Participant: PROMISE AGEP Research Symposium
Canessa J. Swanson
Department: Chemistry and Biochemistry
Institution: University of Maryland, Baltimore County (UMBC)
Structural Basis and Mechanism for HIV-1 Genome Packaging, Canessa J. Swanson, Department of Chemistry and Biochemistry, University of Maryland Baltimore County
Globally, nearly 40 million people are HIV-positive, those that are receiving therapeutic treatment can often develop drug toxicity and viral resistance. Many due to antiretroviral drugs targeting proteins which are susceptible to mutation rendering therapeutics inefficient, and highlighting the need for the discovery of conserved drug targets for pharmaceutical development. Despite this high mutation rate, sequence analysis of the viral genome revealed that the 5ʹ-Leader is not only the most highly conserved but also the most structured, suggesting the physiological importance of the 5ʹ-Leader in the propagation of virus production. Previous studies have shown that genome recognition is mediated by an intermolecular interaction between the nucleocapsid (NC) domain the Gag polyprotein and a conserved stretch of nucleotides within the 5ʹ-Leader, termed the Core Encapsidation Signal (CES). Structural evaluation of the NL4-3 strain CES, revealed a unique tandem three-way junction which has been hypothesized to serve as a mechanism, for the viral genome to outcompete cellular RNAs for packaging. Unfortunately, the three-way junctions exhibit a flexible nature which causes conformational heterogeneity and signal broadening within nuclear magnetic resonance (NMR) spectroscopy. Sequence alignment and Mfold predictions of the 5ʹ-Leader from another HIV-1 strain (MAL) revealed that the proposed tandem three-way junction structure may exhibit more rigidity afforded by stabilizing mutations in comparison to NL4-3. NMR data of the MAL strain showed sharper signals than NL4-3, a spectral feature which could allow for more thorough evaluation of the CES structure and facilitate in the identification of conserved structural components utilized in genomic recognition.
GENERAL SUMMARY OF GRADUATE RESEARCH
Nearly 40 million people are infected with the Human Immunodeficiency Virus (HIV), which has the ability to mutate at high frequency causing therapeutic drug resistance. For this reason new therapeutic targets are necessary to combat HIV. One area of the retroviral replication cycle that that does not have any therapeutic drugs is that of genomic recognition. My research focuses on understanding the structure and mechanism for HIV-1 genomic packaging and recognition.
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