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P38 MAPK in vivo inhibition impacts SIV-mediated immune activation & CD4 T-cell loss
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Reported by Jules Levin
CROI 2018 March 4-7 Boston MA
Anna Aldovini, MD
Boston Children's Hospital, Department of Medicine
Harvard Medical School, Department of Pediatrics
WEBCAST: http://www.croiwebcasts.org/console/player/37054?mediaType=slideVideo&&crd_fl=1&ssmsrq=1521227451522&ctms=5000&csmsrq=1068
CROI: CROI 2018: Comorbidities and Inflammation - David H Shepp, MD Associate Professor of Medicine Zucker School of Medicine at Hofstra-Northwell Manhasset, NY - (03/13/18) - Understanding how protein kinases deliver intracellular activation signals to regulate growth, and development of drugs to block them, has revolutionized the treatment of certain cancers and rheumatologic disorders. There are many different protein kinases utilized by the major classes of cytokine receptors to deliver intracellular activation signals. All utilize the p38 MAP kinase, although none use it exclusively. Aldovini et al. presented the effects of an investigational p38 MAP kinase inhibitor (PH797804) combined with ART in SIV-infected macaques (Aldovini A, abstract 20). PH79804 added to ART, given either 1 or 6 weeks after infection, yielded greater reductions in many inflammatory markers (IFNα, IFNγ , TNFα , IL-6, CRP,sCD163) and T-cell activation markers than did ART alone. No p38 MAP kinase inhibitors are approved for clinical use, but several are being investigated in other diseases. These studies suggest inhibition or p38 MAP kinase should be explored as an adjunct to ART in HIV.
http://jpet.aspetjournals.org/content/331/3/882 - Anti-Inflammatory Properties of a Novel N-Phenyl Pyridinone Inhibitor of p38 Mitogen-Activated Protein Kinase: Preclinical-to-Clinical Translation
Program Abstract:
Persistent immune activation is the hallmark of lentiviral infection in AIDS-susceptible species. p38 MAPK, activated in HIV and SIV infection, is key to induction of Interferon-stimulated genes (ISG) and inflammatory cytokines and is associated with some of the pathology produced by HIV and SIV infection in AIDS-susceptible primates. As small molecule p38 MAPK inhibitors are currently tested in human trials for other inflammatory diseases, we evaluated the effects of treating SIV-infected macaques with a p38 inhibitor, PH-797804, in conjunction with ART.
Rhesus macaques were infected with SIVmac251 and divided in 6 groups: Group 1, had no treatment, Group 2, p38 inhibitor alone, Groups 3 and 5 initiated ART at week 6 or 1 after infection, Group 4 and 6 initiated ART + PH797804 at week 6 or 1 after infection. ART efficacy was evaluated by measuring viral loads and reservoirs. As primary endpoints for PH-797804 efficacy, we evaluated protein levels of selected ISG and differences in expression of surface and intracellular molecules linked to immune activation and inflammatory cytokines plasma levels. As secondary endpoints, we evaluated effects of treatment on viral loads, reservoirs, and immune system preservation.
ART treatment reduces viremia to very low or undetectable levels. PH797804 had no side effects, did not further reduced the viremia, and did not affect immune responses to SIV. Administered alone, it had no significant effect on immune activation. When combined with ART, numerous immune activation markers were significantly reduced compared to ART alone treatment. CD38/HLA-DR and Ki-67 percentages in blood, lymph node and rectal CD4+ and CD8+ T cells and plasma levels of IFN-, IL-6, IL-8, and IP-10 were all significantly reduced. IRF7, pSTAT1 and IP-10 protein accumulation was also reduced. Significant preservation of CD4+/IL22+, CD4+ CM T-cells and improved ratio of Th17+/ Treg+ /CD4+ T cell was observed. After ART interruption, viremia rebounded in a similar fashion in the groups that received ART, with or without the inhibitor.
The p38 MAPK inhibitor used here, already in clinical trials for other inflammatory diseases, significantly reduced immune activation during ART and further reduced SIV-mediated immune system deterioration. However, suppression was not complete and was approximately 65% of that of untreated animals. Residual SIV replication in tissues during ART is under investigation.
"The addition of PH-797804 to ART permits a more significant recovery of CD4+ T-cell
counts than ART alone when the virus damage of the immune system has been more
severe and the combined regimen appears to counteract a later initiation of ART."
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