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University of Washington School of Medicine, Department of Microbiology     

Objectives
The Mullins laboratory uses the techniques of molecular, computational and virus biology to provide basic insights into the HIV-human host relationship. Our goals are to assist the fight against AIDS by gaining insight into the development of the disease and thereby refine therapies and create effective vaccines.

 

Perspective on AIDS
In the early 1980's a new infectious disease emerged that changed the world's attitude towards sex and towards blood and blood products. This disease, acquired immunodeficiency syndrome (AIDS), results from progressive destruction of the immune system and typically develops about 10 years following infection with human immunodeficiency virus (HIV). AIDS is now a global pandemic, though by far the largest burden falls on the developing world. 

AIDS results from the immune destruction caused by human immunodeficiency virus (HIV). In two decades our knowledge of HIV and AIDS has grown exponentially. More importantly, in the last few years, insights as to how the disease process may be halted or potentially reversed have emerged, and effective therapies are in use. However, neither a cure nor a preventive vaccine has been found. 

 

Perspective on HIV
One of the most striking features of HIV is the speed at which its genome evolves. In a single year, an HIV strain within one patient can evolve viruses that are as genetically different from one another as human genes now differ from a chimpanzee's. Rapid mutation, natural selection, and other evolutionary forces contribute to this astonishing in vivo diversification. The relationship of viral diversity to the length and severity of the disease, and its contribution to the ultimate breakdown of the immune system, remain unclear.

 

Our Approaches
We use a variety of techniques to understand the implications of HIV's extraordinary genetic diversity for the pathogenesis of AIDS and with the intention of applying this information to the development of more effective therapies and vaccines. These techniques include virology, molecular biological and statistical analysis of nucleotide sequences, and high-throughput array analysis of cellular transcription.

We are investigating the molecular evolution of HIV-1 and HIV-2 from two viewpoints: From within individual patients and between patients from the human population at large. By examining the evolution of HIV within a host we can determine compartments or cell types within the body that have unique signatures of virus evolution. One way of capitalizing on these signatures is to identify anatomical compartments that are in a therapy shadow, i.e., compartments in which drugs are ineffective against the virus. The identification of such compartments should assist development of more potent and highly targeted therapies that prevent HIV from replicating within these shadows. Evolution of HIV is also being studied between different hosts, where we identify viral lineages or ancestral states with the potential for providing us with promising sequences for vaccine development. In addition, this line of research can lead to a better understanding of the epidemiology of HIV transmission and spread. 

We are using expression array technology to understand the cellular response to infection and expression of viral proteins. We are also using cell culture tools to understand the relationship between viral genotype and phenotype and to assess kinetic parameters of infection and treatment. 

In all cases, molecular, computational and biological analyses conducted in the Mullins laboratory merge with in vivo analyses of biological activity conducted by collaborating laboratories and clinical investigators, in order to ensure that our research program remains focused on the primary goal--improving our ability to fight AIDS.

 

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jim, 5sep01

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