Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1-infected individuals
Mathieu Uzzan, Minami Tokuyama, Adam K Rosenstein, Costin Tomescu, Ivo N SahBandar, Huaibin M Ko, Louise Leyre, Anupa Chokola, Emma Kaplan-Lewis, Gabriela Rodriguez, Akihiro Seki, Michael J Corley, Judith Aberg, Annalena La Porte, Eun-Young Park, Hideki Ueno, Ioannis Oikonomou, Itai Doron, Iliyan D Iliev, Benjamin K Chen, Jennifer Lui, Timothy W Schacker, Glaucia C Furtado, Sergio A Lira, Jean-Frederic Colombel, Amir Horowitz, Jean K Lim, Nicolas Chomont, Adeeb H Rahman, Luis J Montaner, Lishomwa C Ndhlovu, Saurabh Mehandru, Mathieu Uzzan, Minami Tokuyama, Adam K Rosenstein, Costin Tomescu, Ivo N SahBandar, Huaibin M Ko, Louise Leyre, Anupa Chokola, Emma Kaplan-Lewis, Gabriela Rodriguez, Akihiro Seki, Michael J Corley, Judith Aberg, Annalena La Porte, Eun-Young Park, Hideki Ueno, Ioannis Oikonomou, Itai Doron, Iliyan D Iliev, Benjamin K Chen, Jennifer Lui, Timothy W Schacker, Glaucia C Furtado, Sergio A Lira, Jean-Frederic Colombel, Amir Horowitz, Jean K Lim, Nicolas Chomont, Adeeb H Rahman, Luis J Montaner, Lishomwa C Ndhlovu, Saurabh Mehandru
Abstract
Gut homing CD4+ T cells expressing the integrin α4β7 are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although simianized anti-α4β7 monoclonal antibodies have shown promise in preventing or attenuating the disease course of simian immunodeficiency virus in nonhuman primate studies, the mechanisms of drug action remain elusive. We present a cohort of individuals with mild inflammatory bowel disease and concomitant HIV-1 infection receiving anti-α4β7 treatment. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-α4β7 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 maintaining viral reservoirs, their attrition by anti-α4β7 therapy has important implications for HIV-1 therapeutics and eradication efforts and defines a rational basis for the use of anti-α4β7 therapy in HIV-1 infection.
Conflict of interest statement
Competing interests: S.M. and J.-F.C. have an unrestricted, investigator-initiated grant from Takeda Pharmaceuticals to examine novel homing mechanisms to the GI tract. All other authors declare that they have no competing interests.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Figures
![Fig. 1.. Anti-α4β7 therapy decreases the frequency…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6314200/bin/nihms-1003601-f0001.jpg)
![Fig. 2.. Anti-α4β7 therapy results in a…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6314200/bin/nihms-1003601-f0002.jpg)
![Fig. 3.. Anti-α4β7 therapy results in a…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6314200/bin/nihms-1003601-f0003.jpg)
![Fig. 4.. Anti-α4β7 therapy is associated with…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6314200/bin/nihms-1003601-f0004.jpg)
![Fig. 5.. Anti-α4β7 therapy is associated with…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6314200/bin/nihms-1003601-f0005.jpg)
![Fig. 6.. Anti-α4β7 therapy results in the…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6314200/bin/nihms-1003601-f0006.jpg)
![Fig. 7.. Impact of anti-α4β7 therapy on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6314200/bin/nihms-1003601-f0007.jpg)
Source: PubMed