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Infectology

Chairman's Overview

Charles Weissmann, M.D., Ph.D.

Charles Weissmann, M.D., Ph.D.

The Scripps Research Institute's Department of Infectology, established in 2004 as the first department on the Florida campus, focuses on prions, hepatitis C virus (HCV), and human immunodeficiency virus (HIV).

Prions are infectious agents that consist of PrPSc, a misfolded isoform of the host protein PrPC, and are devoid of a nucleic acid-based genome. They cause invariably lethal diseases of the central nervous system, such as mad cow disease (once rampant in the UK), chronic wasting disease of mule deer and elk (now evident in the US), or Creutzfeldt-Jakob disease in humans.

The Weissmann lab has established a novel, precise cell-based assay for prions that allows accelerated characterization of prion strains. Using this assay, it was shown that cloned prion populations become heterogeneous by “mutation” (which in the case of prions means conformational changes of PrPSc) and that distinct prion variants are selected in different environments. Thus, prions, although devoid of a nucleic acid genome, are subject to Darwinian evolution. Different prion strains target distinct brain areas and show specificity for certain cell lines. Current research is directed at elucidating the molecular basis for this cell tropism. The Lasmézas lab focuses on the mechanisms by which prions replicate and lead to neuronal dysfunction and death. It investigates the role of RNA in the misfolding of prion protein into its pathogenic counterpart. Prion diseases share fundamental neurotoxic mechanisms with other age-related protein misfolding neurodegenerative diseases such as Alzheimer’s disease. The lab is working on determining the structure of the toxic prion protein, identifying cellular death pathways, and establishing innovative approaches for high-throughput screening for neuroprotective drugs.

Hepatitis C affects more than 200 million individuals worldwide. Infection by HCV may at first be silent, but then progresses to destroy liver function and causes liver cancer. The Tellinghuisen lab focuses on the life cycle events involved in the replication of HCV, a relatively simple RNA virus. With the capacity to encode only ten proteins, it must exist as an obligate parasite of the human liver cell. Current research goals are to understand how this virus manipulates the host cell to accomplish complex events such as viral RNA replication and virion assembly, and how the alterations of normal cell physiology by the virus predisposes cells to pathology and carcinogenesis. Studies based on the structural analysis of viral proteins focus on inhibiting the replication of the viral RNA and are aimed at developing novel drugs. The Strosberg lab has identified and chemically optimized molecular probes which provide uniquely precise tools for studying the role of the core, a protein component of the viral particle, in assembly of the virion and interaction with proteins of the viral replicase complex. These small molecules disrupt core dimerization, block interaction of the dimer with other viral proteins, and inhibit virus production. The lab also investigates the role of multiprotein complexes in viral assembly.

AIDS, despite the development of effective treatments, continues to be a major scourge, and affects more than 35 million individuals worldwide. Retroviruses, such as the human immunodeficiency virus (HIV), require the assistance of multiple host cellular proteins at each step of their elaborate replication cycle. Host cells, in response, have evolved many mechanisms for inhibiting retroviral replication. The central effort of the Valente lab is to identify, by a genetic approach, host genes and proteins that are critical for HIV replication, to define the relevant molecular interactions and to elucidate the network of physical and functional interactions that underlie the virus-host interaction. By disarming the virus without affecting the viability of the cell, these efforts may lead to novel therapeutic approaches.