PROJECT SUMMARY:
Hematological abnormalities, such as thrombocytopenia, anemia, lymphocytopenia, monocytopenia,
and neutropenia, frequently occur in patients infected with Human Immunodeficiency Virus (HIV)-1.
Of note, Pancytopenia has been considered as the hallmark feature of patients with advanced
Acquired immunodeficiency syndrome (AIDS) (Group IV). In addition, patients with HIV infection are
susceptible to HIV-associated opportunistic infections and bone marrow neoplasms. More
importantly, antiretroviral treatments result in incomplete rescue of hematopoiesis and are known to
impair normal hematopoiesis in patients with HIV infection. Emerging evidence establish a strong
link between HIV-1 and hematopoietic stem cells (HSCs) of the bone marrow. Overall, these studies
provide a compelling rationale for further investigations into mechanisms through which HIV-1
dysregulates hematopoiesis. However, the cellular mechanisms responsible for pancytopenia and
bone marrow failure following HIV-infection remain incompletely understood. More importantly, it
remains unclear if HIV infection is directly affecting the physiology and functions of HSCs. To this end,
the research proposed here aims to unravel the physiologic impact of HIV infection on HSCs and to
identify the progenitors that are susceptible to HIV infection.
The major hypothesis of this study is that HIV infection impairs HSC maintenance in the bone
marrow and their differentiation into myeloid, erythroid, and lymphoid lineages, which
ultimately results in immunodeficiencies. The rationale is that HIV infection alters the physiological
properties of HSCs, such as quiescence, self-renewal and multilineage differentiation, therefore
suppressing their vital functions. To test our hypothesis, we will use a combination of
xenotransplantation, in-vitro culture, molecular cell biology, biochemical and fluorescence correlation
spectroscopy studies. In the first specific aim, we would investigate the impact of HIV infection on
the physiology of HSCs. In the second specific aim, we would identify the HSPC subsets that are
susceptible to HIV-1 both in-vitro and in-vivo. Studies proposed in Aims 1 and 2 are complimentary
and informed by the data of each other, but not dependent on the outcome of the other Aim.
We believe that the proposed research will provide detailed insights into the mechanisms through
which HIV infection impairs HSC biology and causes hematopathology. Knowledge obtained from the
proposed research would be useful to design novel and more effective therapies for human
hematologic diseases that are caused by viral infections.