HIV
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.
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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.
Influenza and H Influenae
Dr. Sarawar's research group is studying secondary bacterial infections following infection with influenza virus. Such secondary infections cause pneumonia or meningitis in young children, debilitated elderly and immunocompromised individuals and result in considerable morbidity and mortality.
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Secondary bacterial infections following influenza virus infection are also associated with significant increase in morbidity and mortality in normal healthy adults during influenza pandemics. The models developed in Dr. Sarawar's laboratory are being used to understand the mechanism by which influenza and bacteria interact leading to more severe disease and may lead to the development of novel methods of therapeutic intervention. Dr Sarawar is also collaborating with Lancell LLC, (San Diego) on strategies to make influenza vaccines more effective and is investigating why respiratory viral infections often trigger asthma attacks.
Smallpox
Smallpox, a highly contagious and sometimes lethal disease, is caused by the variola virus. Due to a successful vaccination program conducted worldwide, smallpox was eradicated in 1979. Recent events have raised concerns regarding the possible use of smallpox, as well as new emerging infections such as monkey pox, as bioterrorism agents.
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Routine immunization against small pox was discontinued during the 1970s and the remaining live vaccinai to be used for immunization does not meet the current safety standards. Furthermore, although this type of immunization was efficacious for extinguishing smallpox, the relevant vaccine antigens capable of expanding appropriated humoral and T cell immune responses are only now beginning to be addressed. Clearly, there is a strong need for the development of better vaccine candidates.
Dr. Pinilla identifies T cell epitopes recognized by vaccinia-immunized donors who are participating in a clinical trial designed to evaluate the safety and efficacy of two different vaccines, namely MVA and Dryvax. Human T cell lines and clones dervided from immunized human donors are being generated. These cell lines and clones will be used to screen combinatorial peptide libraries as well as overlapping panels of peptides of pox virus proteins.
Leishmania
Leishmaniasis is endemic worldwide with more than 2 million new cases reported yearly - source information. The disease is caused by a protozoan parasite of the genus Leishmania, and is transmitted by a sand fly. Depending on the Leishmania species, the disease can have multiple outcomes ranging from localized cutaneous, diffuse cutaneous, mucocutaneous and visceral leishmaniasis.
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The more benign form of disease (localized cutaneous leishmaniasis) is characterized by a protective immune response, whereas the more pathogenic forms are characterized by poor cellular immune responses permitting uncontrolled spread of the parasite, which can be fatal if left untreated. The current drug of choice has many side effects and recently reported as not being totally efficacious, with crescent parasite resistance being detected, especially in highly endemic areas of visceral leishmaniasis.
Dr. Raja Gabaglia's Laboratory of Vaccine Research is currently studying the immune responses to this pathogen, by using animal models and human blood, to characterize proteins and peptides of this parasite relevant in a protective immune response. In animal models, it has been described an important protective role of pro-inflammatory T lymphocytes (Th-1) which secrete cytokines such as IFNgamma and TNFalpha, necessary for the killing of these parasites harbored inside macrophages. The microorganisms causing leishmaniasis, tuberculosis and leprae have in common that they are harbored inside the host cells. Because of this, antibody responses are of no use; only activated T cells can help to clear the infected cells and to control infection. Dr. Raja Gabaglia's lab studies the mechanisms by which to control these intracellular pathogens, how to activate the immune system in the polarized Th1 response and how an efficacious vaccine against this disease can be developed.
Viral Vaccine Development
Dr. Sally Sarawar's research group is studying mechanisms of immune control of persistent viral infections. Certain types of viruses can persist in a latent or inactive form in the body and are controlled by the immune system in normal healthy people.
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However, these viruses can reactivate in immune-compromised individuals, such as patients with HIV-AIDS or transplant recipients receiving immunosuppressive therapy, causing a range of diseases including certain types of cancer. In addition, persistent viral infections have been implicated in the development of cancer in people with seemingly normal immune systems. For example, Epstein Barr virus is implicated in the development of nasopharyngeal cancer in Northern China and Burkitt's lymphoma in certain regions of Africa. Understanding how the immune system controls these viruses in healthy individuals may lead to the design of novel therapies including small molecule drugs, vaccines and antibody-based drugs to combat viral reactivation and treat the diseases caused by persistent viral infection.
