e
syndrome?
The finding that a retrovirus, XMRV, is associated with chronic fatigue
syndrome has lead to the suggestion that the disease might be treated with
some of the antiviral drugs used to treat AIDS. The integrase inhibitor
Raltegravir has been found to block the replication of murine leukemia
virus, which is highly related to XMRV. But the drug exacerbates autoimmune
disease in mice which might rule out its use in treating CFS.
Retroviruses such as XMVR and HIV-1 have genomes composed of single-strande=
d
RNA. This nucleic acid is converted to a DNA copy in infected cells by the
viral enzyme reverse transcriptase. The double-stranded viral DNA is then
integrated into the chromosomal DNA of the host cell, a process accomplishe=
d
by an viral enzyme called integrase.
Raltegravir (pictured above left) is an inhibitor of HIV-1 integrase that
was approved for use in humans in 2007. The drug blocks the integration of
viral DNA into the host genome and therefore inhibits viral replication.
The mouse retrovirus murine leukemia virus (MLV) has been linked to the
development of spontaneous autoimmune disease. The mechanism by which the
virus induces this disease is not known, but stimulation of innate immune
responses by viral DNA might be involved.
Raltegravir also inhibits integration of MLV DNA into the murine genome.
When mice with autoimmune disease were treated with raltegravir, they
succumbed to autoimmune disease a month earlier than untreated animals. Mic=
e
without the disease were not affected by the antiviral drug. The authors
speculate that by inhibiting viral DNA integration, raltegravir increases
the amount of unintegrated viral DNA, elevating innate responses and
exacerbating autoimmunity.
It=E2=80=99s not known if raltegravir is active against XMRV, the retroviru=
s
associated with chronic fatigue syndrome. Given the similarity between the
genomes of MLV and XMRV it seems likely that the drug will inhibit the
virus. If the ability of raltegravir to treat CFS is tested in clinical
trials, it will be important to carefully monitor treated patients for sign=
s
of autoimmunity. CFS has an autoimmune component which could worsen with
raltegrivir treatment.
An obvious question is whether raltegrivir induces autoimmunity in AIDS
patients. I=E2=80=99m not aware of any such reports, which is probably not
surprising given the fact that HIV-1 infection leads to immunosuppression.
CFS sufferers should not despair: other antiretroviral drugs, including
chain terminators such as AZT, do not allow the accumulation of unintegrate=
d
viral DNA. These compounds might be useful for treating the disease.
G.B. Beck-Engeser, D. Eilat, T. Harrer, H.-M. Jack, M. Wabl (2009). Early
onset of autoimmune disease by the retroviral integrase inhibitor
raltegravir Proceedings of the National Academy of Sciences :
10.1073/pnas.0908074106
*Below is an excellent explainer of innate immune responses also written by
microbiology professor Vincent Racaniello:*
In response to viral infection, many organisms mount a remarkable defense
known as the *immune response*. This response to viral infection consists o=
f
an innate, or nonspecific component, and an adaptive, or specific defense.
The innate response is considered the first line of immune defense because
it is active even before infection begins. In fact, many viral infections
are halted by the innate immune system, which responds very quickly =E2=80=
=93 within
minutes to hours after infection.
A key property of the innate immune system is the ability to recognize
viruses as =E2=80=98foreign=E2=80=99. Viral proteins and nucleic acids are =
distinguished
from cellular counterparts by cellular proteins called *pattern recognition
receptors* (illustrated). These are proteins present either in the cell
cytoplasm or on cellular membranes, where they detect viral components. For
example, the cytoplasmic protein RIG-I detects double-stranded RNA (dsRNA)
or single-stranded RNA (ssRNA) with a 5=E2=80=B2-triphosphate. These types =
of RNAs
are usually not found in the cytoplasm of unifected cells; rather they are
typically products of viral replication. When RIG-I binds these viral RNAs,
a series of reactions occur which lead to the synthesis of cytokines, the
primary output of the innate defense system. Other detectors of viruses are
the membrane-bound toll-like receptors (TLRs), which sense viral
glycoproteins, dsRNA, ssRNA, and the sequence CpG in viral DNA. Engagement
of TLRs by these virus-specific ligands also leads to the synthesis of
cytokines, albeit by different pathways.
The presence of cytokines in the blood is typically one of the earliest
indications that the host has been infected with a virus. Over 80 known
cytokines are secreted by infected cells. The first that are produced after
viral infection include interferon-=CE=B1 and -=CE=B2 (IFN-=CE=B1, IFN-=CE=
=B2), tumor necrosis
factor alpha (TNF-=CE=B1), interleukin-6 (IL-6), IL-12, and IFN-=CE=B3.
Cytokines function locally by binding receptors on other cells. For example=
,
IFN produced by infected cells engages receptors on neighboring cells. Thos=
e
cells then produce hundreds of cellular proteins which have antiviral
activities. When cytokines enter the circulation, they elicit symptoms
typical of many viral infections, including fever, sleepiness, lethargy,
muscle pain, loss of appetite, and nausea.
Another key component of the innate response are the so-called *sentinel
cells*: dendritic cells and macrophages present in peripheral compartments
such as skin and mucosal surfaces. Sentinel cells patrol the body, seeking
signs of infection. Dendritic cells bind cytokines produced by
virus-infected cells, and also take up viral proteins released from dying
virus-infected cells. They respond by producing more cytokines to amplify
the original response.
In many viral infections, the early action of cytokines produced by infecte=
d
cells and dendritic cells is sufficient to eliminate the pathogen. If innat=
e
defenses are overwhelmed and virus replication continues unabated, then the
second-line defenses are mobilized to ensure host survival. These comprise
the adaptive immune response =E2=80=93 antibodies and immune cells. Days to=
weeks
are required to mount an adaptive immune response that is specifically
tailored to the infecting virus. The innate response therefore serves as a
crucial rapid response that provides sufficient time for the activation of
the adaptive immune system.
---------------------------------------------
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