Browsing by Author "Pires, A. R."
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- Gut disruption in HIV-2 infection despite reduced viremiaPublication . Fernandes, S. M.; Pires, A. R.; Ferreira, C.; Tendeiro, R.; Correia, L.; Paulo, S. E.; Victorino, R. M.; Sousa, A. E.HIV-2 infection is highly prevalent inWest Africa and has been increasingly observed in non-African countries, mostly associated with migratory populations [1]. It has a much more benign course and lower viremia than HIV-1 [2], though with similar clinical spectra. Half of the HIV-2 infected patients with less than 200 CD4+ T-cells/ml exhibit undetectable viremia, despite harbouring numbers of infected cells comparable to their HIV-1 counterparts [3]. Moreover, CD4+ T-cell loss occurs in direct association with progressive immune activation in both infections, though the depletion rate is much slower in HIV-2 [2,4]. HIV-1 disease progression has been linked to disruption of gut-associated lymphoid tissue (GALT)and increased levels of microbial translocation, leading to systemic immune activation. There are currently no data on the impact of HIV-2 on GALT. Here, we provide evidence of HIV-2 replication in the gut despite the low viremia, which was associated with major mucosal disruption and CD4+ T-cell depletion that recovered upon antiretroviral treatment (ART).
- HIV-2 infection is associated with preserved GALT homeostasis and epithelial integrity despite ongoing mucosal viral replicationPublication . Fernandes, S. M.; Pires, A. R.; Matoso, P.; Ferreira, C.; Nunes-Cabaço, Helena; Correia, L.; Valadas, Emília; Poças, J.; Pacheco, P.; Veiga-Fernandes, Henrique; Foxall, Russell; Sousa, Ana E.The mechanisms that enable preservation of gut mucosal integrity during persistent viral replication and inherent inflammation remain unclear. Here, we investigated, for the first time, gut homeostasis in HIV-2 infection, a naturally occurring form of attenuated HIV disease. We found viral replication in both sigmoid and ileum of asymptomatic HIV-2+ patients (range: 240-851 circulating CD4+T-cells per μl) despite their undetectable viremia, accompanied by interferon-γ-producing CD8 T-cell expansion, irrespective of antiretroviral treatment. Nevertheless, there was no CD4 T-cell depletion, and Foxp3+ and IL-17- or IL-22-producing CD4 T-cell numbers were unaffected. Moreover, IL-22-producing innate lymphoid cells and IL-22-induced antimicrobial peptides and mucins were maintained. In agreement, the epithelium histology was preserved, including tight junction protein zonula occludens (ZO-1) levels. Furthermore, in vitro infection of colon epithelia with primary isolates revealed no HIV-2 impact on ZO-1 expression. Notably, sigmoid transcriptional levels of CCL20 and CCL28 were significantly increased, in direct correlation with GM-CSF, indicating a local response able to enhance CD4 T-cell recruitment. In conclusion, maintenance of mucosal integrity in HIV-2 infection was associated with T-cell recruitment responses, potentially counteracting CD4 T-cell depletion due to HIV-2 replication. These data have unique implications for the design of therapies targeting gut homeostasis in HIV-1 infection and other chronic inflammatory settings.
- Human regulatory T-cell development is dictated by Interleukin-2 and -15 expressed in a non-overlapping pattern in the thymusPublication . Caramalho, I.; Nunes-Silva, V.; Pires, A. R.; Mota, C.; Pinto, A. I.; Nunes-Cabaço, H.; Foxall, R. B.; Sousa, A. E.Thymus-derived FOXP3-expressing regulatory T-cells (tTregs) are master orchestrators of physiological and pathological immune responses, thus constituting ideal targets for the treatment of autoimmunity. Despite their clinical importance, the developmental program governing their differentiation in the human thymus remains poorly understood. Here, we investigated the role of common gamma-chain cytokines in human tTreg differentiation, by performing gain- and loss-of-function experiments in 3D and 2D postnatal thymic cultures. We identified IL-2 and IL-15 as key molecular determinants in this process and excluded a major function for IL-4, IL-7 and IL-21. Mechanistically, IL-2 and IL-15 were equally able to drive tTreg precursor differentiation into FOXP3(+) cells, and promote tTreg proliferation and survival. Both cytokines also increased the expression levels of molecules associated with effector function within FOXP3(+) subsets, supporting their involvement in tTreg functional maturation. Furthermore, we revealed that IL-2 and IL-15 are expressed in a non-overlapping pattern in the human thymus, with the former produced mainly by mature αβ and γδ thymocytes and the latter by monocyte/macrophages and B lymphocytes. Our results identify core mechanisms dictating human tTreg development, with IL-2 and IL-15 defining specific niches required for tTreg lineage stabilization and differentiation, with implications for their therapeutic targeting in autoimmune conditions.
- Thymic HIV-2 infection uncovers posttranscriptional control of viral replication in human thymocytesPublication . Nunes-Cabaço, H.; Matoso, P.; Foxall, R. B.; Tendeiro, R.; Pires, A. R.; Carvalho, Tânia; Pinheiro, A. I.; Soares, R. S.; Sousa, A. E.A unique HIV-host equilibrium exists in untreated HIV-2-infected individuals. This equilibrium is characterized by low to undetectable levels of viremia throughout the disease course, despite the establishment of disseminated HIV-2 reservoirs at levels comparable to those observed in untreated HIV-1 infection. Although the clinical spectrum is similar in the two infections, HIV-2 infection is associated with a much lower rate of CD4 T-cell decline and has a limited impact on the mortality of infected adults. Here we investigated HIV-2 infection of the human thymus, the primary organ for T-cell production. Human thymic tissue and suspensions of total or purified CD4 single-positive thymocytes were infected with HIV-2 or HIV-1 primary isolates using either CCR5 or CXCR4 coreceptors. We found that HIV-2 infected both thymic organ cultures and thymocyte suspensions, as attested to by the total HIV DNA and cell-associated viral mRNA levels. Nevertheless, thymocytes featured reduced levels of intracellular Gag viral protein, irrespective of HIV-2 coreceptor tropism and cell differentiation stage, in agreement with the low viral load in culture supernatants. Our data show that HIV-2 is able to infect the human thymus, but the HIV-2 replication cycle in thymocytes is impaired, providing a new model to identify therapeutic targets for viral replication control. IMPORTANCE: HIV-1 infects the thymus, leading to a decrease in CD4 T-cell production that contributes to the characteristic CD4 T-cell loss. HIV-2 infection is associated with a very low rate of progression to AIDS and is therefore considered a unique naturally occurring model of attenuated HIV disease. HIV-2-infected individuals feature low to undetectable plasma viral loads, in spite of the numbers of circulating infected T cells being similar to those found in patients infected with HIV-1. We assessed, for the first time, the direct impact of HIV-2 infection on the human thymus. We show that HIV-2 is able to infect the thymus but that the HIV-2 replication cycle in thymocytes is impaired. We propose that this system will be important to devise immunotherapies that target viral production, aiding the design of future therapeutic strategies for HIV control.