BIOL 4413/5404

PERSISTENCE OF VIRUSES

• Within an infected host, viruses can either cause acute infections or can establish long-term persistence.
• Virus survival in nature requires a continuous infection of susceptible individuals.
• During acute infections, virus is cleared by the host immune response, necessitating rapid transmission or capacity for extra-organismal survival.
• Some acute viruses (measles, mumps) survive by constant infection of human populations only.
• Flu, yellow fever, rabies and others circulate in more than one species.
• Others possess structural features that permit them to survive the rigors of an extra-organismal environment until contact with a susceptible host occurs.

• Poxviruses are stable in a dried form, whereas enteric viruses (Poliovirus, Rotavirus) can survive in water supplies until ingested by susceptible individuals.
• Viruses may persist within an individual host organism for extended periods of tim
• These virus infections begin as acute infections but progress to latent or chronic infections during which the virus is transmitted periodically to new host organisms.
• The ability to persist in vivo is not confined to a particular virus group and a variety of DNA and RNA-containing viruses can establish long-term infections.

• Persistent viruses cause an increasing proportion of the disease
• AIDS by HIV.
• Chronic hepatitis and hepatocellular carcinoma by hepatitis B virus.
• Anogenital cancer associated with papilloma viruses.
• Herpes virus simplex 2 in the newborn.
• Sensitive techniques, such as PCR will uncover even more evidence of low-level viral persistence
• Additional disease may be found to be caused by viruses persisting at low levels.
• Mechanisms are still not well understood.
• During acute infection, many viruses inhibit the metabolism of host cells they infect so that cytopathic effects or cell death ultimately results.
• If a cytolytic virus establishes a persistent infection, alternative virus-host cell interactions must occur to limit cytopathic effects of the virus.
• Effects of a virus on a host cell are attenuated so that the cell can survive and the virus can persist within it while resisting its defenses.

DNA Viruses that Persist in Humans

Adenovirus

Site of persistence: Adenoids, tonsils, lymphocytes

Consequences: Not known

Cytomegalovirus

Site of persistence: Kidney, salivary glands, lymphocytes ?, macrophages ?, stomal cells ?

Consequences: Pneumonia, retinitis

Epstein-Barr Virus

Site of persistence: Pharyngeal epithelial cells, B cells

Consequences: Infectious mononucleosis, Burkitt's lymphoma, nasopharyngeal carcinoma, oral leukoplakia

Herpes Simplex Virus 1 and 2

Site of persistence: Sensory ganglia neurons

Consequences: Cold sores, genital herpes, encephalitis, keratitis

Human Herpesvirus 6

Site of persistence: Lymphocytes

Consequences: Exanthem subitum

Varicella-Zoster Virus

Site of persistence: Sensory ganglia neurons and/or satellite cells

Consequences: Varicella, zoster

Hepatitis B Virus

Site of persistence: Hepatocytes, lymphocytes ?, macrophages

Consequences: Hepatitis, hepatocellular carcinoma

Hepatitis D Virus

Site of persistence: Hepatocytes

Consequences: Exacerbation of chronic HBV infection

Papillomavirus

Site of persistence: Epithelial skin cells

Consequences: Papilloma, carcinoma

Parvovirus B19

Site of persistence: Erythroid progenitor cells in bone marrow

Consequences: Aplastic crisis in hemolytic anemia, chronic bone marrow deficiency

Polyomavirus BK

Site of persistence: Kidney

Consequences: Hemorrhagic cystitis

Polyomavirus JC

Site of persistence: Kidney, oligodendrocytes in CNS

Consequences: Progressive multifocal leukoencephalopathy

RNA Viruses that Persist in Humans

Hepatitis C Virus

Site of persistence: Hepataocytes, lymphocytes?

Consequences: Hepatitis, hepatocellular carcinoma

Measles Virus

Site of persistence: Neurons and supporting cells in CNS

Consequences: Subacute sclerosis panencephalitis

Rubella Virus

Site of persistence: Central nervous system (CNS)

Consequences: Progressive rubella panencephalitis, insulin-dependent diabetes? Juvenile arthritis?

Measles and rubella viruses typically cause acute infections. However, in rare instances these viruses have been shown to persist in the CNS

Retroviruses that Persist in Humans

Human Immunodeficiency Virus (HIV)

Consequences: AIDS

Human T Cell Leukemia Virus I

Site of persistence: T cells

Consequences: T cell leukemia, tropical spastic paraparesis, polymyositis

Human T Cell Leukemia Virus II

Site of persistence: T cells

Consequences: None known

Patterns of Viral Infection

Viral infections of a host organism can be divided into several categories, based on the patterns and levels of infectious virus detectable in the organism at various times after infection.

Types of Infection

Acute

 Acute infections followed by viral clearance by the host immune response.

Acute infection followed by latent infection in which viruses persist in a non-infectious form with intermittent periods of viral reactivation and shedding.

These viruses must be capable of causing productive infection in certain cells or under certain conditions and non-permissive infection in other cells.

Issues:

What are the mechanisms by which the cytopathic potential of these viruses is limited so they can establish latency?

How are they maintained in a latent form?

How do they reactivate?

Acute Infection Followed by a Chronic Iinfection

The infectious virus is continuously shed from or is present in infected tissues.

Chronic

Infections can be established if the host immune response can not eliminate or clear virus generated during an acute infection.

Slow, Chronic Infection Without Acute Infection

Only observed with unconventional agents such as those causing spongiform encephalophaties.

Conditions Required for a Virus to Persist over a Long Term in the Host

Viruses Have Devised Various Strategies to Accomplish the Following Goals:

• Virus must be able to infect host cells without being cytopathic (no killing or causing excessive damage to cell)
• Are able to establish long-life chronic infections (non-lytic virus-host interaction)
• Most arenaviruses can replicate in a cell without killing it or affecting the growth rate of the cell
• Hepatitis B virus which productively infects hepatocytes with minimal to no cell injury
• There must be mechanisms for long-term maintenance of the viral genome in host cell
• The virus has to avoid detection and elimination by the host's immune system
• A virus may be lytic for certain cell types but not for others
• HIV is more lytic for T cells than for monocytes / macrophages
• Productive infection of T cells can result in cell death whereas mononuclear phagocytes produce viruses for considerable periods of time without cell lysis.
• Infection of non- or semipermissive cells results in latent infection due to restricted expression of viral genes.
• Sensory neurons are nonpermissive for the normally cytolytic herpes virus (HSV), allowing little or no viral gene expression.
• B lymphocytes are nonpermissive for Epstein-Barr virus (EBV). DNA replication occurs when the host cell divides and maintains noncytolytic state.
• Papillomaviruses establish latent infections in basal layer skin cells.
• Viruses remain latent until induced to reactivate by perturbation of the host environment (cell injury, etc.) converting cell from nonpermissive to permissive for viral replication.
  

Viral Strategies for Evading the Immune System

There are Six Proposed Mechanisms

• Restricted gene expression; virus remains latent in the cell with minimal to no expression of viral proteins.
• Infection of sites not readily accessible to the immune system.
• Antigenic variation; virus rapidly evolves and mutates antigenic sites that are critical for recognition by antibody and T cells.
• Suppression of cell surface molecules required for T cell recognition.
• Viral defense molecules that interfere with the function of antiviral cytokines.
• Immunological tolerance