Biomarkers of HIV associated malignancies and of drug interaction between anti-retrovirals (ARVs) and chemotherapy

Flepisi, Thabile Brian (2015-12)

Thesis (PhD)--Stellenbosch University, 2015.

Thesis

ENGLISH ABSTRACT: INTRODUCTION: Altered immune mechanisms play a critical role in the pathogenesis of Non-Hodgkin lymphoma (NHL), as evidenced by increased rates of NHL among HIV+ patients [De Roos et al., 2012; Mellgren et al., 2012]. AIMS: To determine whether biomarkers of B-, T-cell activation, and inflammation are elevated in HIV+NHL patients; and whether cART influences their expression. METHODS: The expression of CD8+CD38 and FoxP3 were determined by flow cytometry; the serum concentrations of circulating sCD20, sCD23, sCD27, sCD30 and sCD44 were determined by enzyme linked immunosorbent assay (ELISA); and the serum concentrations of circulating IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and TNF-α were determined by meso-scale discovery (MSD) assay in 141 participants consisting of HIV positive NHL (HIV+NHL), HIV negative NHL (NHL); combination antiretroviral treated HIV+ (HIV+ cART), treatment naive HIV+ (cART-naïve HIV+) patients; and healthy controls. RESULTS: HIV+NHL patients had higher serum concentrations of sCD20 (p<0.0001 and p=0.0359), sCD23 (p=0.0192 and p<0.0001), sCD30 (p=0.0052 and p<0.0001), sCD44 (p=0.0014 and p<0.0001), and IL-4 (p=0.0234 and p=0.03360); and lower expression of FoxP3 (p<0.0001 and p=0.0171) as compared to NHL and HIV+ cART patients. As compared to NHL patients, the serum concentrations of IL-2 (p=0.0115), and TNF-α (p=0.0258) were higher in HIV+NHL patients, while those of IL-1β (p=0.0039) were significantly lower. HIV+NHL patients had higher expression of CD8+CD38 (p=0.0104), serum concentrations of IFN-γ (p=0.0085), and IL-6 (p=0.0265); and lower serum concentrations of IL-12p70 (p=0.0012) than HIV+ cART patients. As compared to controls, NHL had higher concentrationsof all biomarkers investigated except FoxP3 expression. As compared to HIV+ cART and controls, cART-naïve HIV+ patients had higher concentrations of all biomarkers investigated except sCD23 and FoxP3 expression. CONCLUSION: Biomarkers of chronic B- and T-cell activation and inflammation are up-regulated in HIV+NHL and the untreated HIV+ state. cART decreases immune activation and inflammation.

AFRIKAANSE OPSOMMING: INLEIDING: Versteurde immuun meganisme speel ‘n kritiese rol in die patogenese van Non-Hodgkin limfoom (NHL), soos aangedui deur verhoogde tempo van NHL onder MIV+ pasiënte [De Roos et al., 2012; Mellgren et al., 2012]. DOELWITTE: Om te bepaal indien biomerkers van B-, T-sel aktivering en inflammasie verhoog is in MIV+NHL pasiënte; en indien kART hul uitdrukking beinvloed. METODE: Die uitdrukking van CD8+CD38 en FoxP3 was bepaal deur vloei sitometrie; die serum konsentrasies van sirkulerende sCD20, sCD27, sCD30 en sCD44 was bepaal deur ensiem gekoppelde immuno sorbant toets (ELISA); en die serum konsentrasies van sirkulerende IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13 en TNF-α bepaal was deur meso-skaal ondekking (MSD) toets in 141 deelnemers bestaande uit MIV positiewe NHL (MIV+NHL); MIV negatiewe NHL (NHL), kombinasie antiretrovirale behandeling MIV+ (MIV+ kART); onbehandelde naïewe MIV+ (kART-naïewe MIV+) pasiente; en gesonde kontroles. RESULTATE: MIV+NHL pasiente het hoë serum konsentrasies van sCD20 (p<0.0001 en p=0.0359), sCD23 (p=0.0192 en p<0.0001), sCD30 (p=0.0052 en p<0.0001), sCD44 (p=0.0014 en p<0.0001), en IL-4 (p=0.0234 en p=0.03360); en verlaagde uitdrukking van FoxP3 (p<0.0001 en p=0.0171) in vergelyking met NHL en MIV+ kART patiente. Vergeleke met NHL pasiente, die serum konsentrasies van IL-2 (p=0.0115), en TNF-α (p=0.0258) was hoër in MIV+NHL pasiente, terwyl die van IL-1β (p=0.0039) beduidend laer was. MIV+NHL pasiente het hoër uitdrukking van CD8+CD38 (p=0.0104), serum konsentrasies van IFN-γ (p=0.0085), en IL-6 (p=0.0265); en laer serum konsentrasies van IL-12p70 (p=0.0012) as MIV+ kART pasiente. Vergeleke met die kontroles, NHL het hoër konsentrasies van al die biomerkers wat geondersoek was behalwe vir FoxP3 uitdrukking. Vergeleke met MIV+ kART en die kontroles, kART-naϊewe MIV+ pasiente het ‘n hoer konsentrasies van al die biomerkers wat ondersoek was behalwe sCD23 en FoxP3 die uitdrukking. GEVOLGTREKKING: Biomerkers van kroniese B- en T-sel aktivering en inflammasie is op-gereguleer in MIV+NHL en die onbehandelde MIV+ toestande. kART het immuun aktivering en inflammasie verminder.

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