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HIV-2 infection is associated with preserved GALT homeostasis and epithelial integrity despite ongoing mucosal viral replication

Publication . 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.

2017Journal article

Unknown

Potency of HIV-2-specific antibodies increase in direct association with loss of memory B cells

Publication . Rocha, Cheila; Duarte, Joana; Borrego, Pedro; Calado, Rita; Marcelino, José Maria; Tendeiro, Rita; Valadas, Emília; Sousa, Ana Espada; Taveira, Nuno

Potent HIV-neutralizing antibodies are critical for vaccination and viral reservoir control. High levels of neutralizing antibodies characterize HIV-2 infection, a naturally occurring model of attenuated HIV disease with low-to-undectable viremia. We found that HIV-2-specific antibody potency increased in direct association with the loss of both switched and unswitched memory B cells in untreated HIV-2 infection. Thus, HIV antibody affinity maturation is linked to memory B-cell exhaustion even in reduced viremia settings.

2017Journal article

Open access

HIV infection and gut-associated lymphoid tissue

Publication . Fernandes, Susana Mendes 1980-; Sousa, Ana Espada de, 1962-

HIV-1 disease progression is driven by chronic hyper-immune activation, a process intimately linked with severe mucosal CD4 T -cell depletion throughout the infection's course. The failure to fully re-establish mucosal homeostasis upon effective antiretroviral treatment (ART), and the consequent chronic inflammation, is also linked to morbidity despite viral controI. This work aimed to investigate mechanisms underlying recovery of gut homeostasis in HIV-1 treated infection, and to study, for the first time, the mucosal impact of HIV-2 infection, an attenuated form of HIV/AIDS. We focused the study oflong-term treated HIV-1 infected individuaIs on IL-22, a cytokine essential for intestinal epithelial integrity, and found significant depletion of IL-22-producing CD4 T-cells (Th22) in the sigmoid. However, mucosa was not disrupted, and there was a preserved expression of IL-22-dependent epithelial genes, as well as of innate lymphoid cells able to produce IL-22 (ILC3), thereby implicating this subset in gut homeostasis in HIV -1 infection. Conversely, long-term HIV-2-infected adults maintained mucosal CD4 T -cells irrespectively of ART, and featured no imbalances of CD4 T -cell subsets. The ILC3 compartment was also preserved, as well as the mucosal structure, despite evidence of local viral replication. Importantly, there was increased local production of chemokines, which supports a balanced CD4 T -cell recruitment to counteract cellloss. Df note, we found mucosal CD4 T -cell depletion with gut disruption in a young adult with HIV-2 infection acquired through vertical transmission, suggesting that HIV-2 infection early in infancy may be associated with loss of gut integrity. Nevertheless, there was a full recovery upon 5 years of ART. In conclusion, these studies indicate the importance of targeting gut homeostasis to improve HIV/AIDS outcome, highlighting the contribution of ILC3 and IL-22, and demonstrating for the first time that the protracted course of HIV-2 infection is associated with lack of gut disruption.

2015Doctoral thesis

Open access