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Dissertation-Madara-2018_6.28.2018.pdf (5.51 MB)

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Coevolution of epitopes in HIV-1 pre-integration complex proteins: protein-protein interaction insights

Hetti Arachchilage, Madara Dilhani
http://rave.ohiolink.edu/etdc/view?acc_num=kent1530646538935895

Abstract Details

2018, PHD, Kent State University, College of Arts and Sciences / Department of Biological Sciences.
Recognition of viral epitopes by the host immune system plays a pivotal role in controlling viral infection, while at the same time exerting selective pressure for escape mutations, which in turn leads to many epitopes evolving faster than the adjacent regions. Some epitope regions appear to be highly conserved despite the strong immune pressure due to functional and/or structural constraints acting on them. Yet, we still have relatively little understanding of the nature of protein structural and functional constraints operating on epitope regions. Here, we identify coevolving epitope regions that have high functional and/or structural constraints. We examined patterns of coevolution of protein segment pairs between Integrase-Reverse Transcriptase, Integrase-Vpr, and Reverse Transcriptase-Vpr protein interactions pairs in HIV-1 pre-integration complex. First, to account for a potential effect of background noise contributed by shared phylogenetic history and/or random interactions, we performed molecular coevolutionary analysis using three separate approaches: randomization, closely-related sister pairs, and moderately divergent sister pairs. We identified a set of likely interacting region pairs that exhibited strong coevolution signal consistently in three approaches. We further show that insights gained from the analysis of the closely-related sister pairs reduce false positive coevolution signal. On the other hand, analysis of the moderately divergent sister pairs allows us to address potentially false negative coevolution signal derived from stochastic covariation due to lack of divergence in specific protein regions. Next, we looked at likelihood of these regions being involved in transient interactions as approximated by the disordered nature of involved residues. Our structural analysis shows that in HIV-1, IN, RT, VPR protein regions that are weakly coevolving appear to have higher proportion of disorder residues which associated with strong transient interactions, while strongly coevolving regions have higher proportions of structured regions which associated with more permanent interactions. The regions showing relatively weaker coevolution signal in the divergent sequences compared to that from the closely-related sequences also show a decreased fraction of radical substitutions, indicating that such regions likely experience strong purifying selection. In overall, our findings help to narrow down specific regions in HIV-1 IN, RT and Vpr that are involved in protein-protein interactions, as well as which of these regions are more likely to be involved in intrinsic and transient interactions. Our analysis identifies specific epitope regions that - due to strong constraints against escape mutations; are less likely to experience escape and/or DRMs, and thus, can serve as important targets in the development of vaccines that can induce immune responses against multiple conserved epitopes and/or other therapeutics approaches. This analysis also offers important insights into the nature of protein interactions underlying molecular evolution of HIV genomes.
Helen Piontkivska (Committee Chair)
Randolph Hoeh (Committee Member)
Gary Koski (Committee Member)
John Portman (Committee Member)
Soumitra Basu (Committee Member)
306 p.
Bioinformatics; Biology
HIV; Coevolution; Protein interactions; Epitope; Protein structure; Integrase; Reverse Transcriptase; Vpr

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Citations

  • Hetti Arachchilage, M. D. (2018). Coevolution of epitopes in HIV-1 pre-integration complex proteins: protein-protein interaction insights [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1530646538935895

    APA Style (7th edition)

  • Hetti Arachchilage, Madara. Coevolution of epitopes in HIV-1 pre-integration complex proteins: protein-protein interaction insights. 2018. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1530646538935895.

    MLA Style (8th edition)

  • Hetti Arachchilage, Madara. "Coevolution of epitopes in HIV-1 pre-integration complex proteins: protein-protein interaction insights." Doctoral dissertation, Kent State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1530646538935895

    Chicago Manual of Style (17th edition)

kent1530646538935895
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© 2018, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.