Chronic immune activation and inflammation in HIV-infected immunological non-responders: A study of innate and adaptive immunity and effect of probiotic intervention
Appears in the following Collection
AbstractDespite modern antiretroviral therapy (ART) and persistent viral suppression, approximately 12-30% of people living with HIV (PLWH) do not normalize their CD4+ T cell count, denoted immunological non-responders (INR). INR have increased risk of developing AIDS defining illnesses, non-AIDS related morbidities and higher mortality, probably in part caused by increased chronic immune activation and inflammation. Alterations in the gut microbiota and destruction of the gut mucosal barrier with subsequent leakage of microbial products into the systemic circulation could be one of the sources of chronic inflammation. This thesis aimed to characterize differences in chronic immune activation and inflammation between a cohort of INR and a cohort of ART-treated PLWH with adequate CD4 recovery, to search for biomarkers for incomplete CD4 gain on ART and to evaluate the effects of probiotic intervention in virally suppressed PLWH with a subnormal CD4 count. The patients were recruited from Oslo University Hospital with contribution from Karolinska University Hospital. Blood and fecal samples were collected. The INR cohort displayed a more activated innate and adaptive immune system compared with PLWH on ART with normalized CD4 counts. In particular, plasma interferon-inducible protein 10 (IP-10) was increased in the INR cohort and associated with reduced future CD4 recovery. In a randomized controlled pilot study, eight weeks of intervention with a multistrain probiotic was well tolerated, induced shifts in the gut microbiota consistent with the probiotic strains administered, and seemed to reduce markers of coagulation and inflammation. These findings contribute to the understanding of the immunological mechanisms causing an inadequate CD4 recovery in INR. The usefulness IP-10 as a potential biomarker for incomplete CD4 gain in clinical practice, as well as the potential beneficial effect of probiotic intervention have to be further elaborated in larger prospective studies.
List of papers
|Paper I: Reduced levels of D-dimer and changes in gut microbiota composition after probiotic intervention in HIV-infected individuals on stable ART. Birgitte Stiksrud, Piotr Nowak, Felix Nwosu, Dag Kvale, Anders Thalme, Anders Sonnerborg, Per M. Ueland, Kristian Holm, Stein-Erik Birkeland, Anders E. A. Dahm, Per M. Sandset, Knut Rudi, Johannes R. Hov, Anne M. Dyrhol-Riise and Marius Trøseid. J Acquir Immune Defic Syndr, 2015;70:329-337. DOI: 10.1097/QAI.0000000000000784. The article is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1097/QAI.0000000000000784|
|Paper II: Plasma IP-10 is increased in immunological non-responders and associated with activated regulatory T cells and persisting low CD4 counts. Birgitte Stiksrud, Kristina Berg Lorvik, Dag Kvale, Tom Eirik Mollnes, Per Magne Ueland, Marius Trøseid, Kjetil Taskén and Anne M. Dyrhol-Riise. J Acquir Immune Defic Syndr, 2016;73:138-148. DOI: 10.1097/QAI.0000000000001080. The article is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1097/QAI.0000000000001080|
|Paper III: Activated dendritic cells and monocytes in HIV immunological non-responders; HIV-induced IP-10 correlates with low future CD4 recovery. Birgitte Stiksrud, Hans C. D. Aass, Kristina B. Lorvik, Thor Ueland, Marius Trøseid and Anne M. Dyrhol-Riise. AIDS, 2019;33:1117-11293. DOI:10.1097/QAD.0000000000002173. The article is included in the thesis. Also available at: https://doi.org/10.1097/QAD.0000000000002173|