Dataset Information

Early treatment of SIV+ macaques with an ?4?7 mAb alters virus distribution and preserves CD4+ T cells in later stages of infection.

ABSTRACT: Integrin ?4?7 mediates the trafficking of leukocytes, including CD4+ T cells, to lymphoid tissues in the gut. Virus mediated damage to the gut is implicated in HIV and SIV mediated chronic immune activation and leads to irreversible damage to the immune system. We employed an immuno-PET/CT imaging technique to evaluate the impact of an anti-integrin ?4?7 mAb alone or in combination with ART, on the distribution of both SIV infected cells and CD4+ cells in rhesus macaques infected with SIV. We determined that ?4?7 mAb reduced viral antigen in an array of tissues of the lung, spleen, axillary, and inguinal lymph nodes. These sites are not directly linked to ?4?7 mediated homing; however, the most pronounced reduction in viral load was observed in the colon. Despite this reduction, ?4?7 mAb treatment did not prevent an apparent depletion of CD4+ T cells in gut in the acute phase of infection that is characteristic of HIV/SIV infection. However, ?4?7 mAb appeared to facilitate the preservation or restoration of CD4+ T cells in gut tissues at later stages of infection. Since damage to the gut is believed to play a central role in HIV pathogenesis, these results support further evaluation of ?4?7 antagonists in the study and treatment of HIV disease.

SUBMITTER: Santangelo PJ

PROVIDER: S-EPMC5976508 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Early treatment of SIV+ macaques with an α4β7 mAb alters virus distribution and preserves CD4+ T cells in later stages of infection.

Santangelo P J PJ Cicala C C Byrareddy S N SN Ortiz K T KT Little D D Lindsay K E KE Gumber S S Hong J J JJ Jelicic K K Rogers K A KA Zurla C C Villinger F F Ansari A A AA Fauci A S AS Arthos J J

Mucosal immunology 20171220 3

Integrin α4β7 mediates the trafficking of leukocytes, including CD4+ T cells, to lymphoid tissues in the gut. Virus mediated damage to the gut is implicated in HIV and SIV mediated chronic immune activation and leads to irreversible damage to the immune system. We employed an immuno-PET/CT imaging technique to evaluate the impact of an anti-integrin α4β7 mAb alone or in combination with ART, on the distribution of both SIV infected cells and ...[more]

PMID: 29346349

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Project description:Treating macaques with an anti-α4β7 antibody under the umbrella of combination antiretroviral therapy (cART) during early SIV infection can lead to viral remission, with viral loads maintained at < 50 SIV RNA copies/ml after removal of all treatment in a subset of animals. Depletion of CD8+ lymphocytes in controllers resulted in transient recrudescence of viremia, suggesting that the combination of cART and anti-α4β7 antibody treatment led to a state where ongoing immune responses kept the virus undetectable in the absence of treatment. A previous mathematical model of HIV infection and cART incorporates immune effector cell responses and exhibits the property of two different viral load set-points. While the lower set-point could correspond to the attainment of long-term viral remission, attaining the higher set-point may be the result of viral rebound. Here we expand that model to include possible mechanisms of action of an anti-α4β7 antibody operating in these treated animals. We show that the model can fit the longitudinal viral load data from both IgG control and anti-α4β7 antibody treated macaques, suggesting explanations for the viral control associated with cART and an anti-α4β7 antibody treatment. This effective perturbation to the virus-host interaction can also explain observations in other nonhuman primate experiments in which cART and immunotherapy have led to post-treatment control or resetting of the viral load set-point. Interestingly, because the viral kinetics in the various treated animals differed-some animals exhibited large fluctuations in viral load after cART cessation-the model suggests that anti-α4β7 treatment could act by different primary mechanisms in different animals and still lead to post-treatment viral control. This outcome is nonetheless in accordance with a model with two stable viral load set-points, in which therapy can perturb the system from one set-point to a lower one through different biological mechanisms.

Dataset Information

Early treatment of SIV+ macaques with an ?4?7 mAb alters virus distribution and preserves CD4+ T cells in later stages of infection.

Publications

Early treatment of SIV+ macaques with an α<sub>4</sub>β<sub>7</sub> mAb alters virus distribution and preserves CD4<sup>+</sup> T cells in later stages of infection.

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