Browsing by Author "Doroana, Manuela"
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- Baseline susceptibility of primary HIV-2 to entry inhibitorsPublication . Borrego, Pedro; Calado, Rita; Marcelino, José M.; Bártolo, Inês; Rocha, Cheila; Cavaco-Silva, Patricia; Doroana, Manuela; Antunes, Francisco; Maltez, Fernando; Caixas, Umbelina; Barroso, Helena; Taveira, NunoBackground The baseline susceptibility of primary HIV-2 to maraviroc (MVC) and other entry inhibitors is currently unknown. Methods The susceptibility of 19 HIV-2 isolates obtained from asymptomatic and AIDS patients and seven HIV-1 clinical isolates to the fusion inhibitors enfuvirtide (ENF) and T-1249, and to the coreceptor antagonists AMD3100, TAK-779 and MVC, was measured using a TZM-bl cell-based assay. The 50% inhibitory concentration (IC50), 90% inhibitory concentration (IC90) and dose–response curve slopes were determined for each drug. Results ENF and T-1249 were significantly less active on HIV-2 than on HIV-1 (211- and 2-fold, respectively). AMD3100 and TAK-779 inhibited HIV-2 and HIV-1 CXCR4 tropic (X4) and CCR5 tropic (R5) variants with similar IC50 and IC90 values. MVC, however, inhibited the replication of R5 HIV-2 variants with significantly higher IC90 values (42.7 versus 9.7 nM; P<0.0001) and lower slope values (0.7 versus 1.3; P<0.0001) than HIV-1. HIV-2 R5 variants derived from AIDS patients were significantly less sensitive to MVC than variants from asymptomatic patients, this being inversely correlated with the absolute number of CD4+ T-cells. Conclusions T-1249 is a potent inhibitor of HIV-2 replication indicating that new fusion inhibitors might be useful to treat HIV-2 infection. Coreceptor antagonists TAK-779 and AMD3100 are also potent inhibitors of HIV-2 replication. The reduced sensitivity of R5 variants to MVC, especially in severely immunodeficient patients, indicates that the treatment of HIV-2-infected patients with MVC might require higher dosages than those used in HIV-1 patients, and should be adjusted to the disease stage.
- Bulk cytokine production versus frequency of cytokine-producing cells in HIV1 infection before and during HAARTPublication . Sousa, Ana E.; Chaves, Ana F.; Doroana, Manuela; Antunes, Francisco; Victorino, Rui M. M.Cytokine imbalances play a major role in HIV immunopathogenesis. This study analyzes simultaneously the frequency of cytokine-producing cells at the single cell level by flow cytometry and the disturbances in cytokine secretion assessed by ELISA in a cohort of asymptomatic HIV1 patients in different stages of CD4 depletion and during antiretroviral therapy (HAART). Early in the disease, there is an increased frequency of IFN-γ lymphocytes and bulk IFN-γ+ production, in parallel with a reduced proportion of IL4+ cells and IL4 secreted. The two IL4 measurements are significantly correlated. No such correlation was found for IFN-γ, which is consistent with a large variation in the amount of IFN-γ released per individual cell. Moreover, HAART was associated with a reduction to normal levels in the bulk IFN-γ secretion concomitant with a persistency of the overexpanded IFN-γ+ cell subset in the peripheral blood. This study emphasizes the importance of using a conjoint approach to assess the cytokine network in trials of antiretroviral and/or immune-based therapies to avoid missing significant effects which are possibly relevant in the clinical setting.
- Cell-associated viral burden provides evidence of ongoing viral replication in aviremic HIV-2-infected patientsPublication . Soares, Rui S.; Tendeiro, Rita; Foxall, Russell B.; Baptista, António P.; Cavaleiro, Rita; Gomes, Perpétua; Camacho, Ricardo; Valadas, Emília; Doroana, Manuela; Lucas, Margarida; Antunes, Francisco; Victorino, Rui M. M.; Sousa, Ana E.Viremia is significantly lower in HIV-2 than in HIV-1 infection, irrespective of disease stage. Nevertheless, the comparable proviral DNA burdens observed for these two infections indicate similar numbers of infected cells. Here we investigated this apparent paradox by assessing cell-associated viral replication. We found that untreated HIV-1-positive (HIV-1(+)) and HIV-2(+) individuals, matched for CD4 T cell depletion, exhibited similar gag mRNA levels, indicating that significant viral transcription is occurring in untreated HIV-2(+) patients, despite the reduced viremia (undetectable to 2.6 × 10(4) RNA copies/ml). However, tat mRNA transcripts were observed at significantly lower levels in HIV-2(+) patients, suggesting that the rate of de novo infection is decreased in these patients. Our data also reveal a direct relationship of gag and tat transcripts with CD4 and CD8 T cell activation, respectively. Antiretroviral therapy (ART)-treated HIV-2(+) patients showed persistent viral replication, irrespective of plasma viremia, possibly contributing to the emergence of drug resistance mutations, persistent hyperimmune activation, and poor CD4 T cell recovery that we observed with these individuals. In conclusion, we provide here evidence of significant ongoing viral replication in HIV-2(+) patients, further emphasizing the dichotomy between amount of plasma virus and cell-associated viral burden and stressing the need for antiretroviral trials and the definition of therapeutic guidelines for HIV-2 infection.
- Envelope-specific antibody response in HIV-2 infectionPublication . Marcelino, Jose Maria; Nilsson, Charlotta; Barroso, Helena; Gomes, Perpetua; Borrego, Pedro; Maltez, Fernando; Rosado, Lino; Doroana, Manuela; Antunes, Francisco; Taveira, NunoObjective: To examine the unspecific and envelope-specific IgA and IgG responses in acute and chronic HIV-2 infection. Methods: Twenty-eight chronically infected adults and two children with perinatal infection were studied. Total plasma concentrations of. - Fundacao para a Ciencia e Tecnologia [POCTI/ESP/48045]. - The present work was supported by Fundacao para a Ciencia e Tecnologia (project POCTI/ESP/48045). Jose Marcelino is the recipient of a PhD scholarship from Fundacao para a Ciencia e Tecnologia (FCT), Portugal. The Instituto Portugues do Sangue (IPS), Port
- The role of the humoral immune response in the molecular evolution of the envelope C2, V3 and C3 regions in chronically HIV-2 infected patientsPublication . Borrego, Pedro; Marcelino, Jose Maria; Rocha, Cheila; Doroana, Manuela; Antunes, Francisco; Maltez, Fernando; Gomes, Perpetua; Novo, Carlos; Barroso, Helena; Taveira, NunoBackground: This study was designed to investigate, for the first time, the short-term molecular evolution of the HIV-2 C2, V3 and C3 envelope regions and its association with the immune response. Clonal sequences of the env C2V3C3 region were obtained fr. - Fundacao para a Ciencia e Tecnologia [POCTI/ESP/48045]. - This work was supported by Fundacao para a Ciencia e Tecnologia (project POCTI/ESP/48045). Pedro Borrego is supported by a PhD grant from Fundacao para a Ciencia e Tecnologia.
- Thrombocytopenia is associated with an increased risk of cancer during treated HIV diseasePublication . Borges, Álvaro H.; Lundgren, Jens D.; Ridolfo, Annalisa; Katlama, Christine; Antunes, Francisco; Grzeszczuk, Anna; Blaxhult, Anders; Mitsura, Viktar M.; Doroana, Manuela; Battegay, Manuel; Gargalianos, Panagiotis; Mocroft, AmandaObjective: To assess the relationship between platelet counts and risk of AIDS and non-AIDS-defining events. Design: Prospective cohort. Methods: EuroSIDA patients with at least one platelet count were followed from baseline (first platelet ≥ 1 January 2005) until last visit or death. Multivariate Poisson regression was used to assess the relationship between current platelet counts and the incidence of non-AIDS-defining (pancreatitis, end-stage liver/renal disease, cancer, cardiovascular disease) and AIDS-defining events. Results: There were 62 898 person-years of follow-up (PYFU) among 12 279 patients, including 1168 non-AIDS-defining events [crude incidence 18.6/1000 PYFU, 95% confidence interval (CI) 17.5-19.6] and 735 AIDS-defining events (crude incidence 11.7/1000 PYFU, 95% CI 10.8-12.5). Patients with thrombocytopenia (platelet count ≤100 × 10/l) had a slightly increased incidence of AIDS-defining events [adjusted incidence rate ratio (aIRR) 1.42, 95% CI 1.07-1.86], when compared to those with platelet counts 101-200 × 10/l, whereas the incidence of non-AIDS-defining events was more than two-fold higher (aIRR 2.66, 95% CI 2.17-3.26). Among non-AIDS-defining events, the adjusted incidence of cancer (aIRR 2.20, 95% CI 1.61-3.01), but not cardiovascular disease (aIRR 0.66, 95% CI 0.32-1.34), was significantly higher in patients with thrombocytopenia. The association between thrombocytopenia and cancer remained unaltered in sensitivity analyses requiring repeated platelet counts to confirm thrombocytopenia and lagging platelets by 1 year prior to clinical events. Conclusion: Patients with thrombocytopenia had increased incidence of AIDS-defining and non-AIDS-defining events, but the association with the latter, in particular cancer, was stronger. Future studies should investigate whether the pathophysiological processes underlying thrombocytopenia are associated with the development of cancer during treated HIV disease.