Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals

Uzzan, M.; Tokuyama, M.; Rosenstein, A. K.; Tomescu, C.; SahBandar, I. N.; Ko, H. M.; Leyre, L.; Chokola, A.; Kaplan-Lewis, E.; Rodriguez, G.; Seki, A.; Corley, M. J.; Aberg, J.; La Porte, A.; Park, E.-y.; Ueno, H.; Oikonomou, I.; Doron, I.; Iliev, I. D.; Chen, B. K.; Lui, J.; Schacker, T. W.; Furtado, G. C.; Lira, S. A.; Colombel, J.-F.; Horowitz, A.; Lim, J. K.; Chomont, N.; Montaner, L. J.; Ndhlovu, L. C.; Mehandru, S.

doi:10.1101/346684

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bioRxiv · 10.1101/346684

Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals

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Abstract

Herein, we present the first human study of anti-4{beta}7 therapy in a cohort of HIV-1 infected subjects with mild inflammatory bowel disease. 4{beta}7+ gut homing CD4+ T cells are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although, simianized anti-4{beta}7 monoclonal antibodies (Mab) have shown promise in preventing or attenuating the disease course of SIV in Non-Human Primate studies, the mechanisms of drug action remain elusive and the impact on HIV-1 persistence remains unanswered. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-4{beta}7 therapy led to a significant and unexpected attenuation of lymphoid aggregates, most notably in the terminal ileum. Given that lymphoid aggregates serve as important sanctuary sites for establishing and maintaining viral reservoirs, their attrition by anti-4{beta}7 therapy has important implications for HIV-1 therapeutics and eradication efforts, and defines a rational basis for the continued evaluation of anti-4{beta}7 therapy in HIV-1 infection.\n\nOne Sentence SummaryAnti-4{beta}7 integrin therapy results in attrition of lymphoid aggregates within the gastrointestinal tract of HIV-1 infected individuals

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Uzzan, M., Tokuyama, M., Rosenstein, A. K., Tomescu, C., SahBandar, I. N., Ko, H. M., Leyre, L., Chokola, A., Kaplan-Lewis, E., Rodriguez, G., Seki, A., Corley, M. J., Aberg, J., La Porte, A., Park, E.-y., Ueno, H., Oikonomou, I., Doron, I., Iliev, I. D., Chen, B. K., Lui, J., Schacker, T. W., Furtado, G. C., Lira, S. A., Colombel, J.-F., Horowitz, A., Lim, J. K., Chomont, N., Montaner, L. J., Ndhlovu, L. C., Mehandru, S.. 2018-06-14. Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals. https://doi.org/10.1101/346684

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