Cytopenias (loss of blood cells) are a major risk factor in HIV infection, heart disease, and cancer. Cytopenias that arise from abnormal hematopoiesis such as its inhibition leads to, or cause, multiple cytopenias in HIV infected individuals with thrombocytopenia emerging as a major risk factor for morbidity and mortality and even more so in patients also suffering from heart conditions. Thrombocytopenia is also a major risk factor in cancer patients undergoing chemotherapy.

Hematopoiesis is the differentiation of bone marrow or liver derived stem cells. To understand the role of HIV on hematopoiesis more completely by stem cell engraftment which can be easily manipulated in a suitable animal model, the same must also be susceptible to productive HIV infection. The chimeric SCID mouse coimplanted with human fetal thymus and liver tissues resulting in a functional human hematopoietic organ (SCID-hu Thy/Liv), provides an appropriate model to study the direct role of HIV on hematopoiesis, in the absence of confounding factors found in HIV infected patients. The SCID-hu system also allows the controlled introduction of a cloned HIV strain into a functioning hematopoietic organ, in the absence of confounding factors such as opportunistic infections or antiretroviral or recreational drugs. In addition, no host immune response is mounted, thus eliminating immune mediated phenomena from the pathogenic profile. Since the mouse itself is not infected, effects of stress on normal murine physiologic functions also should be minimal. Thus this model allows the causal role of HIV itself on hematopoiesis to be assessed under changing conditions of HIV affected stem cells. Dr. Koka's laboratory will also use the combined humanized NOD/SCID-hu systemic to further dissect such mechanisms of hematopoiesis to develop therapeutic strategies. These proposed studies will enable us to understand and overcome inhibition of differentiation of stem cells into multiple cell lineages and help restore blood cell levels.

Dr. Binley uses HIV virus-like particles ("VLPs") as a vaccine platform. Based on the past successes of vaccines for polio, smallpox, measles, mumps, rubella, and papilloma, among others, it has been shown that inactivated vaccines, including VLPs that closely resemble the live infectious virus, might be our best hope for a successful vaccine.

In work supported by the Gates Foundation, Dr. Binley's lab is also using VLPs to investigate why certain infected patients generate more effective antibody immune responses than others. This laboratory is also using VLPs to try to "fish out" the genetic information of this special virus fighting antibodies from infected patients so that they can be expressed in large quantities for a more detailed analysis.

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