HIV IMMUNOPATHOGENESIS: COMPARISON OF THE IMPACT OF HIV-2 AND HIV-1 INFECTIONS IN LYMPHOID TISSUES.

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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

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