Serge Blaise Emaleu M.D
Postdoctoral Fellow
Title: Immunological and redox biomarkers of neutrophils function in HIV/AIDS and Tuberculosis diseases.
Background. Previous have shown that HIV /AIDS disease is associated with persistent bacterial and fungal infection which would otherwise be cleared by a functional innate immune system. These observations support the idea that although HIV virus infects only CD4 T cells, the disease leads to an impairment of both innate and adaptive immune system.
Hypothesis. Thus, we hypothesize that HIV disease and specific treatments thereof (e.g., protease inhibitors) modulate the activity of leukocyte subsets that are not conventional targets of HIV, most notably neutrophils. Furthermore, we hypothesize that leukocyte (neutrophils) redox and/or functional imbalance underlies important events in HIV disease, including appearance of opportunistic infections.
Aims
- Determine whether HIV patients show redox abnormalities (low glutathione, ROS etc) in neutrophils (and other blood leukocytes), that associate with disease and treatment history
- Determine whether HIV patients show functional abnormalities in granulocytes (activation status, phagocytosis, signaling pathways), that associate with disease and treatment history
Approach/Methods. These aims will be pursued by longitudinal assessment whole blood from HIV patients (treatment-naïve, ART including protease inhibitors and ART without protease inhibitors), at 5 time points spread over two years (0, 3, 6, 12, 24 months). Whole blood will be analyzed by biochemical and HI-D FACS based redox and functional assays developed in our laboratory. Data from HIV patients will be compared to that from retroviral disease controls (HBV or HCV infection, without HIV) and healthy controls.
Expected Results/Impact and Significance. This study will help revisit current immunometabolic concepts that fail to explain the whole spectrum of symptoms in HIV disease in vivo. In doing so, we hope to achieve better understanding of innate immune subsets, especially neutrophils, in the context of HIV disease. Indeed, neutrophils may be impacted by HIV disease progression (i.e., in their function and not only their numbers), but also, HIV disease progression may in turn be impacted by neutrophils dysfunction (i.e., I the context of failed innate immune response to opportunistic pathogens). Hence, our study may help delineate simple whole blood biomarkers that will ameliorate the clinical monitoring and prognostic capabilities in HIV/AIDS disease.
Preliminaries Results:
Using multi-color flow Cytometry we measured markers of activation of innate immune cells including neutrophils, eosinophils, NK cells and monocytes in freshly obtained whole blood without any in vitro stimulations. These include CD63, CD11b, CD184, CD195, CD66b, CD14 and CD16. Here we show that patients with HIV/AIDS tend to express higher levels of CD11b on neutrophils. The other markers of neutrophils and other innate immune cells (NK cells, eosinophils and monocytes) activation did not show significant difference when compared to age matched controls. HAART naive early stage HIV patients do not express increased levels of CD11b on their neutrophils. More importantly, late stage HIV patients on HAART therapy show significantly higher levels of CD11b on neutrophils. Hence, our study shows that CD11b expression on neutrophils can be used as a reliable biomarker for early detection of opportunistic infections and to monitor response to therapy in HIV disease. Our methods offer a simple and reliable method that can be easily adopted in all HIV clinical laboratories without the need to acquire new instrumentation for the assays.
Preliminary Conclusion at Time T0,T1,T2
Our study shows that CD11b expression on neutrophils can be used as reliable biomarker for early detection of opportunistic infections and to monitor response to therapy in HIV disease. Our methods offer a simple and reliable method that can be easily adopted in all HIV clinical laboratories without the need to acquire new instrumentation for the assays.
We are still to complete the two remaining time point before drawing a general conclusion of the study
