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Dissertation
Identification of HIV-1, X4, R5, and R5 subgroup genetic signatures in the viral promoter, Tat, and Vpr
Doctor of Philosophy (Ph.D.), Drexel University
Nov 2012
DOI:
https://doi.org/10.17918/00000372
Abstract
Human immunodeficiency virus type 1 (HIV-1) adaptation, under selective pressures, likely involves genetic alterations across the genome preferentially associated with viral phenotypes: CCR5-utilizing (R5), CXCR4-utilizing (X4) and the dual tropic (X4R5) viruses. The Env-V3 sequence is currently a major determinant of co-receptor usage, which can be predicted by in silico methodologies. Previous studies have demonstrated specific single nucleotide polymorphisms (SNPs) within C/EBP site I (3T, C-to-T change at position 3), and Sp site III (5T, C-to-T change at position 5) that correlate with late stage HIV-1 disease, and HIV-1-associated dementia (HAD). A co-selected SNP, 3T5T, was also identified within PBMC-derived LTRs from the D REXELMED HIV/AIDS Genetic Analysis (DM) Cohort that was selectively presented with the R5 Env-V3, with specific Tat genotypes, and observed before the onset of neurological impairment. Utilizing the PSSM algorithm, Env-V3 sequences derived from the Los Alamos National Laboratory (LANL) Database and DREXELMED HIV/AIDS Genetic Analysis Cohort, can be classified into X4 and R5 groups, with specific co-linear LTR, Tat, and Vpr genotypic signatures. The high genetic diversities of the X4 Env-V3 exhibited a direct connection with the high genetic diversities of Tat and LTR while the R5 Env-V3 represented the contrary, except Vpr. Differential amino acid (DAA) and differential nucleotide (DN) changes were identified within the R5 sequences, but not in X4, suggesting the existence of a specific R5 genotype signature within the LTR, Tat, and Vpr. Three methodologies were developed to define X4 and R5 subgroups; based on the PSSM algorithm, genetic diversity, and genetic relatedness. The 18-35 residue fragment differential scanning technology was developed, and shown to successfully define the differential sequence regions between the X4 and R5, as well as between the R5 subgroups comparisons, across the LTR, Tat and Vpr sequences. For the first time, utilizing these identified DAA residues within Vpr, and Tat, in silico prediction technology was established with at least 85% co-receptor usage prediction accuracy. These results leads to further definition of the next generation diagnostic and prognostic tools to examine HIV disease and to develop new therapeutics and vaccines to prevent and treat HIV/AIDS.
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Details
- Title
- Identification of HIV-1, X4, R5, and R5 subgroup genetic signatures in the viral promoter, Tat, and Vpr
- Creators
- Benjamas Aiamkitsumrit
- Contributors
- Brian Wigdahl (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xxvii, 444 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991014970339804721