Deciphering hematopoietic stem cell defects in HIV exposed, uninfected infants born to ART-treated mothers - PROJECT SUMMARY: Intensive research of the past few decades demonstrated that Human Immunodeficiency Virus (HIV)- infected individuals develop severe hematopathologies, including anemia, thrombocytopenia, pancytopenia, and bone marrow failure. Even though a great deal of information is available on HIV- induced hematopoietic defects in people living with HIV, hematopathologies caused by in-utero exposure of HIV in HIV-exposed uninfected (HEU) children remains largely unknown. Particularly, physiological impact of maternal exposure of HIV on hematopoietic stem cells (HSCs) of HEU infants remain completely unknown. A vast majority of HEU children have higher risk of opportunistic infections within the first 6 months of life. Indeed, HEU infants have 2- to 4- fold higher mortality rate, largely due to respiratory infections and bacterial sepsis, when compared with HIV-unexposed uninfected (HU) infants. Emerging evidence establish a strong link between HIV-1 and HSCs of the bone marrow. More importantly, antiretroviral treatments result in incomplete rescue of hematopoiesis and immune functions in patients living with HIV infection. Overall, these studies provide a compelling rationale for further investigations into cellular and molecular mechanisms that contribute to immune dysfunctions and increased susceptibilities to microbial infections in HEU children. To this end, research proposed here aims to unravel the physiologic impact of in-utero HIV exposure on HSC maintenance and myeloid differentiation and to identify the upstream mechanisms through which HIV exposure impairs HSCs in HEU children. The major hypothesis of this study is that self-renewal and differentiation of HSCs are compromised in HEU children, most likely due to HIV-associated chronic inflammation, which eventually results in defective peripheral immune functions. To test our hypothesis, we will use a combination of xenotransplantation, in-vitro culture, molecular cell biology, biochemical and spectral flow cytometry studies. In the first specific aim, we would investigate the physiological and molecular alterations caused by HIV-exposure on HSCs. In the second specific aim, we would assess myeloid differentiation capacities of HEU-HSCs and evaluate the functions of HEU-HSC-derived DCs and macrophages to mount effective immune responses against respiratory infections. In the third specific aim, we would identify the cellular source of inflammation and evaluate the therapeutic benefit of inhibiting inflammatory circuits in HEU infants. Studies proposed in Aims 1, 2 & 3 are complimentary and informed by the data of each other, but not dependent on the outcome of the other Aims. We believe that studies described here would be of major clinical relevance as it attempts to unravel the cellular and molecular mechanisms that may be responsible for increased morbidities and mortalities in HEU children.
