Philip J. Norris, M.D.
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Key Work for Vaccine Discovery
Developing a vaccine to end the public health disaster of HIV is the biggest challenge faced by AIDS researchers. So far this task has proven difficult. There are no documented cases of complete recovery from HIV. It is unknown whether a vaccine can be developed to provide a natural protective state against the virus, however, there are long-term survivors, who might provide an understanding of virus suppression. Looking into the immune systems of these survivors is more than a window on a mere curiosity. It allows researchers to delve into this unusual immune response and search for a cellular model that might control the virus. This basic research in to the effects of HIV on the immune system is key to the discovery of a vaccine.
Dr. Norris is in the vanguard of this research. His group has focused on the role CD4+ T cells play in immune response to HIV (CD4+ T cells play a crucial role in the immune response, signaling other cells in the immune system to perform their special functions.) The group has demonstrated that HIV-specific CD4+ T cells can suppress virus replication. Applications for this research could lead to a method of long-term suppression of HIV and the need for current medications with severe side effects may be reduced.
CD4+ T Cell Effector Functions
Evidence suggests that HIV-specific T helper cells contribute to effective control of HIV replication, but the functional characteristics and the precise mechanisms by which this happens have yet to be defined. Studies of HIV-specific T helper cells have shown that these cells multiply in response to HIV. They also control the virus’ ability to reproduce. One possible interpretation of these data is that HIV-specific T helper cells contribute to the immune control of the virus. Acting on this hypothesis, Dr. Norris’ group developed a panel of HIV-specific CD4+ T-cell clones. The cells proved to possess virus specific cytolytic activity (the ability to destroy infected cells). The cells also secreted interferon gamma, which plays a central role in the immunoregulatory process.
While HIV-specific, CD4+ T cells present ideal targets for HIV infection, the group recently demonstrated the cell’s ability to fight back against the virus. T helper cell clones and CD4+ T cells were taken from an HIV-infected long-term survivor to see if these would suppress virus replication. The premise proved correct and the results shed light on the human immune response to retroviral infections.
CD4+ T Cell Antigen Recognition
One characteristic of HIV is its quick mutation within the body. This rapid mutation makes it difficult to develop a vaccine based on antibodies. In an effort to discover other routes of vaccine development, Dr. Norris’ group looked at immune system response when challenged with genetic variations or mutations of the virus sequence. In particular, the group sought to describe how CD4+ cells or T-helper cells responded to virus mutation.
In early studies, antigenic regions within the Gag p24 protein (a major core protein of HIV) were identified and it was shown that naturally occurring variations within these regions led to significantly decreased immune recognition of mutated virus. The HIV epidemic is characterized by the presence of unique clades (or HIV genetic subtypes) present in each region of the world. The results implied that vaccine development might need to be tailored for each specific clade present in different global regions.