PRIMARY FACULTY

Christopher Broder, Ph.D.
Professor
Microbiology & Immunology
 
4301 Jones Bridge Road
Bethesda MD 20814
Office: 301-295-3401
Fax: 301-295-1996
cbroder@usuhs.mil

We are pursuing structural and functional analyses on the interactions between enveloped viruses and their cellular receptors through immunological, biochemical, and genetic approaches with an emphasis on the expression of recombinant cDNAs in the vaccinia virus system. HIV-1 and new emerging paramyxovirus agents are the two main areas of research work presently being pursued. The goals of our work are to identify the steps and requirements of viral envelope glycoprotein (Env)-mediated membrane fusion, the determinants of viral tropism, the discovery of new viral receptors, and the mechanism of Env-mediated fusion. A detailed understanding of these processes will lead to the discovery of new methods of intervention.

Current work on HIV-1 includes the Env glycoprotein (gp120/gp41) mediated fusion mechanism and its interaction with CD4 and coreceptors. The HIV-1 Env serves two functions that are critical in the replication cycle of the virus: binding to host cells and mediating membrane fusion through what is believed to be receptor induced conformational alterations in its structure. In earlier work we identified two distinct cofactors (CXCR4/CCR5) for HIV-1 Env-mediated fusion and virus infection. These molecules are members of the chemokine receptor superfamily, and are now recognized as actual coreceptors for HIV-1 and they influence both the species and cell-type tropism of the virus. We are engaged in an extensive analysis of the roles these coreceptors play in the fusion process on the molecular level, and what role they may play in HIV-1 pathogenesis.

We are also interested in the structure of these viral envelope glycoproteins with particular emphasis on the immunological characteristics of the native glycoproteins. With the use of recombinant vaccinia virus expressed HIV-1 Env we have carried out an extensive analysis of the antigenic structure of native oligomeric Env, with particular emphasis in anti-Env monoclonal antibody development and characterization, and use of oligomeric Env as a vaccine immunogen, otherwise known as gp140. Ongoing research work includes the analysis of HIV-1 primary isolate-derived oligomeric gp140 preparations from a host of alternate HIV-1 clades, including a variety of genetically modified versions of the proteins with the goal of enhancing a neutralizing antibody response when used in small animals. In addition, in collaboration with other laboratories we are pursuing novel prime-boost vaccination strategies, with particular HIV-1 isolate Env proteins, using Venezuelan Equine Encephalitis (VEE) replicons and soluble oligomeric gp140 immunogen preparations in small animals and non-human primates.

The second area of work is relatively new and is the investigation Hendra virus and Nipah virus, which are newly emerging and highly lethal zoonotic agents. These studies are in collaboration with several scientists located at CSIRO Livestock Industries, Australian Animal Health Laboratory, Geelong, Victoria, one of only 4 facilities in the world where zoonotic BSL-4 agents may be researched. Both viruses are new members of the Paramyxoviridae , enveloped, negative-sense RNA viruses, and are now the prototypic members of a new Genus, Henipahvirus. They are related to the Morbilliviruses, of which Human Measles virus is a member, yet they are uniquely distinct from all other known Paramyxoviruses, both on the genomic molecular level as well as their biological, species tropism characteristics. Both viruses are classified as zoonotic BSL-4 agents. Hendra virus emerged in 1994, and was isolated from fatal cases of respiratory disease in horses and humans. Later in 1998-1999, an outbreak of severe encephalitis in people with close contact exposure to pigs in Malaysia and Singapore occurred. In all, more than 276 cases of encephalitis, including 106 deaths, had been reported a near 40% fatality rate upon infection. Pigs appeared to be an amplifier of the Nipah virus, and these viruses can also be economically devastating: over 1.2 million pigs were slaughtered to stem the Nipah virus outbreak. They appear to infect through the respiratory system initially and are capable of causing viremia. Hendra and Nipah both have broad species tropism, which is unusual because most paramyxoviruses are species restricted and do not have other reservoirs in nature. Current evidence points to several species of flying foxes (large Australian fruit bats).

The potential to be weaponized and used as biological warfare agents is clearly possible. They may be amplified in cell culture or embryonated chicken eggs, and could be used as a terror weapon targeting humans as well as livestock, the later which would serve as virus amplifiers. Recent evidence has also indicated that nosocomial transmissibility of Nipah virus from patients with encephalitis to healthcare workers is also possible. There are no existing antiviral therapies effective against these viruses, and the only therapies in existence to any viruses in the paramyxovirus family are live-attenuated vaccines. We have developed recombinant gene expression systems to study the attachment and membrane fusion-entry mechanisms of these viruses, and are developing novel reagents which may serve as potential vaccines as well as specifically blocking virus infection and spread. We are also engaged in recombinant virus-like particle formation and assembly for reagent development and to understand the requirements of particle formation in these novel viral agents.

Selected Publications

Resources