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The influence of single nucleotide polymorphisms and epigenetics on HIV disease progression

Malinauskas, Jenna (2019) The influence of single nucleotide polymorphisms and epigenetics on HIV disease progression. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Human immunodeficiency virus (HIV) is one of the most significant public health issues globally, however; little is known about the factors contributing to the rate of AIDS progression. Due to antiretroviral therapy, disease progression classification can no longer be attained, therefore; retrospective samples from the Multicenter AIDS Cohort Study (MACS) are used to study host genetic factors contributing to progression though studying Nonprogressors (NPs) and Progressors (PRs). The genetic response to HIV infection can be influenced by polymorphisms, or epigenetic factors such as chromatin accessibility. Using previously acquired microarray data, we observe multiple genes differentially regulated when comparing immature dendritic cells (iDCs) from NPs and PRs, and recent studies by Rappocciolo et al, 2014 demonstrate that iDCs from NPs have inefficient trans-infection due to reduced cellular cholesterol. I hypothesize that sequence variation and/or epigenetic regulation may be influencing these processes and contributing to slower disease progression.
Next generation sequencing was used to determine whether SNPs in the promoter regions of palladin, contribute to differential gene expression. Assay for transposase chromatin accessibility (ATAC-seq) was validated for use on MACS samples to determine if chromatin accessibility differs between NPs and PRs.
Promoter region sequencing results demonstrate a variant within palladin with an allele frequency of 0.929 in the NP cohort near the promoter region of isoform 4. The variant is absent in the PR cohort and is located within the transcription factor binding site for RB1. RB1 controls heterochromatin structure contributing to gene expression, therefore; a variant within the binding site may influence isoform 4 expression in NPs.
ATAC-sequencing results indicate successful sequencing of healthy donor iDCs using the Omni-ATAC-seq protocol described by Corces, et al, 2018. Library complexity, sequencing depth and coverage were acceptable when analyzed with ATACseqQC. These results suggest that the Omni-ATAC-seq method can successfully be used on MACS cohort samples to determine differences in chromatin accessibility between NPs and PRs.
Public Health Significance: Understanding how host genetics influence disease progression to AIDS is important for the development of new therapies. Additionally, we are discovering novel innate mechanisms of infectious disease control that may be applicable to viral infections broadly.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Malinauskas, Jennajlm412@pitt.edujlm412
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMartinson, Jeremyjmartins@pitt.edujmartins
Committee MemberMailliard, Robbierbm19@pitt.edurb19
Committee MemberMacatangay, Bernardbcm36@pitt.edubcm26
Date: 30 January 2019
Date Type: Publication
Defense Date: 10 December 2018
Approval Date: 30 January 2019
Submission Date: 27 November 2018
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 47
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: HIV, AIDS, Genetics
Date Deposited: 30 Jan 2019 17:33
Last Modified: 13 Mar 2019 18:40
URI: http://d-scholarship.pitt.edu/id/eprint/35626

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