Browsing by Author "Cavaleiro, R."
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- Major depletion of plasmacytoid dendritic cells in HIV-2 infection, an attenuated form of HIV diseasePublication . Cavaleiro, R.; Baptista, A. P.; Soares, R. S.; Tendeiro, R.; Foxall, R. B.; Gomes, P.; Victorino, R. M.; Sousa, A. E.Plasmacytoid dendritic cells (pDC) provide an important link between innate and acquired immunity, mediating their action mainly through IFN-alpha production. pDC suppress HIV-1 replication, but there is increasing evidence suggesting they may also contribute to the increased levels of cell apoptosis and pan-immune activation associated with disease progression. Although having the same clinical spectrum, HIV-2 infection is characterized by a strikingly lower viremia and a much slower rate of CD4 decline and AIDS progression than HIV-1, irrespective of disease stage. We report here a similar marked reduction in circulating pDC levels in untreated HIV-1 and HIV-2 infections in association with CD4 depletion and T cell activation, in spite of the undetectable viremia found in the majority of HIV-2 patients. Moreover, the same overexpression of CD86 and PD-L1 on circulating pDC was found in both infections irrespective of disease stage or viremia status. Our observation that pDC depletion occurs in HIV-2 infected patients with undetectable viremia indicates that mechanisms other than direct viral infection determine the pDC depletion during persistent infections. However, viremia was associated with an impairment of IFN-alpha production on a per pDC basis upon TLR9 stimulation. These data support the possibility that diminished function in vitro may relate to prior activation by HIV virions in vivo, in agreement with our finding of higher expression levels of the IFN-alpha inducible gene, MxA, in HIV-1 than in HIV-2 individuals. Importantly, serum IFN-alpha levels were not elevated in HIV-2 infected individuals. In conclusion, our data in this unique natural model of "attenuated" HIV immunodeficiency contribute to the understanding of pDC biology in HIV/AIDS pathogenesis, showing that in the absence of detectable viremia a major depletion of circulating pDC in association with a relatively preserved IFN-alpha production does occur.
- Marked immunosuppressive effects of the HIV-2 envelope protein in spite of the lower HIV-2 pathogenicityPublication . Cavaleiro, R.; Sousa, A. E.; Loureiro, A.; Victorino, R. M.Objective: HIV-1 envelope proteins have immunosuppressive properties and it is thought that they have a role in the establishment of immunodeficiency. This study characterizes the immunological effects of HIV-2 envelope protein gp105, a virus which is associated with a slower rate of disease progression. Methods: The effects of recombinant baculovirus-expressed envelope proteins from HIV-IIIB HIV-1MN, HIV-2ROD and SIVmac251 on anti-CD3-stimulated peripheral blood mononuclear cells (PBMC) from healthy donors were evaluated by incorporation of 3H-thymidine, flow cytometric analysis of bromodeoxyuridine incorporation in different T cell subsets, kinetics of expression of costimulatory molecules (CD40L/OX40) and assessment of cell death by annexin V/propidium iodide staining. The effects on production of tumour necrosis factor α (TNF-α) by monocytes were assessed at the single-cell level after a 6 h culture of unstimulated PBMC. Results: HIV-2 gp105 was more inhibitory than HIV-1 gp120 of T cell proliferation and the upregulation of CD40L and OX40; in the absence of signficant induction of apoptosis. This inhibition affected both CD4 and CD8 T cells and was only partially reversed by costimulation with interleukin 2 or CD28. gp105 strongly inducted TNF-α production by monocytes. Conclusion: The immunosuppressive properties of the HIV envelope proteins could be beneficial rather than detrimental to the host by interfering with the heightened state of immunocellular activation that characterizes HIV infection and by limiting the bursts of viral replication. This hypothesis could in part explain the slower decline of CD4 cell numbers in HIV-2 infection and deserves further exploration.
- Memory and naive-like regulatory CD4+ T cells expand during HIV-2 infection in direct association with CD4+ T-cell depletion irrespectively of viremiaPublication . Foxall, R. B.; Albuquerque, A. S.; Soares, R. S.; Baptista, A. P.; Cavaleiro, R.; Tendeiro, R.; Gomes, P.; Victorino, R. M.; Sousa, A. E.Objective: The dynamics of CD4+ regulatory T cells (Treg) during HIV-1 infection remains unclear. To further investigate Treg in this context, we characterized, for the first time, this population in HIV-2-positive individuals. Although both HIV infections are associated with hyperimmune activation and CD4+ T-cell lymphopenia, most HIV-2-positive individuals display slower disease progression and low-to-undetectable viremia. Design/methods: Samples were obtained from cohorts of untreated HIV-2-positive and HIV-1-positive, treated HIV-1-positive and seronegative individuals. The proportion of CD4+ T cells bearing a Treg phenotype, defined in terms of high-level CD25 or Foxp3 expression, was assessed by flow cytometry and correlated with markers of disease progression. The proportions of naive and memory-like subsets as well as cycling cells were determined. Results: We observed an increased proportion of Treg, associated with disease progression, as well as increased proportions of cycling (Ki67+) memory Treg, in untreated HIV-2-positive and HIV-1-positive individuals. We also noted an expansion of Treg that persisted over time in treated, immunologically discordant HIV-1-positive individuals, who, similarly to HIV-2-positive patients, present undetectable viremia and low CD4 T-cell count. Conclusion: Overall, we demonstrated that Treg frequency was increased in all lymphopenic HIV-2-positive and HIV-1-positive individuals irrespective of the presence or absence of viremia or antiretroviral treatment. This, in turn, suggests that the observed alterations in Treg frequency in HIV/AIDS are more directly related to the degree of CD4 depletion than to viremia.
- Memory B-cell depletion is a feature of HIV-2 infection even in the absence of detectable viremiaPublication . Tendeiro, R.; Fernandes, S.; Foxall, R. B.; Marcelino, J. M.; Taveira, N.; Soares, R. S.; Baptista, A. P.; Cavaleiro, R.; Gomes, P.; Victorino, R. M.; Sousa, A. E.Objective: Memory B-cell loss has long been recognized as an important contributor to HIV immunodeficiency. HIV-2 infection, which is characterized by a slow rate of progression to AIDS and reduced to undetectable viremia, provides a unique model to investigate B-cell disturbances. Design and methods: B-cell subsets were evaluated in 38 HIV-2-infected individuals, along with markers of T-cell activation and serum levels of immunoglobulins and a major B-cell homeostatic cytokine, B-cell activating factor (BAFF). Untreated HIV-1-infected and seronegative control individuals were studied in parallel. Statistical analysis was performed using Mann–Whitney tests and Spearman's correlations. Results: We found that HIV-2 was associated with significant depletion of both unswitched (CD27+IgD+) and switched (CD27+IgDneg) memory B-cells that directly correlated with T-cell activation, even in individuals with undetectable plasma viral load. Nevertheless, the presence of detectable viremia, even at low levels, was associated with significant memory B-cell loss and higher BAFF levels. Moreover, these alterations were not recovered by antiretroviral-therapy, as treated HIV-2-infected patients showed more pronounced B-cell disturbances, possibly related to their extended length of infection. Conclusion: These first data regarding B-cell imbalances during HIV-2 infection show that, irrespective of viremia, prolonged HIV infection leads to irreversible damage of memory B-cell homeostasis.
- Monocyte and myeloid dendritic cell activation occurs throughout HIV type 2 infection, an attenuated form of HIV disease.Publication . Cavaleiro, R.; Tendeiro, R.; Foxall, R. B.; Soares, R. S.; Baptista, A. P.; Gomes, P.; Valadas, Emília; Victorino, R. M.; Sousa, A. E.Monocytes and myeloid dendritic cells (mDCs) are important orchestrators of innate and human immunodeficiency virus (HIV)-specific immune responses and of the generalized inflammation that characterizes AIDS progression. To our knowledge, we are the first to investigate monocyte and mDC imbalances in HIV type 2 (HIV-2)-positive patients, who typically feature reduced viremia and slow disease progression despite the recognized ability of HIV-2 to establish viral reservoirs and overcome host restriction factors in myeloid cells. We found a heightened state of monocyte and mDC activation throughout HIV-2 infection (characterized by CD14(bright)CD16(+) expansion, as well as increased levels of soluble CD14, HLA-DR, and CD86), together with progressive mDC depletion. Importantly, HIV-2-positive patients also featured overexpression of the inhibitory molecule PD-L1 on monocytes and mDCs, which may act by limiting the production of proinflammatory molecules. These data, from patients with a naturally occurring form of attenuated HIV disease, challenge current paradigms regarding the role of monocytes in HIV/AIDS and open new perspectives regarding potential strategies to modulate inflammatory states.
- Monocyte-mediated T cell suppression by HIV-2 envelope proteinsPublication . Cavaleiro, R.; Brunn, G. J.; Albuquerque, A. S.; Victorino, R. M.; Platt, J. L.; Sousa, A. E.HIV-2 is associated with an attenuated form of HIV disease. We investigate here the immunosuppressive effects of the HIV-2 envelope protein, gp105. We found that gp105 suppresses activation of T cells through a monocyte-mediated mechanism. Suppression of T cell activation by gp105 depends on contact between monocytes and T cells, but not on CD4+CD25+ T cells. The TLR4 pathway is likely involved, since gp105 activates TLR4 signaling and induces TNF-α production by monocytes. Immunosuppression is viewed as the main pathophysiologic consequence of infection by HIV. However, the main immunologic defect caused by HIV, depletion of T cells, requires T cell activation. Our findings are consistent with a new concept that HIV-2 envelope proteins act on monocytes to suppress T cell activation and that this property may contribute to the benign course of HIV-2. We hypothesize that the HIV-2 envelope immunosuppressive properties limit bursts of T cell activation, thus reducing viremia and contributing to the slow rate of disease progression that characterizes HIV-2 disease.
- Preserved CD4 T-cell telomere length during long-lasting HIV-2 infection --Manuscript Draft--Publication . Tendeiro, R.; Albuquerque, A. S.; Foxall, Russell B.; Cavaleiro, R.; Soares, R. S.; Baptista, A. P.; Soares, M. V.; Gomes, P.; Sousa, A. E.HIV-2 infection features a much slower course than HIV-1 infection, often asymptomatic for over 20 years, without antiretroviral therapy (ART). Nevertheless, CD4 T cells progressively decline, in direct correlation with immune activation and cell cycling. We report, for the first time, preserved telomere length within naive and memory CD4 subsets in prolonged HIV-2 infection despite the increased CD4 turnover.
- Preserved monocyte-derived dendritic cell differentiation and maturation in the presence of HIV-2 envelopePublication . Cavaleiro, R.; Baptista, A. P.; Foxall, R. B.; Victorino, R. M.; Sousa, A. E.Dendritic cells (DCs) are fundamental for the initiation of immune responses and are important players in AIDS immunopathogenesis. Impairment of DC function may result from bystander effects of HIV-1 envelope proteins independently of direct HIV-1 infection. HIV-2 envelope proteins are thought to interact with a broader range of receptors than those of HIV-1, and have been shown to have T cell immunosuppressive properties mediated by monocytes. The effects of HIV-2 envelope on DC differentiation and maturation were investigated. The modulatory properties of the HIV-2 envelope on DC generated from monocytes were assessed using both recombinant proteins (HIV-2(ROD) and HIV-2(ALI)) and whole chemically inactivated virus (aldrithiol-2-treated HIV-2(ROD)). DC phenotype was assessed by flow cytometry and DC function by their ability to stimulate allogeneic T cells and to produce cytokines. We demonstrate that HIV-2 Env had no effects upon DC differentiation and maturation despite its broad receptor usage and ability to modulate monocyte function. It is plausible to speculate that a reduced ability of the HIV-2 Env to impair myeloid DC function could represent a contributory factor to the relatively benign course of HIV-2 disease.