This lecture contrasts acute, self-limiting viral infections with persistent infections that last the host's lifetime. It explores the mechanisms enabling persistence, including failure of immune clearance, immune modulation strategies like MHC class I downregulation and CTL escape mutations, antagonism of CTL function, infection of immune cells, and establishment in immune-privileged sites (e.g., CNS, eye, testes, as exemplified by Ebola). Specific persistent human viruses are discussed: Measles (rarely causing fatal SSPE), Polyomaviruses (largely benign but causing PML in immunosuppressed), Anelloviruses (ubiquitous and benign), Hepatitis B and C (causing chronic liver disease and cancer, with HBV persistence risk higher in newborns), and the Herpesvirus family. Herpesviruses (HSV, VZV, EBV, CMV, HHV6/7) establish latency via different mechanisms β silenced non-replicating DNA in neurons (HSV, VZV), replicating episomes in B cells (EBV) or myeloid cells (CMV), or even integration into host chromosomes (HHV6). Reactivation mechanisms, triggers (like stress for HSV), and associated diseases (cold sores, shingles, mono, cancers, birth defects) are detailed. The lecture concludes by emphasizing the high prevalence of multiple persistent viral infections in humans and the critical need to consider their potential role in other chronic diseases.
Summary of Persistent Viral Infections Lecture:
0:00:24 Introduction to Persistent Infections: Unlike acute infections, persistent viral infections last for the host's lifetime. Most people harbor several such viruses.
0:00:46 Defining Persistence: Persistent infections are long-term, contrasting with rapid, self-limiting acute infections. They often begin as an acute phase that isn't cleared.
0:01:36 Reasons for Persistence: Key factors include the primary infection not being cleared by the immune response, continuous (though sometimes variable) production of viral components, viruses being non-cytopathic (eliciting weaker immunity), and extensive viral immune modulation.
0:03:00 Examples of Persistent Viruses: Many DNA and RNA viruses persist in various human tissues (lymphocytes, kidney, liver, neurons), causing diverse outcomes from benign presence to severe disease (list provided).
0:03:37 Immune Evasion: MHC1 Modulation: Cytotoxic T lymphocytes (CTLs) normally clear infected cells by recognizing viral peptides on MHC class I molecules. Persistent viruses extensively interfere with this pathway at multiple steps (peptide generation, transport, MHC display, MHC transcription). Herpesviruses are notable examples.
0:06:55 Immune Evasion: CTL Escape Mutants: Viruses mutate peptides presented by MHC1 so they are no longer recognized by CTLs. This helps the virus persist within the host but doesn't aid spread between hosts due to MHC polymorphism.
0:09:42 Immune Evasion: Killing CTLs: Some infected cells can induce apoptosis in the CTLs that try to kill them (e.g., via Fas ligand), protecting the infected cell.
0:11:37 Immune-Privileged Sites: Tissues like the Central Nervous System (CNS), eye, and testes have reduced immune surveillance to prevent damage. Viruses reaching these sites may persist because they aren't effectively cleared.
0:13:00 Ebola as an Example: Ebola, typically acute, was found persisting in the eyes (causing uvitis) and testes (allowing late sexual transmission) of survivors from the West Africa outbreak, demonstrating persistence in immune-privileged sites.
0:16:45 Immune Evasion: Infecting Immune Cells: Viruses like Measles and HIV infect immune cells, directly impairing the host's ability to clear infections.
0:17:55 Measles Virus & SSPE: Though typically acute, Measles virus can rarely persist in the brain, causing a fatal neurological disease (Subacute Sclerosing Panencephalitis - SSPE) 5-10 years later. This involves a defective virus spreading neuron-to-neuron. Vaccination prevents both measles and SSPE.
0:20:55 Polyomaviruses (BK, JC, etc.): Very common, acquired early, persist latently (likely in kidneys). Usually asymptomatic but can reactivate in immunosuppressed individuals (e.g., MS patients on Tysabri), causing Progressive Multifocal Leukoencephalopathy (PML).
0:24:03 Anelloviruses: Extremely common (>90% prevalence), circular ssDNA viruses. Persist benignly in many tissues, transmitted widely. Levels increase with immunosuppression, but no disease association known.
0:25:24 Hepatitis B Virus (HBV): DNA virus using reverse transcriptase. Transmitted by blood, birth, sex. Causes acute and chronic hepatitis. Chronic infection risk is much higher if infected as a newborn (~90%) vs. adult (~5%). Leads to CTL-mediated liver damage, cirrhosis, and liver cancer. Newborn vaccination is critical.
0:31:15 Hepatitis C Virus (HCV): RNA flavivirus. Transmission similar to HBV. High rate of persistence (60-90%) leading to chronic liver disease and cancer. No vaccine available. Opioid crisis has increased US incidence.
0:35:21 Patterns of Persistence: Includes latent infections with reactivation (HSV), persistent asymptomatic shedding (Polyoma), and persistent infections leading to late-onset pathology (HIV, SSPE).
0:36:40 Mechanisms of Latency: Viral genomes persist, sometimes with limited protein expression. Examples: non-replicating DNA in non-dividing cells (HSV/VZV in neurons), replicating episomes in dividing cells (EBV in B cells), and genome integration (HHV6).
0:38:08 Herpes Simplex Virus (HSV-1/2): Causes oral/genital herpes. >80% seropositive. Establishes lifelong latency in peripheral neurons (e.g., trigeminal ganglia). Viral DNA is silenced, non-replicating; only latency-associated transcripts (LATs/microRNAs) are made. Reactivation causes sores. Currently incurable ("Herpes is forever").
0:42:10 HSV Reactivation Trigger: Stress (sunburn, exams, hormones) activates neuronal kinases (JNK) that phosphorylate histones on the latent viral genome, partially de-repressing it and allowing the lytic cycle to begin.
0:48:31 Epstein-Barr Virus (EBV): Causes mononucleosis, associated with lymphomas and Multiple Sclerosis (MS). 95% seropositive. Latent as a replicating episome in memory B cells. Reactivates periodically for transmission via saliva.
0:51:46 Varicella-Zoster Virus (VZV): Causes chickenpox (varicella), then latent in nerve ganglia. Reactivation (often >50 years old) causes shingles (zoster). Latent genome is a non-replicating episome in neurons. Vaccines available for both chickenpox and shingles.
0:54:55 Cytomegalovirus (CMV): High seroprevalence, transmitted by saliva, urine, etc. Latent in myeloid progenitor cells. Usually asymptomatic but causes severe disease in transplant recipients and congenital infection (birth defects).
0:58:39 Human Herpesvirus 6 & 7 (HHV-6/7): Cause common childhood rash (roseola/sixth disease). Latent in immune cells. Uniquely, HHV-6 can integrate its genome into host telomeres, allowing germline transmission in ~1% of cases.
01:00:22 Conclusion & Implications: Almost all humans carry multiple persistent viral infections. This "virome" is a critical, often overlooked factor in human health and must be considered when studying the causes and progression of other chronic diseases (e.g., diabetes, autoimmunity). The EBV-MS link illustrates how this challenge can be addressed.