HIV Infections and the Safety of the Blood Supply
Principal Investigator: Andrew I. Dayton, MD, PhD
Office / Division / Lab: OBRR / DETTD / LMV
Blood can efficiently transfer diseases from infected donors to uninfected recipients.
We study blood-borne viruses belonging to two classes: retroviruses (including simple retroviruses as well as complex retrovirus such as Human Immunodeficiency Virus - HIV) and flaviviruses (West Nile Virus - WNV - and dengue virus - DV). Our goals are to improve techniques for detecting viruses in blood and other clinical sample types, reduce transmission of viruses by blood donation, and improve technologies for monitoring virus levels in patients receiving anti-virus therapy. We plan to meet these goals by developing new detection technologies and studying how viruses spread, replicate, and cause disease. These studies are now taking place in our laboratories. Depending on the results, our findings could lead to studies in humans.
HIV continually evolves through gene mutations. These mutations can change the virus enough to thwart blood donor screening tests that were designed to identify the original version of the virus. This complicates interpretation of tests that researchers use to predict if a specific variant of HIV will be resistant to a specific anti-viral drug. Therefore, the ability to predict the emergence and/or the biological effects of viral mutations could improve the accuracy of diagnostic and blood donor screening tests for viruses such as HIV WNV, and DV. It could also improve the ability of scientists to monitor the development of resistance to anti-viral drugs in patients with HIV/AIDS.
In addition, improved understanding of how viruses and their human host cells interact with one another will enable researchers to develop improved therapies based on patient-specific factors such as their genetic makeup. Our laboratory is studying the interactions between viruses and their hosts (with emphasis on human hosts). We are trying to understand how the host's natural killer (NK) cells (immune cells that launch the body's early defense against viruses) combat infection progression; how certain viruses (particularly HIV) can survive (or "hide") in immune cells such as macrophages; and how viruses regulate their own replication and assemble new virions that subsequently escape from the infected cell.
We study blood-borne and/or bioterrorism viral agents belonging to two classes: retroviruses (primarily Human Immunodeficiency Virus - HIV, but also simple retroviruses) and flaviviruses (primarily West Nile Virus - WNV - and dengue virus - DV). Our goals are to 1) improve viral detection; 2) reduce virus transmission; and 3) improve therapeutic monitoring technology, including personalized predictions of prognosis and optimal therapeutic regimen. We approach these goals through developing detection technologies, and improving our understanding of viral pathogenesis and immune responses to virus infection and characterizing host cofactors involved in viral replication towards the goal of identifying surrogate markers for viral transmission, repliation and pathogenesis.
Investigating the role of the innate immune system in early viral infection, and focusing on the potential roles of natural killer (NK) cells, we have discovered complex interactions involving several cytokines that support NK activation, including IL-2, IL-18 and IL-12. We have also identified a novel mechanism of NK cell autoregulation, by which IL-12 downregulates its own signaling by upregulating specific miRNAs. These findings illuminate the transient efficacy of IL-12 in clinical trials and suggest IL-12 therapies coud be improved by inhibition of specific miRNAs.
In other studies we have adapted interferometric techniques to detect HIV-1 p24 with rapid technology suitable for point of care and battlefield use, achieving over a log better sensitivity than EIA. We are now adapting this technique to detect influenza virus in blood and anticipate that the platform technology will be readily adaptable to other emerging pathogens and bioterror threats.
In recent work we have identified in the genomes of both MLV (murine leukemia virus) and XMRV (xenotropic murine leukemia virus-related virus) constitutive transport elemenbts (CTEs) in the env and 3'LTR regions of the genome. These CTEs are needed to transport RNAs out of the nucleus into the cytoplasm and may be necessary for viral replication as well as efficient production of envelope protein, which is critical for certain retroviral-based vaccine vectors. CTEs also qualify exported RNAs not only for correct translation of gag/pol proteins but also for correct processing and assembly of gag into virions and should be critical to species jump of potentially zoonotic retroviruses, as may typically be encountered in xenotransplantation scenarios.
We are interested in how host RNA binding proteins interact with viral genomic RNA to regulate viral expression because we believe such host factors can eventually be developed as host surrogate markers for virus transmission, replication and pahtogenesis. We have discovered that host P100 and host nucleolin each bind to the 3' regulatory region RNA of the dengue virus genome and are needed for dengue virus replication.
J Steroid Biochem Mol Biol 2013 Nov;138:63-71
Effect of sex steroid hormones on replication and transmission of major HIV subtypes.
Ragupathy V, Devadas K, Tang S, Wood O, Lee S, Dastyer A, Wang X, Dayton A, Hewlett I
Blood 2011 Dec 22;118(26):6793-802
MicroRNA regulation of STAT4 protein expression: rapid and sensitive modulation of interleukin-12 signaling in human natural killer cells.
Huang Y, Lei Y, Zhang H, Hou L, Zhang M, Dayton AI
J Leukoc Biol 2011 Jul;90(1):87-97
Interleukin-12 treatment down-regulates STAT4 and induces apoptosis with increasing ROS production in human natural killer cells.
Lei Y, Zhang H, Zhang M, Dayton A
Retrovirology 2011 Jul 20;8(1):62
Matrin 3 and HIV Rev regulation of mRNA.
J Gen Virol 2011 Apr;92(Pt 4):796-806
Functional interaction between cellular p100 and the dengue virus 3' UTR.
Lei Y, Huang Y, Zhang H, Yu L, Zhang M, Dayton A
Mol Immunol 2010 Oct;47(16):2604-10
Role of interleukin-18 in human natural killer cell is associated with interleukin-2.
Huang Y, Lei Y, Zhang H, Zhang M, Dayton A
BMC Immunol 2010 Jan 20;11:3
Anti-West Nile virus activity of in vitro expanded human primary natural killer cells.
Zhang M, Daniel S, Huang Y, Chancey C, Huang Q, Lei YF, Grinev A, Mostowski H, Rios M, Dayton A
Transfusion 2009 Jun;49(6):1102-14
Quantitative estimate of the risks and benefits of possible alternative blood donor deferral strategies for men who have had sex with men.
Anderson SA, Yang H, Gallagher LM, O'Callaghan S, Forshee RA, Busch MP, McKenna MT, Williams I, Williams A, Kuehnert MJ, Stramer S, Kleinman S, Epstein J, Dayton AI
J Infect Dis 2008 Nov 1;198(9):1300-8
In Vitro Evaluation of the Protective Role of Human Antibodies to West Nile Virus (WNV) Produced during Natural WNV Infection.
Rios M, Daniel S, Dayton AI, Wood O, Hewlett IK, Epstein JS, Caglioti S, Stramer SL
Retrovirology 2008 Sep 22;5(1):82
Beta-estradiol attenuates the anti-HIV-1 efficacy of Stavudine (D4T) in primary PBL.
Zhang M, Huang Q, Huang Y, Wood O, Yuan W, Chancey C, Daniel S, Rios M, Hewlett I, Clouse KA, Dayton AI
Retrovirology 2008 Feb 1;5:15
Hitting HIV where it hides.
Retrovirology 2006 Aug 30;3:55
Beyond open access: open discourse, the next great equalizer.
J Leukoc Biol 2006 Jun;79(6):1328-38
HIV regulation of the IL-7R: a viral mechanism for enhancing HIV-1 replication in human macrophages in vitro.
Zhang M, Drenkow J, Lankford CS, Frucht DM, Rabin RL, Gingeras TR, Venkateshan C, Schwartzkopff F, Clouse KA, Dayton AI
Transfusion 2006 Apr;46(4):659-67
Monocytes-macrophages are a potential target in human infection with West Nile virus through blood transfusion.
Rios M, Zhang MJ, Grinev A, Srinivasan K, Daniel S, Wood O, Hewlett IK, Dayton AI
J Virol 2005 Nov;79(21):13735-46
Human immunodeficiency virus type 1 Vpr interacts with antiapoptotic mitochondrial protein HAX-1.
Yedavalli VS, Shih HM, Chiang YP, Lu CY, Chang LY, Chen MY, Chuang CY, Dayton AI, Jeang KT, Huang LM
J Biol Chem 2004 Nov 19;279(47):49055-63
Polyarginine inhibits gp160 processing by furin and suppresses productive human immunodeficiency virus type 1 infection.
Kibler KV, Miyazato A, Yedavalli VS, Dayton AI, Jacobs BL, Dapolito G, Kim SJ, Jeang KT
Retrovirology 2004 Oct 29;1(1):35
Within you, without you: HIV-1 Rev and RNA export.