Human immunodeficiency virus (HIV) infects an estimated 34 million individuals worldwide, leading to the deaths of over 30 million since its identification and nearly 2 million in 2011 alone. HIV has been immensely difficult to combat largely because of its propensity to quickly mutate, permitting rapid evolution of drug resistance and immune escape. Furthermore, multiple cross-species transmission events and founder effects have led to the existence of distinct types, groups, and subtypes of HIV, further complicating treatment and hindering vaccine development. However, the impact of HIV type, group, and subtype on even the most basic of virological properties still often remains unclear. We propose here to examine the impact of HIV type, group, and subtype on viral mutagenesis, a key driver of viral evolution. Additionally, we propose to explore the ability of opioids to alte viral mutagenesis, as many individuals are simultaneously exposed to HIV and opioids, either through drug abuse or the legitimate use of opioids for managing pain. The impact of these factors on viral mutagenesis will be analyzed using Illumina sequencing of viruses subjected to a single round of replication, which will allow for a detailed and systematic comparison of mutation rates, spectra, and hotspots. Overall, the proposed research will determine the extent to which type/group/subtype and opioid use alter viral mutagenesis, as well as providing a powerful re-examination of much earlier studies on the mutagenesis of HIV. Ultimately, we anticipate that our research will shed light on factors that influence viral mutagenesis and aid in the customization of antiviral therapy for HIV-infected individuals based upon their infecting subtype(s) as well as whether they abuse opioids. Furthermore, the proposed research may have implications on the legitimate use of opioids for pain management in HIV-infected individuals.

Public Health Relevance

There are 34 million individuals worldwide infected with HIV, a virus composed of distinct types, groups, and subtypes. This study focuses on understanding how HIV lineage impacts viral mutagenesis, a key driver of viral evolution. Additionally, we propose to examine the extent to which opioids, a class of drugs commonly abused by HIV-infected individuals, alter viral mutagenesis. Ultimately, the research proposed here will benefit human health by improving our understanding of HIV diversity, mutagenesis, and evolution, thus aiding the customization of treatment based upon the infecting lineage of HIV and the presence of opioids, either in the context of opioid abuse or the legitimate use of opioids for pain management.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31DA035720-01A1
Application #
8727884
Study Section
Special Emphasis Panel (ZRG1-AARR-C (22))
Program Officer
Babecki, Beth
Project Start
2015-02-05
Project End
2016-02-04
Budget Start
2015-02-05
Budget End
2016-02-04
Support Year
1
Fiscal Year
2015
Total Cost
$29,752
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Dentistry
Type
Schools of Dentistry
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Rawson, Jonathan M O; Gohl, Daryl M; Landman, Sean R et al. (2017) Single-Strand Consensus Sequencing Reveals that HIV Type but not Subtype Significantly Impacts Viral Mutation Frequencies and Spectra. J Mol Biol 429:2290-2307
Rawson, Jonathan M O; Roth, Megan E; Xie, Jiashu et al. (2016) Synergistic reduction of HIV-1 infectivity by 5-azacytidine and inhibitors of ribonucleotide reductase. Bioorg Med Chem 24:2410-22
Rawson, Jonathan M O; Daly, Michele B; Xie, Jiashu et al. (2016) 5-Azacytidine Enhances the Mutagenesis of HIV-1 by Reduction to 5-Aza-2'-Deoxycytidine. Antimicrob Agents Chemother 60:2318-25
Rawson, Jonathan M O; Landman, Sean R; Reilly, Cavan S et al. (2015) Lack of mutational hot spots during decitabine-mediated HIV-1 mutagenesis. Antimicrob Agents Chemother 59:6834-43