Persistent Infections

1.         Long-term Viral infections

a.         Many viruses, especially those that remain localized in the respiratory tract or the intestinal tract, cause only acute (self-limited) infections, which result rarely in death or in recovery with elimination of the virus from the body.

b.         Others have the capacity to establish infections that persist for years or even for life.

c.            Presumably this offers such viruses a long-term evolutionary advantage provided they do not bring about the demise of the host.

d.            Maintenance of a persistent infection requires:

i.            avoidance of elimination by the immune system.

ii.            limitation of expression of the genome.

e.         In the case of a true latent infection in which the genome persists in the absence of any viral replication, there is the further requirement that reactivation of the latent genome to instigate a round of viral replication must occur during life of the host.

f.            Importance of persistent viral infections:

i.          they are often of epidemiologic importance, since the carriers of the virus serve as a source of infection for other persons, thereby enabling such viruses to persist in small populations, even if their infectivity is low.

ii.          they may be reactivated and cause acute episodes of disease.

iii.         they may lead to immunopathologic disease.

iv.         they are sometimes associated with neoplasms.

v.         they may become established even in vaccinated persons unless the vaccine has elicited a strong memory T-cell response.

vi.         they cannot be eradicated by antiviral chemotherapy because the latent genome is not susceptible to antiviral agents when not replicating.

2.            Categories of Persistent Infections

a.         Acute infections with late complications: SSPE

b.         Latent infections, in which infectious virus is not demonstrable except when reactivation occurs, and the disease is usually absent except perhaps during some or all of such recurrences: herpesviruses.

c.         Chronic infections, in which the infectious virus is always demonstrable and often shed, and disease may be absent or chronic, or may develop late, often with an immunopathologic or neoplastic basis: hepatitis B and C.

d.         Slow infections, in which infectious virus gradually increases during a very long preclinical phase, leading to slowly progressive lethal disease: AIDS and subacute spongiform encephalopathies.

3.            Subacute Sclerosing Panencephalitis

a.         A classic example of an acute infection with rare late complications is subacute sclerosing panencephalitis (SSPE).

b.         It is an invariably fatal complication occurring 1-10 years after recovery from measles.

c.         It occurs in only 1 in 300,000 cases and has become very rare following the reduction in measles itself by widespread immunization of children.

d.         Patients with SSPE reveal very little measles virus in the brain but exceptionally high titers of neutralizing antibodies in cerebrospinal fluid.

e.         The RNA viral genome is detectable in neurons by nucleic acid hybridization, and nucleocapsids are demonstrable by electron microscopy and immunofluorescence.

4.         Latent Infections

a.         All six human herpesviruses are common and important pathogens which establish lifelong latency and may be reactivated at any time.

b.         When the trigger is profound immunosuppression, as in AIDS or organ transplanation, reactivation of a latent herpesvirus infection may be lethal.

c.         Though all herpes viruses share the common lifestyle of latency, they have evolved divergent strategies for achieving that end.

d.         A key distinction is that herpes simplex and varicella-zoster viruses persist in neurons, which are nondividing but long-lived cells, whereas cytomegalovirus, EB virus, and human herpesvirus 6 persist in lymphocytes, which are dividing but short-lived.

e.         Herpes simplex:

i.          primary infectioins with herpes simplex virus type 1 may be subclinical or may produce an acute stomatitis in early childhood or tonsilitis / pharyngitis in adolescence.

ii.          at intervals of months or years after recovery from the primary infection, the characteristic vesicular lesions reappear usually on the lips.

iii.         herpes simplex virus type 2 causes comparable initial and recurrent lesions on the male and female genitalia.

iv.         during primary infection of the host with herpes simplex virus, viral nucleocapsids are translocated by retrograde axonal flow to the cranial or spinal sensory ganglia, where the viral genome thereafter persists indefinitely.

v.            following reactivation by immunosuppression, replication of virus is induced and virus is transported down the axon to the periphery where it multiplies again in the epithelial cells.

vi.         a T-cell mediated inflammatory response quickly leads to elimination of infected epithelial cells, and preexisting antibody mops up any free virions to bring the recurrence of the disease to a halt.

f.            Varicella-Zoster:

i.            characterized by a rash that is usually limited largely to an area of skin innervated by a single sensory ganglion.

ii.          zoster results from the reactivation of virus that has remained latent since an attack of varicella, typically many years earlier.

iii.         latency is tightly maintained – reactivation is triggered only by declining immunity to virus, not by fever or ultraviolet light.

iv.         most latent VZV infections never reactivate, and in the remaining 15%, only a single recurrence occurs and this is largely confined to the elderly.

g.            Epstein-Barr virus:

i.          long-term latency in short-lived dividing lymphocytes has involved stimulation of the lymphocyte to divide and maintenance of the genome in the form of a plasmid.

ii.          EBV infection in childhood may lead decades later to death from Burkitt’s lymphoma, or masopharyngeal carcinoma.

h.            Cytomegalovirus:

i.            infections with CMV and EBV are characterized by initial prolonged excretion of virus followed by a state of latency.

ii.          the CMV infections are normally subclinical, but severe disease occurs in patients with some kind of immunodeficiency.

iii.         CMV establishes latent infection in salivary glands and kidneys, as well as monocytes and/or lymphocytes.

iv.         virus is shed, intermittently or continuously, particularly into the oropharynx, from which it may be transmitted via saliva, and also into the urine.

I.            Progressive Multifocal Leukoencephalopathy:

i.          a rare, lethal manifestation of reactivation of an almost universal latent infection with human JC polyomavirus.

ii.          the acute infection generally occurs in childhood and is usually subclinical.

iii.         the virus then persists for life in the kidneys and in the brain. and is shed in urine from time to time.

iv.         the condition is a demyelinating disease of the brain, seen only in severely immunocompromised patients.

v.         the target cell is the oligodendrocyte, not the neuron.

5.            Persistent infections with viral latency and recrudescence

6.            Hepatitis B

a.            Hepatitis B is the most important chronic viral infection of humans, especially in Asia and Africa, where there are some 250 million carriers.

b.         During acute infections the virus replicates in the liver and circulates in the plasma, usually in association with a great excess of smaller particles composed of viral surface antigen (HBsAg).

c.         In most infected individuals HBsAg and virions are cleared from the circulation, but in 5-10%, including over 90% of those infected during infancy, a persistent infection is established which can extent for many years, often for life.

d.         The carrier state is characterized by continuous production of HBsAg and usually infectious particles, which are plentiful in blood stream and less so in saliva and semen.

e.         Some carriers develop chronic hepatitis and cirrhosis, and HBV is an important cause of primary hepatocellular carcinoma.

7.         HIV

a.            Features of Infection:

i.          displays features of latent, chronic, and slow infections.

ii.          at any time far more cells carry the viral genome silently than are producing new virions.

iii.         yet, at all times some cells are manufacturing virus, and this is continuously shed.

b.         Once infected via genital secretions or blood, the host mounts an immune response but fails to eliminate the virus.

c.         A lifelong persistent infection is established in lymphoid organs and the brain, with the virus replicating slowly, principally in CD4 T cells.

d.         Survival mechanisms in host:

i.            inducing formation of syncytia which enable it to spread from cell to cell without encountering antibody.

ii.          viral cDNA can persist indefinitely intracellularly as a latent infection to be reactivated later.

iii.         reverse transcriptase is error-prone, so numerous nucleotide substitutions accumulate in the genome as years go by, producing different HIV mutants, and enabling the virus to evade neutralization by antibodies.

iv.            principal pathologic effect of the virus to suppress the immune system of the host by destruction of helper T cells and macrophages.

8.            Subacute Spongiform Encephalopathies

a.         A generic name for several lethal neurodegenerative diseases – scrapie of sheep, kuru, Creutzfeldt-Jakob disease.

b.         The basic lesion is a progressive vacuolation in neurons, astrocytes and oligodendrocytes, an extensive astroglial hypertrophy and proliferation, and finally a spongiform change in the gray matter.

c.         The preclinical phase is very long, up to 3 years, and once signs have appeared the disease progresses slowly but inevitably to paralysis and death.

d.         The etiologic cause is unknown; the widely accepted hypothesis is that infectivity resides in a prion, defined as a small proteinaceous infectious particle.

9.            Ineffective Immune responses in persistent viral infections

10.            Reactivation of persistent viral infections in humans