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Persistent Viral Infections

Persistent viral infections can establish lifelong latent or chronic infections through several mechanisms: 1. Modulation of viral and host gene expression limits recognition of infected cells and immune responses. 2. Viruses infect immunoprivileged sites or alter lymphocyte and macrophage functions to evade immunity. 3. Herpesviruses like HSV1/2 and VZV enter neurons and establish latent infections in ganglia, expressing genes that maintain latency until stress triggers reactivation and spread to skin/mucosa.

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Santhoshi Sadhanaa Sankar
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33 views

Persistent Viral Infections

Persistent viral infections can establish lifelong latent or chronic infections through several mechanisms: 1. Modulation of viral and host gene expression limits recognition of infected cells and immune responses. 2. Viruses infect immunoprivileged sites or alter lymphocyte and macrophage functions to evade immunity. 3. Herpesviruses like HSV1/2 and VZV enter neurons and establish latent infections in ganglia, expressing genes that maintain latency until stress triggers reactivation and spread to skin/mucosa.

Uploaded by

Santhoshi Sadhanaa Sankar
Copyright
© © All Rights Reserved
Available Formats
Download as PPTX, PDF, TXT or read online on Scribd
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Persistent Viral infections

Persistent infections

Latent

Chronic

Slow

Persistence : Modulation of viral and cellular gene expression

Modification of host immune response

Reactivation

Change in physiology

Superinfection

Physical stress/ trauma


1.Limitation of recognition molecules on infected cells:
a.Restricted expression of viral antigens (e.g., HIV, measles virus in
subacute sclerosing panencephalitis).
b.Antiviral antibody-induced internalization and modulation of viral
antigens (e.g., measles virus).
c.Viral antigenic variation (e.g., HIV).
d.Blocking antibody that prevents the binding of neutralizing antibody
(e.g., measles virus).
e.Decreased expression of cell major histocompatibility complex
recognition molecules (e.g., CMV, adenoviruses).
f.Restricted expression of the cell adhesion molecules LFA-3 and ICAM-1
(e.g., EBV, CMV).
2.Altered lymphocyte and macrophage functions, including modified
production of cytokines and immunosuppression (e.g., HIV-1, HIV-2, EBV).
3.Infection in immunologically privileged anatomic sites (e.g., HSV-1, HSV-
2, VZV in the central nervous system).
4.Compromised nonspecific defenses (e.g., interferon).
5.Immune tolerance (?).
The second factor is modulation of viral gene expression.

Examples include down regulation of some viral genes by


viral or cellular regulatory gene products (e.g., HIV,
HPVs),

specific latency-associated proteins (e.g., EBNA-1) and

possibly by synthesis of latency-associated transcripts


(e.g., HSV-1, HSV-2) and

viral variants (e.g., HIV, measles).


Proposed mechanisms for persistence and escape of
immune surveillance by HIV-infected cells include:

1.Restricted expression of provirus by cellular and viral factors.


2.Avoidance of neutralizing antibodies by spreading directly from
cell to cell.
3.Budding of virus particles into cytoplasmic vacuoles, resulting in
masked virus production.
4.Inhibition of antigen-induced lymphocyte proliferation by Tat
protein.
5.Genetic (antigenic) variation among HIV isolates.
6.Multiplication in immunologically privileged sites.
7.Mobility of latently infected cells within the host.
8.Inhibition of immune and nonspecific defenses.
During persistence CMV appears to impair immune
responses at several levels:
a) altered expression and intracellular distribution of antigen-
presenting molecules such as MHC class I;
b) b) altered production of lymphocyte adhesion (e.g., ICAM-
1, LFA-1) or co-stimulatory molecules (e.g., B7);
c) c) inhibition of complement-mediated lysis due to an
increased production of inhibitory factors (e.g., CD55);
d) d) masking of the cell surface with overproduction of Fc
receptors that are able to bind IgG, thus preventing
immune lysis;
e) e) excretion of immune modulators (e.g., TGF beta, TNF
alpha) by CMV-infected cells;
f) f) CMV encodes G protein coupled receptors that resemble
cellular molecules and through molecular mimicry may
escape immune recognition.
Herpes Simplex Virus Types 1 and 2
During acute herpes simplex virus (HSV) infection
(see Ch. 68), virus and/or viral components (e.g.,
nucleocapsids) containing viral genetic material
ascend in nerve axons from the initial site of infection
to the sensory gangliamainly the trigeminal ganglia
HSV-l, and the lumbar and sacral ganglia for HSV-2
(Fig. 46-4A). In the sensory ganglia, the virus may
cause a cytolytic infection or establish a latent,
noncytolytic infection. Sympathetic ganglia and other
cell types of the central nervous system may also
serve as sites of virus latency.
In the neuron, viral DNA is maintained as an extrachromosomal plasmid (episome)
with 1 to 20 copies per cell.
Current studies are examining the possibility that
latent virus is restricted by virus DNA-encoded antisense RNA molecules known as
latency-associated transcripts (LATs).
Transcription of LATs is regulated by LAT promoter elements.
The LAT promoter region contains a series of consensus
elements, including a TATA box, Sp1 binding motifs, cAMP response element
and LAT promoter binding factor.

Reactivation of latent infection and an associated


down regulation of the LAT promoter, often occurs after various stress-related
stimuli, e.g., heat, cold, ultraviolet light, unrelated immune hypersensitivity reactions
, pituitary or adrenal hormones, immunosuppression, and emotional disturbance.

When the latent virus is reactivated, its genome passes anterograde in axons to
the epithelium, where productive replication takes place
(A) Establishment of herpes simplex virus or varicella-zoster virus latency in ganglia after
primary infection of skin or mucosa. (B) Reactivation of virus in ganglion and spread
through nerves to skin or mucosa to cause surface lesions or retrograde spread through
nerves to central nervous system to cause encephalitis (infrequent).
VZV

After recovery from acute varicella (chickenpox), the virus establishes latency in multiple
ganglia of the human neuraxis (Fig. 46-4A). Years later, the virus may reactivate, and the
distribution of lesions in the skin corresponds closely to areas of innervation (dermatome)
from an individual dorsal root ganglion (Fig. 46-4B). However, in immunocompromised
patients, life-threatening disseminated infections can occur. Studies suggest that the virus is
harbored in sensory ganglia (trigeminal and/or dorsal) and satellite cells. In these cells,
limited transcription may take place from some, but not all, of the immediate early and
early genes of the latent viral genome. Thus, expression of latent varicella-zoster virus genes
appears to be different from that of HSVs. Where mainly non-polyadenylated LATs that are
antisense to immediate early transcripts are expressed and accumulate in neuronal cells.
VZV-encoded LATs are polyadenylated transcripts of the sense direction that have a short
half-life and are detectable in non-neuronal, satellite cells and in ganglia as well.
However, there is no significant viral protein synthesis detectable from the polyadenylated
transcripts during latency.
The molecular basis of latency and reactivation of latent virus has not been fully characterized.

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