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The effect of timing of antiretroviral therapy on CD4+ T-cell reconstitution in the intestine of HIV-infected patients; Gut Microbiota & CD4 Recovery
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Download the PDF here
Download the PDF here
Download the PDF here
Download the PDF here
Incomplete regeneration of the mucosal immune system during treated HIV infection likely promotes disease progression. In patients with initiation of cART during chronic HIV infection, repopulation of the intestinal mucosa with CD4+ T cells was insufficient to achieve full reconstitution.
The clinical consequences of this persistent defect in the mucosal immune system are currently unknown. An association between impaired mucosal CD4+ T-cell reconstitution and non-specific enteritis has recently been described.23 Moreover, evidence for increased incidence of adenomas and intestinal malignancies in treated chronically HIV-infected patients38, 39 suggests that mucosal immune defects increase the risk of adverse outcome despite otherwise effective long-term cART. Our findings of increased systemic immune activation and enterocyte damage indicate ongoing inflammatory disease progression in treated patients with persistent mucosal CD4+ T-cell depletion.
In conclusion, our study demonstrates that preservation of mucosal CD4+ T cells at both the quantitative and the differentiation levels is possible if cART is initiated during the acute phase of HIV infection. In chronically HIV-infected persons, restoration capacity of mucosal CD4+ T-cell counts is irreversibly compromised. Both persistent depletion of mucosal CD4+ T cells and enhanced levels of CD4+ T-cell activation in the largest immunological organ are characteristic features of treated chronic HIV infection, regardless of the timing of cART initiation. Taken together, our findings highlight the importance of the development of adjunctive immunomodulatory therapies43, 44 aiming at immune restoration in the intestinal mucosa of chronically HIV-infected patients.
The proportion of mucosal effector memory CD4+ T cells normalized only if cART was initiated at >350 CD4+ T cells per μl blood but not with delayed treatment. In conclusion, mucosal CD4+ T-cell numbers can be preserved if cART is initiated in acute HIV infection. In chronically HIV-infected patients, early cART improves mucosal CD4+ T-cell differentiation but cannot prevent the persistent lack of total CD4+ T cells. https://www.nature.com/articles/mi201558
Disruption of Intestinal CD4+ T Cell Homeostasis Is a Key Marker of Systemic CD4+ T Cell Activation in HIV-Infected Individuals
This mucosal CD4+ T cell loss would then result in an impairment of mucosal immune function, increased mucosal and systemic immune activation that is (at least in part) caused by microbial translocation, increased virus replication due to higher numbers of activated CD4+ T cells that act as targets for HIV, and further systemic and mucosal CD4+ T cell depletion.
Association Between Gut Microbiota and CD4 Recovery in HIV-1 Infected Patients
Our study has shown that gut microbiota changes were associated with CD4+ T-cell counts and immune activation in HIV-infected subjects. Interventions to reverse gut dysbiosis and inhibit immune activation could be a new strategy for improving immune reconstitution of HIV-1-infected individuals.
Irreversible depletion of intestinal CD4+ T cells is associated with T cell activation during chronic HIV infection
Our GI cohort underpins the central role of the intestine in HIV-1 pathology and demonstrates poor restoration of gut mucosal immunity, in particular within the small intestine, by otherwise effective ART.
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