups) and 36 (DT group). RESULTS: At the June 2009 Data Safety Monitoring Board (DSMB) review, 130 of 150 targeted participants had enrolled. Efficacy analysis included 79 individuals randomized ≥72 weeks previously. For the primary end point, the IT group at week 72 had a better outcome than the DT group at week 72 (P = .005) and the DT group at week 36 (P = .002). The differences were primarily due to the higher rate of progression to needing treatment in the DT group (50%) versus the IT (10%) group. The DSMB recommended stopping the study because further follow-up was unlikely to change these findings. CONCLUSIONS: Progression to meeting criteria for antiretroviral initiation in the DT group occurred more frequently than anticipated, limiting the ability to evaluate virologic set point. Antiretrovirals during early HIV-1 infection modestly delayed the need for subsequent treatment. CLINICAL TRIALS REGISTRATION: NCT00090779.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Desoxicitidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Lopinavir/uso terapêutico , Organofosfonatos/uso terapêutico , Ritonavir/uso terapêutico , Carga Viral , Adenina/uso terapêutico , Adulto , Desoxicitidina/uso terapêutico , Progressão da Doença , Esquema de Medicação , Combinação de Medicamentos , Quimioterapia Combinada , Emtricitabina , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/genética , Humanos , Masculino , RNA Viral/sangue , Tenofovir , Resultado do TratamentoRESUMO
Acute human immunodeficiency virus type 1 (HIV-1) infection is characterized by high levels of immune activation. Immunomodulation with cyclosporine combined with antiretroviral therapy (ART) in the setting of acute and early HIV-1 infection has been reported to result in enhanced immune reconstitution. Fifty-four individuals with acute and early infection were randomized to receive ART with 4 weeks of cyclosporine versus ART alone. In 48 subjects who completed the study, there were no significant differences between treatment arms in levels of proviral DNA or CD4(+) T cell counts. Adjunctive therapy with cyclosporine in this setting does not provide apparent virologic or immunologic benefit.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Ciclosporina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Imunossupressores/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Ciclosporina/administração & dosagem , Quimioterapia Combinada , Feminino , HIV-1/efeitos dos fármacos , Humanos , Imunossupressores/administração & dosagem , Masculino , Carga Viral/efeitos dos fármacosRESUMO
Clinical trial AIN503/A5217 investigates whether a period of early treatment with antiretroviral therapy might lower the viral setpoint in subjects recently infected with HIV-1. We consider two statistical issues. First, even under the null hypothesis control arm subjects are more likely than treatment arm subjects to be missing final outcome data because of disease progression. The analysis must adjust for this missing data, or it may be unacceptably biased. Second, comparing outcomes between treatment and control arms at identical times post-randomization gives different information than comparing outcomes at the same amount of time off-therapy, as measured post-randomization. This may make interpretation of results problematic. We formulate the null hypothesis of the study as exchangeability under a time-shift between arms, which we call "time delay" between the study arms. This captures clinically relevant information, and allows us to formalize a two-stage hypothesis test in which stage one is a comparison between arms at identical times post-randomization, and stage two is a comparison between arms at identical times off-therapy, as measured post-randomization. Importantly, within this framework we can show that the two-stage test can be adjusted for the missing data using a simple worst-rank substitution.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Coleta de Dados/estatística & dados numéricos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Síndrome da Imunodeficiência Adquirida/epidemiologia , Fármacos Anti-HIV/efeitos adversos , Viés , Biomarcadores , Contagem de Linfócito CD4 , Progressão da Doença , Infecções por HIV/epidemiologia , Humanos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Reprodutibilidade dos Testes , Fatores de Tempo , Carga ViralRESUMO
Transmitted resistance to antiretroviral drugs in acute and early HIV-1 infection has been well documented, although overall trends vary depending on geography and cohort characteristics. To describe the changing pattern of transmitted drug-resistant HIV-1 in a well-defined cohort in New York City, a total of 361 patients with acute or recent HIV-1 infection were prospectively studied over a decade (1995-2004) with respect to HIV-1 genotypes and longitudinal T-cell subsets and HIV-1 RNA levels. The prevalence of overall transmitted resistance changed from 13.2% to 24.1% (P = 0.11) during the periods 1995 to 1998 and 2003 to 2004. Nonnucleoside reverse transcriptase inhibitor resistance prevalence increased significantly from 2.6% to 13.4% (P = 0.007) during the same periods, whereas prevalence of multidrug-resistant virus shifted from 2.6% to 9.8% (P = 0.07) but did not achieve statistical significance. A comparable immunologic and virologic response of appropriately treated individuals was observed regardless of viral drug susceptibility status, suggesting that initial combination therapy guided by baseline resistance testing in the case of acute and early infection may result in a favorable treatment response even in the case of a drug-resistant virus. These data have important implications for selection of empiric first-line regimens for treatment of acutely infected antiretroviral-naive individuals and reinforce the need for baseline resistance testing in acute and early HIV-1 infection.
Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/isolamento & purificação , Adulto , Feminino , Genoma Viral/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Protease de HIV/genética , Transcriptase Reversa do HIV/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Cidade de Nova Iorque/epidemiologia , Filogenia , Prevalência , RNA Viral/sangue , Análise de Sequência de DNA , Subpopulações de Linfócitos T , Resultado do Tratamento , Carga ViralRESUMO
As the AIDS epidemic continues unabated, the development of a human immunodeficiency virus (HIV) vaccine is critical. Ideally, an effective vaccine should elicit cell-mediated and neutralizing humoral immune responses. We have determined the in vitro susceptibility profile of sexually transmitted viruses from 91 patients with acute and early HIV-1 infection to three monoclonal antibodies, 2G12, 2F5, and 4E10. Using a recombinant virus assay to measure neutralization, we found all transmitted viruses were neutralized by 4E10, 80% were neutralized by 2F5, and only 37% were neutralized by 2G12. We propose that the induction of 4E10-like antibodies should be a priority in designing immunogens to prevent HIV-1 infection.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Anticorpos Monoclonais/administração & dosagem , Feminino , Anticorpos Anti-HIV/administração & dosagem , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/genética , Humanos , Masculino , Testes de Neutralização , Recombinação Genética , Comportamento SexualRESUMO
The meaning of viral blips in human immunodeficiency virus type 1 (HIV-1)-infected patients treated with seemingly effective highly active antiretroviral therapy (HAART) is still controversial and under investigation. Blips might represent low-level ongoing viral replication in the presence of drug or simply release of virions from the latent reservoir. Patients treated early during HIV-1 infection are more likely to have a lower total body viral burden, a homogenous viral population, and preserved HIV-1-specific immune responses. Consequently, viral blips may be less frequent in them than in patients treated during chronic infection. To test this hypothesis, we compared the occurrence of viral blips in 76 acutely infected patients (primary HIV infection [PHI] group) who started therapy within 6 months of the onset of symptoms with that in 47 patients who started HAART therapy during chronic infection (chronic HIV infection [CHI] group). Viral blip frequency was approximately twofold higher in CHI patients (0.122 +/- 0.12/viral load [VL] sample, mean +/- standard deviation) than in PHI patients (0.066 +/- 0.09/VL sample). However, in both groups, viral blip frequency did not increase with longer periods of observation. Also, no difference in viral blip frequency was observed between treatment subgroups, and the occurrence of a blip was not associated with a recent change in CD4(+) T-cell count. Finally, in PHI patients the VL set point was a significant predictor of blip frequency during treatment.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Viremia , Contagem de Linfócito CD4 , Humanos , RNA Viral/sangue , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
Given its population of CCR5-expressing, immunologically activated CD4(+) T cells, the gastrointestinal (GI) mucosa is uniquely susceptible to human immunodeficiency virus (HIV)-1 infection. We undertook this study to assess whether a preferential depletion of mucosal CD4(+) T cells would be observed in HIV-1-infected subjects during the primary infection period, to examine the anatomic subcompartment from which these cells are depleted, and to examine whether suppressive highly active antiretroviral therapy could result in complete immune reconstitution in the mucosal compartment. Our results demonstrate that a significant and preferential depletion of mucosal CD4(+) T cells compared with peripheral blood CD4(+) T cells is seen during primary HIV-1 infection. CD4(+) T cell loss predominated in the effector subcompartment of the GI mucosa, in distinction to the inductive compartment, where HIV-1 RNA was present. Cross-sectional analysis of a cohort of primary HIV-1 infection subjects showed that although chronic suppression of HIV-1 permits near-complete immune recovery of the peripheral blood CD4(+) T cell population, a significantly greater CD4(+) T cell loss remains in the GI mucosa, despite up to 5 yr of fully suppressive therapy. Given the importance of the mucosal compartment in HIV-1 pathogenesis, further study to elucidate the significance of the changes observed here is critical.
Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Linfócitos T CD4-Positivos/imunologia , Sistema Digestório/imunologia , HIV-1 , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade , Sistema Digestório/virologia , Humanos , Mucosa Intestinal/imunologia , Receptores CCR5/análiseRESUMO
Although intermittent episodes of low-level viremia are often observed in well-suppressed highly active antiretroviral therapy (HAART)-treated patients, the timing and amplitude of viral blips have never been examined in detail. We analyze here the dynamics of viral blips, i.e., plasma VL measurements of >50 copies/ml, in 123 HAART-treated patients monitored for a mean of 2.6 years (range, 5 months to 5.3 years). The mean (+/- the standard deviation) blip frequency was 0.09 +/- 0.11/sample, with about one-third of patients showing no viral blips. The mean viral blip amplitude was 158 +/- 132 human immunodeficiency virus type 1 (HIV-1) RNA copies/ml. Analysis of the blip frequency and amplitude distributions suggest that two blips less than 22 days apart have a significant chance of being part of the same episode of viremia. The data are consistent with a hypothetical model in which each episode of viremia consists of a phase of VL rise, followed by two-phase exponential decay. Thus, the term "viral blip" may be a misnomer, since viral replication appears to be occurring over an extended period. Neither the frequency nor the amplitude of viral blips increases with longer periods of observation, but the frequency is inversely correlated with the CD4(+)-T-cell count at the start of therapy, suggesting that host-specific factors but not treatment fatigue are determinants of blip frequency.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade , HIV-1/isolamento & purificação , RNA Viral/sangue , Carga Viral , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Contagem de Linfócito CD4 , Humanos , Estudos Prospectivos , Fatores de TempoRESUMO
OBJECTIVE: To assess the efficacy of tenofovir disoproxil fumarate (TDF) monotherapy by following the initial rate of decline in plasma viral load, which is a measure of the efficacy of therapy in blocking viral replication. DESIGN: An open-label, single-site study of TDF monotherapy in 10 antiretroviral drug-naive chronically HIV-1-infected individuals. METHODS: Antiviral responses were assessed at baseline and during 21 days of monotherapy with TDF by measuring plasma HIV-1 RNA levels. The rate of change in HIV-1 RNA from baseline was determined both by linear regression and by fitting to a published model. Slopes were compared with those previously determined for ritonavir monotherapy. RESULTS: Over 21 days, mean plasma HIV-1 RNA levels in the TDF-treated patients fell 1.5 log(10) copies/ml (range, 0.7-2.0). The initial rates of decline in plasma HIV-1 RNA in the 10 TDF-treated patients and in 25 protease inhibitor-naive subjects treated with ritonavir monotherapy were nearly identical. CONCLUSIONS: The reduction in plasma HIV-1 RNA with TDF monotherapy was comparable with the decline observed in previous studies of protease inhibitor monotherapy. TDF is a potent antiretroviral agent and has comparable inherent antiviral activity with that of ritonavir, a potent protease inhibitor. These data support further study of TDF-based regimens in simplified combinations of antiviral agents as initial treatment for chronic HIV-1 infection.
Assuntos
Adenina/análogos & derivados , Adenina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Organofosfonatos , Compostos Organofosforados/uso terapêutico , Pró-Fármacos/uso terapêutico , Adulto , Doença Crônica , Feminino , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir , Carga ViralRESUMO
Despite the clinical benefits of combination antiviral therapy, whether maximal antiviral potency has been achieved with current drug combinations remains unclear. We studied the first phase of decay of human immunodeficiency virus type 1 (HIV-1) RNA in plasma, one early indicator of antiviral activity, after the administration of a novel combination of lopinavir/ritonavir, efavirenz, tenofovir disoproxil fumarate, and lamivudine and compared it with that observed in matched cohorts treated with alternative combination regimens. On the basis of these comparisons, we conclude that the relative potency of highly active antiretroviral therapy may be augmented by as much as 25%-30%. However, it is important to emphasize that further study is warranted to explore whether these early measurements of relative efficacy provide long-term virologic and clinical benefits. Nevertheless, we believe that optimal treatment regimens for HIV-1 have yet to be identified and that continued research to achieve this goal is warranted.