Cellular Response to Virus Infection: Global Proteome Analysis of Macaque Models of HIV and Influenza Infection
EMSL Project ID
16317
Abstract
Of all viral infections afflicting humans, HIV-1 is the only one that leads to the profound and relentless destruction of CD4+ T helper lymphocytes. The ultimate devastation of the immune system results in the emergence of opportunistic infections and cancers that would otherwise be prevented. These illnesses most often progress in severity resulting in full-blown AIDS and eventually death. The number of AIDS deaths worldwide reached ~ 3 million in 2004 and an estimated 40 million people were living with the disease, including 5 million newly diagnosed cases for that year. While improved treatment regimens have increased survival rates in patients with AIDS, these treatments can have significant side effects and fail to eliminate reservoirs of the virus. Taken together, these observations underscore the need for a better understanding of HIV infection and pathogenesis to identify novel targets for therapeutic and prophylactic intervention. By contrast, the effects of Influenza virus infection on the immune system are typically far less destructive. Most people who get influenza recover in a few weeks and yearly vaccination protects against infection with currently circulating forms of the virus. However, Influenza remains a significant public health concern given the ability of the virus to occasionally generate particularly virulent strains that are capable of causing worldwide pandemics and concerns about emerging infectious disease and bioterrorism threats. The best known of these pandemics, the 1918 "Spanish flu," resulted in approximately 500,000 deaths in the U.S. and over 40 million worldwide. Despite advances in medical care and technology, another pandemic is thought to be inevitable. Additional studies are needed to increase our understanding of the factors contributing to the high virulence of such viruses and are expected to provide novel targets for therapeutic and prophylactic intervention and, critical markers for both diagnostic and prognostic applications following a natural or bioterrorism event.Through our affiliation with the Washington National Primate Research Center (Seattle, WA) we have been actively involved in the generation of non-human primate models of virus infection. Characterization of the immunobiology of non-human primate models will greatly expand our understanding of their use as models for virus infection in humans and has significant implications for future drug and vaccine efforts. Our goal is to utilize functional genomics technologies to develop an increasingly comprehensive understanding of the molecular events that occur during the course of infection, therapy, or vaccination and subsequent challenge. Our efforts are focused on the characterization of a rhesus macaque model for AIDS research and a pigtail macaque model for Influenza research. We propose to use state-of-the-art proteomic technologies to globally examine, at the protein level, the host cell response to HIV and influenza virus infection. The goals of this EMSL user proposal are three-fold: 1) to generate preliminary LC-MS/MS peptide identifications using peptide digests of mock and chimeric SIV/HIV (SHIV)-infected periperhal blood mononuclear cells obtained from rhesus macaques; 2) to generate preliminary LC-MS/MS peptide identifications using peptide digests of mock and influenza-infected lung tissue obtained from pigtail macaques; and 3) to take advantage of the semi-quantitative relationship between the total number of peptide identifications and the relative abundance of the corresponding protein as a first pass means to identify protein expression changes associated with virus infection. The preliminary data generated from these studies will be included in the submission of an application for competitive renewal of a P51 Primate Research Center Grant awarded to the University of Washington. Proteomics will be a key component of the competitive renewal where we will propose to utilize the AMT tag approach to perform quantitative proteome analyses of the non-human primate models of HIV/AIDS and Influenza virus infection. The funding obtained from this grant would support the proposed proteomics collaboration with the Biological Systems Analysis and Mass Spectrometry group headed by Dr. Richard Smith at Pacific Northwest National Laboratory (PNNL).
Project Details
Start Date
2005-10-10
End Date
2008-10-12
Status
Closed
Released Data Link
Team
Principal Investigator