Shohreh Amini

amini

Office: 203 Biology- Life Sciences Building Temple University
Philadelphia, PA 19122
Phone: (215) 204-0604
E-mail:shohreh.amini@temple.edu
Center for Neurovirology and Cancer Biology

My laboratory is involved in several exciting research programs aimed at the understanding of the mechanism by which human viruses induce diseases in the central nervous system. In addition, we have a special interest on the development of molecular gene therapy strategies against viral-induced CNS dysfunction as detailed below.

  1. Molecular biology of retrovirus-host cell interaction in the Central Nervous System (CNS). Human retrovirus HIV-1 (Human Immunodeficiency Virus-1) is believed to be the causative agent for AIDS (Acquired Immunodeficiency Syndrome). AIDS is frequently associated with multiple disorders of the CNS such as severe encephalopathy and peripheral neuropathy. Detection of HIV-1 DNA in the brain and recovery of infectious virus from cerebrospinal fluid of AIDS strongly suggest that HIV is responsible for some of the neurological complications observed in these individuals. HIV-1, in addition to viral structural proteins, expresses several regulatory proteins among which Tat acts as transactivator of viral gene expression. There has been substantial investigation into the mechanism of Tat transactivation of the HIV-1 LTR, with a focus on the interaction of the Tat protein with a target sequence called the trans-acting responsive (TAR) element present just 3' to the start site of transcription. One of the goals of my research is to study transcriptional regulation of the HIV-1 LTR in glial cells since our previous observations have indicated the involvement of a novel regulatory pathway in CNS-derived cells that potentiates expression of the viral promoter. Our studies indicate that Tat has the capacity to increase LTR activity in the absence of TAR element in glial cells and that this activity is glial-cell specific and not detected in non-glial cells so far examined. Furthermore, it has been proposed that through transcellular communication Tat protein could reprogram cellular gene expression of infected as well as uninfected cells and contribute to the wide range of clinical complications seen in the affected individuals. Tat has been directly implicated in the development of immunodeficiency as evidenced by its ability to specifically inhibit antigen-induced proliferation of lymphocytes. However, the effect seems to be indirect and may utilize cytokines, such as Transforming Growth Factor -1 (TGF-1) and Tumor Necrosis Factor alpha (TNF-). The increased levels of TGF-1 and TNF- observed within the brains of HIV-1 infected individuals compared to the brains of uninfected ones suggests that HIV-1 infection directly or indirectly alters the expression of these cytokines in the CNS. In this regard, we have demonstrated that Tat protein increases transcription of TGF-1 and some cellular matrix-associated proteins in tissue culture system. Utilizing TGF-1 promoter deletion construct we have identified Tat-responsive element and have identified a trans-regulatory factor that in combination with Tat may result in alteration of TGF-1 gene expression in HIV-1 infected brain. The significance of Tat-induced transactivation of TGF-1 is several fold: 1) TGF-1 may function in a paracrine fashion resulting in the alteration of the expression of other cytokines and other responsive cellular genes such as genes encoding matrix-associated proteins (as we have previously shown); 2) TGF-1 has the capacity to act as a potent chemotactic agent for the recruitment of HIV-1 infected monocytes into the brain; 3) TGF-1 by inducing expression of other opportunistic latent viruses could contribute to the occurrence of encephalopathy in the brain of AIDS patients. Recently, we have reported on the use of herpes virus vector expressing Tat in an in vivo animal model. Following intracerebral infection of mice with this viral construct we were able to show that TGF-1 message level was significantly increased compared to the control animals infected with the vector lacking Tat sequences. This observation further supports our in vitro analyses indicating Tat as a transactivator of this potent and multifunctional cytokine. Recently, we have initiated studies in which the effect of purified Tat injected intracerebrally is examined on the expression of TNF- in an animal model. Pathological assessments will be performed to correlate cytokine dysregulation to neurotoxicity.

  2. In a separate yet related set of experiments we are exploring mechanisms involved in transcriptional modulation of the cellular genes specifically expressed within the nervous system. Myelin basic protein (MBP) as a protein exclusively produced in glial and Schwann cells is our candidate for this type analysis. Understanding tissue-specific transcription of this gene during myelination will enhance our current knowledge regarding demyelination induced by neurotropic pathogenic viruses. One of the focused areas in my research is to identify regulatory factors that in concert with cis-elements control MBP promoter activity in cell-type and developmental stage specific manner. Further molecular cloning of the gene(s) encoding the regulatory protein(s) will lead to investigation of the structure and function of this protein. Because the regulatory factor(s) that determines neural-specific gene regulation is itself probably regulated in a tissue-specific fashion, these experiments will also provide essential steps in approaches to deciphering the neural developmental program.

  3. Gene Therapy: The use of retroviruses and adeno-associated viruses as viral vectors for high efficiency delivery system of foreign genes and for the correction of some genetic defects has been my long-term interest. Strategies are being designed for tissue/cell-targeted delivery of therapeutic genes to the brain using these as well as herpes viral vectors.