Microbial translocation during human immunodeficiency virus infection

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Early human immunodeficiency virus (HIV) infection, is characterized by persistent immune activation which continues after initiation of anti-retro viral therapy (ART).Movement of microbes from the leaky gut into peripheral venous blood (PVB) is thought to be one mechanism causing this immune activation and is termed microbial translocation (MT). Currently MT is poorly understood in terms of extreme disease progression profiles, the spectrum of microbes translocated and,the resultant immune activation.In this thesis different aspects of MT were assessed in HIV compared to healthy subjects (HS). Direct measurements were measured in different blood fractions including plasma, blood cell and granulocytes and included cell wall components forbacteria (Lipopolysaccharide; LPS) and fungus (1,3 beta D glucan). Quantitative polymerase chain reaction (Q-PCRs) were also performed on bacterial 16S ribosomal DNA (16S rDNA), archaeal 16S rDNA and fungal internal transcribed spacer 1 DNA (ITS1) as an alternative direct measurement. Indirect measurements of MT were assessed through soluble CD14 (sCD14) and LPS- binding protein (LBP).Additionally, thirteen cytokines involved in the T-helper cell type 17 immune response pathway were assayed (IL-1ß, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22,IL-23, IL-33, IFN- γ, s-CD40L and TNF-α). Finally, 16S sequencing in blood cell pellets was performed to assess different microbial profiles translocating between HIV patients and HS.Results demonstrated MT in HIV is highest in early disease involving the three domains of life within the GI tract detectable in all PVB fractions which was significant for both bacteria and fungus. A distinct bacterial profile at the genus level in HIV subjects compared to HS was also observed. Through multivariate analysis the most significant measurement for MT in HIV was both measurements of fungal translocation into the granulocyte fraction. The novel use of granulocytes in this field of research was particularly significant when taken with significantly increased concentrations of IFN- γ and TNF-α perhaps pointing to an important role of the innate immune response when discussing MT in HIV. Alternative indirect
Date of Award1 Aug 2021
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJohn Cason (Supervisor)

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