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Anti-?4?7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1-infected individuals.

ABSTRACT: Gut homing CD4+ T cells expressing the integrin ?4?7 are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although simianized anti-?4?7 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-?4?7 treatment. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-?4?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 maintaining viral reservoirs, their attrition by anti-?4?7 therapy has important implications for HIV-1 therapeutics and eradication efforts and defines a rational basis for the use of anti-?4?7 therapy in HIV-1 infection.

SUBMITTER: Uzzan M

PROVIDER: S-EPMC6314200 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Uzzan Mathieu M Tokuyama Minami M Rosenstein Adam K AK Tomescu Costin C SahBandar Ivo N IN Ko Huaibin M HM Leyre Louise L Chokola Anupa A Kaplan-Lewis Emma E Rodriguez Gabriela G Seki Akihiro A Corley Michael J MJ Aberg Judith J La Porte Annalena A Park Eun-Young EY Ueno Hideki H Oikonomou Ioannis I Doron Itai I Iliev Iliyan D ID Chen Benjamin K BK Lui Jennifer J Schacker Timothy W TW Furtado Glaucia C GC Lira Sergio A SA Colombel Jean-Frederic JF Horowitz Amir A Lim Jean K JK Chomont Nicolas N Rahman Adeeb H AH Montaner Luis J LJ Ndhlovu Lishomwa C LC Mehandru Saurabh S

Science translational medicine 20181001 461

Gut homing CD4<sup>+</sup> 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 ...[more]

PMID: 30282696

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Project description:BackgroundVitamin D deficiency (VDD) is a worldwide disease. VDD is also associated with an increased risk of HIV-related comorbidities and mortality, and patients have a tendency to develop active tuberculosis compared to those with latent tuberculosis infection. Vitamin D supplementation may modulate HIV replication, improve TB inflammation and reduce progression of HIV-TB co-infection.MethodsWe meta-analyzed individual participant data from cohort studies, cross-sectional study, and RCTs of vitamin D in HIV group, TB group, and HIV-TB group. The primary outcomes were differences in vitamin D level and VDD prevalence between three groups, the secondary outcomes were CD4 count, HIV viral load, time to sputum smear conversion, time to culture conversion, relapse, morality, and TB score.ResultsFor vitamin D levels, the overall mean difference (MD) between HIV group and TB group was -0.21 (95% CI, -20.80-20.38; p = 0.9, I2 = 84%), HIV group and HIV-TB group was 0.87 (95% CI, -11.45-13.20; p = 0.89, I2 = 87%), and TB group and HIV-TB group was 1.17 (95% CI, -5.21-7.55; p = 0.72, I2 = 85%). For vitamin D deficiency prevalence, the overall odds ratio (OR) for HIV group versus TB group was 1.23 (95% CI, 0.46-3.31; p = 0.68; I2 = 70%), HIV group versus HIV-TB group was 1.53 (95% CI, 1.03-2.29; p = 0.04; I2 = 0%), and TB group versus HIV-TB group was 0.85 (95% CI, 0.61-1.20; p = 0.36; I2 = 22%). In HIV-TB group, the overall OR for vitamin D group versus placebo group was 0.78 (95% CI, 0.34-1.67; p = 0.52; I2 = 60%).ConclusionOur findings indicated that there were no variations in vitamin D levels between three groups. The prevalence of vitamin D deficiency was higher in the HIV-TB group than in the HIV group. Additionally, the administration of vitamin D supplements did not have obvious impact on CD4 count and viral load. Likewise, vitamin D had no effect on time to sputum smear conversion, time to culture conversion, relapse, 12-month morality, and TB score.

Dataset Information

Anti-?4?7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1-infected individuals.

Publications

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

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