Interactions of HIV-1 proteins with their cellular partners : insights from computational methods
Year: 2013
Type: dissertation
Abstract: HIV-1 attacks vital cells in the human immune system. HIV-1 differs from many viruses since it is characterized by a very high genetic variability. This means that many variants of HIV-1 virus can be generated in a single infected patient in the course of one day. HIV-1 hypervariability causes drug resistance and, consequently, medical treatment failure. Targeting the interactions between proteins from HIV-1 and from Homo sapiens may represent an excellent solution for drug design because it may avoid drug resistance problems. However rational drug design requires the knowledge of the structural determinants of the complexes, in most cases experimentally unavailable. In this thesis I have used a variety of computational approaches for the structural prediction of specific HIV-1 protein / cellular partners complexes. The first model I predicted is HIV-1 integrase (IN) in complex with one of its essential cellular partners, human prolyl-isomerase-1 (hPin1). This interaction occurs during viral integration, a crucial step of HIV-1 life cycle since it generates the DNA-template for productive infection. The model has been validated against experiments performed by the Molecular Medicine group of Prof. Mauro Giacca, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy. The model provides a rationale for the effect of mutating charged residues at the HIV-1 IN surface, which are known to hamper virus replication in vivo without affecting integrase enzymatic activity. Next, I predicted the structural determinants of HIV-1 trans-activator of transcription (Tat) in complex with human p300/(CREB-binding protein)-associated factor (PCAF) bromodomain, which occurs during viral transcription step. PCAF binds to Tat only when the latter is acetylated at lysine 50. The proposed complex is consistent with the available experimental data reported. Acetylation is one of the most common protein post-translational modifications. Hence, our model may help in defining the structural determinants of other protein interactions involving lysine acetylation. The work presented in my thesis might help developing new ligands capable of interfering with HIV-1 interactions.
Source: RWTH Publications (RWTH Aachen)
Authors: Võ Cẩm Quy, Paolo Carloni
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2734770019