LATENT PERIOD OF INFECTION: IN DEPTH VIEW OF THE PATHOPHYSIOLOGY OF EPSTEIN-BARR VIRUS, CYTOMEGALOVIRUS, HERPES ZOSTER AND HERPES SIMPLEX

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1 LATENT PERIOD OF INFECTION: IN DEPTH VIEW OF THE PATHOPHYSIOLOGY OF EPSTEIN-BARR VIRUS, CYTOMEGALOVIRUS, HERPES ZOSTER AND HERPES SIMPLEX Megan Jensen,Emiliano Davenigno, Matthew Lowry, Jarett Wanihadie, Shawn Jacklin, Harlito Arraut White, Karar Alameedi, Kiah Britton Microbiology presentation Block4 MD3 Summer 2016 Saint James School of Medicine, Anguilla Campus Faculty: Subhajit Dasgupta, PhD; Hareesh Gugnani, PhD

2 DEFINITION OF LATENCY Latency is a state of cryptic viral infection associated with genomic persistence and highly restricted gene expression in the lysogeny like settlement condition in human cells in tissues. Its hallmark is reversibility: under circumstances favourable for these viruses, expression of the entire viral genome can be induced, resulting in the production of infectious progeny. Source: J Virol Oct; 84(19):

3 Clinical Importance of Latency: The period of latency of a virus is important because some viruses can be transmitted during this time Some patients can have a virus without knowing they have infection because there is a lack of symptoms Misdiagnosis can happen during latency leading the individual to infect others Latency can lead to increased opportunistic infections by other organisms Source:

4 Clinical importance and Maintenance of latency Some viral genes may inhibit apoptosis and/or induce cellular grow. This induction of cellular grow and viral replication may lead to an uncontrolled cell division and increasing risk of developing cancer. Latency is maintained expressing latency-associated genes that will avoid the viral genome from been digested in ribosome or been recognized by the immune-system.

5 EPSTEIN-BARR VIRUS Structure: Epstein-Barr virus (EBV) is dsdna dsdna genome is inside an icosahedral capsid which is surrounded by the tegument and enclosed by a host cell membrane-derived envelope. Source:

6 Source: Cell entry: EBV envelope glycoproteins induce viral entry. B-Cells: viral gp350 binds to type 2 complement receptor (CD21) on B-cells Complex of gp42, gh, and gl, causes fusion of the cell membrane and the viral envelope Induction occurs via MHC II on the B-cell. Epithelial cells: viral BMRF2 binds to β1-integrins on the epithelial cell fusion of the membranes is facilitated by a complex of gh and gl. gp110 improves the efficiency of EBV to infect B-cells and epithelial cells

7 Latency of EBV during Progression of Infection Source: Cell Host & Microbe , DOI: ( /j.chom Cell Host & Microbe , DOI: ( /j.chom

8 EBV Gene Expression during latency Source:

9 Significance of Latency in EBV Source: Leach CT., Sumaya CV. Epstein-Barr Virus. In: Feigin RD, Cherry JD, Demmler GJ, Kaplan SL. Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia: Saunders; p Unlike HSV and other latent virus the EBV generally does not cause specific symptomology after latency. The clinical significance of EBV latency lies in the latent phase itself: In the latent phase EBV DNA within the B-Cell causes increase in proliferation and decrease in apoptosis which predisposes the host to many different diseases

10 EBV Latency Health Consequences a Source: figure/c27ymq-f0d-nv1-xy4/?report=objectonly Source: Mediterr J Hematol Infect Dis. 2010; 2(1): e published online 2010 Aug 10. doi: /MJHID

11 Cytomegalovirus (CMV; HHV-5) dsdna virus Infects people of all ages Transmission Incubation Source: s/ckb/33/37033tn.jpg n10/full/nm html

12 CMV Pathogenesis Primary Infection Secondary Infection Source: Source:

13 Immune response: CMV Cellular Response Humoral Response Innate Response Source: /full Source:

14 Herpes Zoster - Pathophysiology Initial Reaction is Varicella Zoster Virus Herpes Zoster is the reactivation of Varicella Zoster after latent period

15 Herpes Zoster -Mechanism of Latency Varicella-Zoster Virus In contrast, neurons latently infected with VZV express several immediate early and early VZV proteins.therefore, in theory, the host immune system may be able to recognize neurons latently infected with VZV and limit reactivation. Herpes Simplex Virus Neurons latently infected with HSV express a unique class of viral RNA molecules ( latencyassociated transcripts ) but do not express any HSV proteins.thus, in theory, the immune system has no means of recognizing neurons latently infected with HSV.

16 Herpes Zoster - Latency VZV is never eradicated from the host but remains in the host ganglia in a dormant state that may last for decades difficulties in working with the virus poor growth of VZV in culture, which has made study of the virology and biology of the virus difficult the lack of an animal model of VZV latency where reactivation can be achieved There is considerable evidence to show that at least five viral genes are transcribed during latency knowledge of which viral genes are expressed is crucial in devising novel antiviral therapy using expressed genes as therapeutic targets.

17 Herpes Simplex Virus (HSV; HHV-1 and HHV2) Source: the-herpes-virus-and-hashimotos/ Enveloped, linear ds DNA genome, icosahedral nucleocapsid, nuclear replication Source:

18 HSV Establishing Latent Infection Initial infection of epithelial cells by HSV Enter Nerve Cell and retrograde axonal transport to Ganglion Establishment of Latent Infection in Trigeminal Ganglion for HSV1 and Lumbar or Sacral Ganglion for HSV2 Source:

19 Significance of Latency in HSV In nucleus, expression of LAT RNA causes association viral DNA with histones in heterochromatin resulting in latent infection. Intermittent activation with production of virion particles and anterograde axonal movement to epithileal locations producing vesicular eruptions. Source:

20 Source: Complications of HSV Infection Keratoconjunctivitis (HSV-1) - may lead to blindness Genital Herpes (HSV-2) - painful recurrent eruptions, highly contagious during eruption Herpetic encephalitis - further retrograde movement of virus to brain in immunocompromised patient

21 HIV Pathophysiology Glycoproteins gp 120/41 form spikes on virion s Surface and bind to CD4+ of cell membrane CCR5, CXCR4 cause conformational changes, Forms pores, and injects the viral genome into Host cell Gag p24 forms the core after the gag protein Is cleaved LEDGF/p75, ESCRT-I, II, III,TSG101

22 Latency in HIV Activated or resting CD4+ l T-Cell Latency

23 Transcriptional Interference HIV-1 Latency Provirus integrated in same polarity As upstream gene: Occlusion Provirus and cellular region Integrated in opposite polarity: Collision

24 Chromatin Compaction HIV-1 Latency Compaction around HIV-1 provirus Prevents transcription factors to 5 repeat Condensed Chromatin reversed By activated cells

25 HIV Latency and Treatment Studying CD4+ T-cells in latent period Has helped develop potential treatments And occurrence of active phase of HIV Latency Reversal Agents possibly help Treat by activating the virus and promoting Lysis of cells The latent period of HIV prevents total Eradication of the disease

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28 SOURCES Adland E, Klenerman P, Goulder P, Matthews PC. Ongoing burden of disease and mortality from HIV/CMV coinfection in Africa in the antiretroviral therapy era. Frontiers in Microbiology. 2015;6:1016. doi: /fmicb Berngruber TW, Weissing FJ, Gandon S. Inhibition of Superinfection and the Evolution of Viral Latency. Journal of Virology. 2010;84(19): doi: /jvi CDC (2016). Cytomegalovirus. Accessed July 26, Retrieved from: Clyde S. Crumpacker II. Cytomegalovirus (CMV) In: Bennett J, Dolin R, Blaser M, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 8th ed. New York, NY: Saunders; 2015: e4 Draborg AH, Duus K, Houen G. Epstein-Barr Virus in Systemic Autoimmune Diseases. Clinical and Developmental Immunology. 2013;2013: doi: /2013/ Emma Poole, Mark Wills, and John Sinclair, Human Cytomegalovirus Latency: Targeting Differences in the Latently Infected Cell with a View to Clearing Latent Infection, New Journal of Science, vol. 2014, Article ID , 10 pages, doi: /2014/313761

29 SOURCES Eligio P, Delia R, Valeria G. EBV Chronic Infections. Mediterranean Journal of Hematology and Infectious Diseases. 2010;2(1):e doi: /mjhid Gandhi MK, Khanna R. Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments. Lancet Infect Dis Dec;4(12): PubMed PMID: Griffiths P, Baraniak I, Reeves M. The pathogenesis of human cytomegalovirus. J Pathol Jan;235(2): doi: /path Review. PubMed PMID: Kenfak-Foguena A, Schöni-Affolter F, Bürgisser P, Witteck A, Darling KEA, Kovari H, et al. Hepatitis E virus seroprevalence and chronic infections in patients with HIV, Switzerland Jun. Kenfak-Foguena A, Schöni-Affolter F, Bürgisser P, et al. Hepatitis E Virus Seroprevalence and Chronic Infections in Patients with HIV, Switzerland.Emerging Infectious Diseases. 2011;17(6): doi: /eid

30 SOURCES Kumar, Sreeja P., et al. "Pathogenesis and life cycle of herpes simplex virus infection-stages of primary, latency and recurrence." Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology (2016). doi: /j.ajoms Downloaded on from Iizasa H, Wulff B-E, Alla NR, et al. Editing of Epstein-Barr Virus-encoded BART6 MicroRNAs Controls Their Dicer Targeting and Consequently Affects Viral Latency. The Journal of Biological Chemistry. 2010;285(43): doi: /jbc.m Nature Medicine (2016). Cytomegalovirus. Accessed July 26, Retrieved from: Speck, S. H., & Ganem, D. (2010). Viral latency and its regulation: Lessons from the γ-herpesviruses. Cell Host & Microbe, 8(1), doi: /j.chom