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Evolution of Epitope Regions in Hiv Genome: Delineating Selective Forces Acting on Conformational and Linear Epitopes

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Evolution of Epitope Regions in Hiv Genome: Delineating Selective Forces Acting on Conformational and Linear Epitopes EVOLUTION OF EPITOPE REGIONS IN HIV GENOME: DELINEATING SELECTIVE FORCES ACTING ON CONFORMATIONAL AND LINEAR EPITOPES A thesis submitted to Kent State University in partial fulfillment of the requirements for the degree of Master of Sciences By Satish Kumar Perikala May 2010 Thesis Written by Satish Kumar Perikala B.V.Sc & A.H, Acharya N.G Ranga Agricultural University, India 2004 M.S Kent State University, 2010 Approved by ___________________________________, Advisor Helen Piontkivska ___________________________________, Member, Masters Thesis Committee Gail Fraizer ___________________________________, Member, Masters Thesis Committee Michael Tubergen Accepted by ___________________________________, Chair, Department of Biomedical Sciences Robert V Dorman ___________________________________, Dean, College of Arts and Sciences John R.D. Stalvey ii TABLE OF CONTENTS LIST OF FIGURES.......................................................................................................v LIST OF TABLES........................................................................................................vii LIST OF ABBREVIATIONS………………………………………………………..ix ACKNOWLEDGEMENTS…………………………………………….…………….x CHAPTER 1: INTRODUCTION……………………………………………………………1 HIV Genome……………………………………………….…………..4 Geographical Distribution of HIV world wide…………….…………..5 Different Types of Immune Epitopes in HIV…………….……………6 Thesis Overview………………………………………….……………9 CHAPTER 2: MATERIALS AND METHODS……………………………………...……...13 HIV genomic sequence data and multiple sequence alignment……...14 HIV Epitopes………………………………………………………....15 Nucleotide Substitution Patterns………………………………….….15 Reconstruction of Ancestral Sequence……………………………….17 Radical and Conservative Amino acid Substitutions…………………18 Phylogenetic Analysis…………………………………………...……18 CHAPTER 3: Patterns of synonymous and nonsynonymous substitutions at different epitope regions among B-subtype and CRF subtype HIV-1 sequences……..30 Results………………………………………………………………….31 Discussion…………………………………………..……………….…35 CHAPTER 4: Patterns of radical and conservative amino acid changes at different epitope regions among selected B-subtype and CRF HIV-1 sequences……..43 iii Results………………………………………………………………..44 Discussion……………………………………………………………50 SUMMARY…………………………………………………………………………66 LITERATURE CITED………………………………………………………………81 APPENDIX 1. Box Plots showing the d S - d N values in different epitope regions of Env gene…………………………………………………………………………..68 2. Box Plots showing the d S - d N values in different epitope regions of Gag gene…………………………………………………………………………..70 3. Box Plots showing the d S - d N values in different epitope regions of Pol gene………………………………………………………………………..…71 4. List of CTL epitopes used…………………………...……………..…..….72 5. List of T-Helper epitopes used……………………...………………...…...76 6. List of Antibody epitopes used……………………………………….…...79 7. List of conformational epitopes used………………………………..….…80 iv LIST OF FIGURES Fig 1.1 Overview of the Life cycle of HIV (From: Sewell 2000)…………..………..11 Fig 1.2 Structure of HIV Genome (Modified from Los Alamos HIV database)… ….11 Fig 1.3 Global Distribution of HIV subtypes (From: International AIDS Vaccine Initiative) Report, 2003.………………… … ……………….……….……………...12 Fig 2.1 Example showing the Synonymous and Nonsynonymous Substitutions.........19 Fig 2.2 Phylogenetic tree showing the ancestral sequence of Env gene of B-subtype sequences……………………………………………………….…………………….19 Fig 2.3 Phylogenetic tree showing the ancestral sequence of Gag gene of B-subtype sequences……………………………………….………………………….…………20 Fig 2.4 Phylogenetic tree showing the ancestral sequence of Pol gene of B-Subtype sequences…………………………………………………………………..…………20 Fig 2.5 Phylogenetic tree showing the ancestral sequence of Env gene of CRF-subtype sequences……………………………………………………………………………21 Fig 2.6 Phylogenetic tree showing the ancestral sequence of Gag gene of CRF-subtypes sequences……………………………………………………………………………22 Fig 2.7 Phylogenetic tree showing the ancestral sequence of Pol gene of CRF-subtypes sequences……………………………………………………………………………23 Fig 3.1 Bar graph showing the mean d N and d S values of different epitope regions of Env gene for B and CRF sequences ………………………………………….…………..38 Fig 3.2 Bar graph showing the mean d N and d S values of different epitope regions of Gag gene for B and CRF sequences ………………………………………………...39 v Fig 3.3 Bar graph showing the mean d N and d S values of different epitope regions of Pol gene for B and CRF sequences…………………………………………….………40 Fig 4.1 Bar graph showing number of Radical and Conservative amino acid changes at different epitope regions of Env ,Gag and Pol genes from B and CRF sequences based on the classification of amino acids by Polarity…………………………..……..…54 Fig 4.2 Bar graph showing number of Radical and Conservative amino acid changes at different epitope regions of Env ,Gag and Pol genes from B and CRF sequences based on the classification of amino acids by Charge……………………………………55 Fig 4.3 Bar graph showing number of Radical and Conservative amino acid changes at different epitope regions of Env ,Gag and Pol genes from B and CRF sequences based on the classification of amino acids by Polarity AND Volume……………………56 Fig 4.4 Bar graphs showing the proportion of Radical changes relative to the total number of changes in Env gene……………………………………………………………..57 Fig 4.5 Bar graphs showing the proportion of Radical changes relative to the total number of changes in Gag gene…………………………………………………..…..……58 Fig 4.6 Bar graphs showing the proportion of Radical changes relative to the total number of changes in Pol gene…………………………………………………….………59 vi LIST OF TABLES Table 2.1 GenBank accession numbers of 67 B subtype sequences ………..…..24 Table 2.2 GenBank accession numbers of 135 CRF subtype sequences …….…26 Table 2.3 Distribution of different types of epitope regions in each gene and the number of codons in each epitope category for the 3 longest genes, Gag, Pol and Env…27 Table 2.4: Average nucleotide p-distance values for different epitope regions of Env, Gag and Pol genes from HIV-1 sequences of B-subtype and CRFs...….28 Table 2.5 Three types of amino acid classifications based on physicochemical properties (Modified from Zhang 2000)………………………..………….………………..29 Table 3.1 Average estimates of synonymous (d S) and nonsynonymous (d N) Nucleotide substitutions in different epitope regions of Env gene among B subtype and CRF sequences …………………………………………………………………………41 Table 3.2 Average estimates of synonymous (d S) and nonsynonymous (d N) Nucleotide substitutions in different epitope regions of Gag gene among B subtype and CRF sequences…………………………………………………………………….……42 Table 3.3 Average estimates of synonymous (d S) and nonsynonymous (d N) Nucleotide Substitutions in different epitope regions of Pol gene among B subtype and CRF sequences…………………………………………………………………….……42 Table 4.1 Number of Radical and Conservative amino acid substitutions at Env gene from pairwise comparisons of B and CRF sequences along with the number of No change sites………………………………………………………………….…….61 Table 4.2 Number of Radical and Conservative amino acid substitutions at Gag gene vii from pairwise comparisons of B and CRF sequences along with the number of No change sites ……………………………………………………………………………..…62 Table 4.3 Number of Radical and Conservative amino acid substitutions at Pol gene from pairwise comparisons of B and CRF sequences along with the number of No change sites …………………………………………………….…………….....…..63 Table 4.4 Number of Radical and Conservative amino acid substitutions at Env gene from Pairwise comparisons of B-subtype sequences estimated with CRF ancestral sequence ……………………………………………………………………..………64 Table 4.5 Number of Radical and Conservative amino acid substitutions at Gag gene from Pairwise comparisons of B-subtype sequences estimated with CRF ancestral sequence ………………………………………………………………………………65 Table 4.6 Number of Radical and Conservative amino acid substitutions at Pol gene from Pairwise comparisons of B-subtype sequences estimated with CRF ancestral sequence …………………………………………..…………………………………65 viii LIST OF ABBREVIATIONS Ab - Antibody (Neutralizing antibody) AIDS - Acquired Immunodeficiency Syndrome AOCE – All Overlapping Conformational Epitopes AOLE – All Overlapping Linear Epitopes CE – Conformational Epitope CRF- Circulating Recombinant Forms CTL – Cytotoxic T Lymphocytes HIV – Human Immunodeficiency virus MEGA - Molecular Evolutionary Genetics Analysis SIV – Simian Immunodeficiency Virus Th – T-Helper ix Acknowledgements It is a pleasure to thank the many people who made this thesis possible. It is difficult to overstate my gratitude to my Masters principle Advisor, Dr. Helen Piontkivska. With her enthusiasm, inspiration, and her great efforts to explain things clearly and simply, helped me to make the subject fun for me. Throughout my thesis- writing period, she provided encouragement, sound advice, good teaching, and lots of good ideas. I would have been lost without her. Besides my advisor, I would like to thank the rest of my thesis committee: Dr. Gail Fraizer and Dr. Michael Tubergen, for their encouragement and insightful comments. My sincere thanks to all my Professors who taught me in the Graduate school and also to all my teachers from India. I sincerely thank my labmate and friend, Sinu Paul for his support all through. I wish to thank the rest of my friends, Pawan Puri, Teja, Sourabh ,Sudhakar, Hari and many more for helping me get through the difficult times, and for all the support, entertainment, and caring they provided. Lastly, and most importantly, I wish
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