Tuesday, January 22, 2013

A Tale of Two Viruses

Note: Although attempts have been made to connect AIDS to ME and CFS,
as this article shows scientists are dealing with a much more complex

A Tale of Two Viruses: Why AIDS Was Pinned to HIV, but Chronic Fatigue
Remains a Mystery
Discover Crux blog / Vincent Racaniello

Vincent Racaniello is Higgins Professor of Microbiology & Immunology
at Columbia University, where he oversees research on viruses that
cause common colds and poliomyelitis. He teaches virology to graduate,
medical, dental, and nursing students, and writes about viruses at

The detection of a new virus called XMRV in the blood of patients with
chronic fatigue syndrome (CFS) in 2009 raised hope that a long-sought
cause of the disease, whose central characteristic is extreme
tiredness that lasts for at least six months, had been finally found.
But that hypothesis has dramatically fallen apart in recent months.
Its public demise brings to mind an instance when a virus *was*
successfully determined to be behind a mysterious scourge: the case of
HIV and AIDS. How are these two diseases different—how was it that
stringent lab tests and epidemiology ruled one of these viruses out,
and one of them in?

The first inklings of the disease now called AIDS surfaced in Los
Angeles in the summer of 1981. The 5 June 1981 issue of Morbidity and
Mortality Weekly Report described 5 homosexual men with Pneumocystis
carinii pneumonia (abbreviated PCP), normally only observed in
individuals with weakened immune systems. The article suggested the
possibility of an immune dysfunction related to exposure to something
that would make individuals vulnerable to opportunistic infections.
Soon clusters of PCP and Kaposi's sarcoma, a rare skin cancer, were
observed in gay men in other urban centers. The Centers for Disease
Control and Prevention established a simple case definition—Kaposi's
sarcoma or opportunistic infections—and began scouring hospital
records. Over time this definition was modified, but its early use
identified an ongoing epidemic, and identified groups at risk for the
disease as men who have sex with men and injection drug users.

The next year the new disease was called AIDS, and soon the U.S.
Public Health Service recommended that members of risk groups not
donate blood or plasma. Soon came reports that the disease could be
acquired by newborn babies from their mothers, and also by
heterosexual contact. By the fall there were nearly 700 people who had
been diagnosed with AIDS in the U.S., of whom almost 300 had died. The
CDC and World Health Organization worked together to publish global
data on the disease, and issue recommendations to prevent its spread.

During the early years, the epidemiology of AIDS suggested an
infectious cause, and in 1983, just two years after the disease was
identified, a novel retrovirus was isolated from a patient at risk for
AIDS. A year later a commercial blood test was developed, which
allowed comprehensive studies to be done that showed clearly that the
virus, later named human immunodeficiency virus type I (HIV-1), was
the cause of AIDS. This conclusion was strengthened by the
transmission of AIDS to hospital workers when they inoculated
themselves with HIV-containing blood by accidental needle sticks.

By 1987 the first anti-HIV drug, azidothymidine or AZT, was licensed
for the treatment of AIDS. Today over 20 anti-HIV drugs have been
approved. When given in combinations of three, the emergence of
drug-resistant viral variants is minimized, transforming AIDS from a
death sentence to a life-long chronic disease.

The story of CFS, generally defined as persistent fatigue of six
months or greater not relieved by rest and accompanied by other
specific symptoms, is markedly different. This syndrome was first
reported in Los Angeles as well, but in 1934. There were subsequent
sporadic outbreaks, some of which were reviewed by DA Henderson in
1959, who noted that females were more frequently affected, and
suggested that a virus might be involved. In the 1980s Daniel Peterson
identified antibodies against Epstein-Barr virus (EBV) in the blood of
a group of CFS patients in Incline Village, Nevada. The CDC entered
the investigation but was unable to confirm that antibodies to the
virus were consistently present in patient blood. A subsequent
case-control study failed to identify EBV as the causative agent of
the disease, which was subsequently named chronic fatigue syndrome.

The search for that agent of CFS has continued to be fruitless. In
addition to EBV, a host of other viruses have been found in CFS
patients, including enteroviruses, measles virus, herpesviruses, and
human T-lymphotropic virus type II. However, none have been
consistently detected in CFS patients and therefore are not considered
to cause the disease.

The possibility of a viral cause of CFS re-emerged in 2009 with the
detection of a retrovirus called XMRV in the blood of a substantial
fraction of CFS patients. A second laboratory subsequently identified
sequences related to murine leukemia viruses, also retroviruses, in
the blood of CFS patients. However, many other laboratories were
unable to replicate these findings, and both papers have been

Why do the stories of AIDS and CFS have such different outcomes? One
reason is that it has been difficult to reach a consensus on a
clinical definition of CFS. At the onset the case definition of AIDS
was simple—"Kaposi's sarcoma or opportunistic infections"—which made
it possible to rapidly and accurately identify new cases, especially
among different research groups around the country. This led to the
establishment of risk factors, and the epidemiological data obtained
from this work made it highly likely that an infectious agent was
involved, spurring the search for the causative pathogen. The case
definition for CFS has undergone a number of revisions over the years.
When different research groups use different definitions of the
disease, it becomes difficult to compare findings. Most importantly,
there is no indicator or diagnostic test that can be used to identify
CFS, and since diagnosing CFS is a long and difficult process, cohorts
established by different investigators vary, leading to different
findings, confusion, and contention. In contrast, AIDS was readily
identifiable and easily diagnosed once a blood test for HIV was

Another problem is that in contrast to their excellent work on AIDS, the CDC has stumbled when tackling CFS. The CDC has dismissed evidence that CFS is an organic disease, and spent funds on investigating psychiatric and trauma-related causes, rather than infectious origins. The agency also diverted funds designated for CFS to other programs. These and other missteps alienated the CFS patient community—the opposite of what the agency accomplished with the AIDS community.
In part due to the standardized case definition of AIDS,
identification of a candidate virus was relatively rapid. Determining
its role in the disease was facilitated by the development of a blood
test, which could be used to prove that HIV-1 caused AIDS. The
relationship between HIV and AIDS was further confirmed by the
development of antiviral drugs that inhibited viral replication and
helped alleviate the symptoms of the disease.

Why have investigators failed to identify a virus behind CFS? (It is
not due to the lack of appropriate technology; this has improved
substantially since the 1980s with the development of polymerase chain
reaction and rapid DNA sequencing.)
One explanation for this dilemma
is that an infectious agent does not cause CFS. However, there is
plausible evidence for an infectious etiology, including observations
that the disease is known to occur in outbreaks. Furthermore, in many
cases the onset of symptoms appears to begin with a flu-like illness.
Additionally, CFS is a heterogeneous disease, and may be caused by
several different agents or a combination of viruses and
non-infectious conditions. Another possibility is that an infection
initiates an immune response that spirals out of control, leading to
CFS symptoms. This scenario implies that at least some CFS patients
have underlying deficits in immune regulation. If that's true, it will
be very difficult to identify the virus involved because it will
likely have been eliminated from patients' systems by the time CFS
symptoms become apparent.

In retrospect, it is clear that the properties of AIDS made it an easy
disease to understand. While the path to understanding CFS has been
clouded by non-scientific issues, in the end the main reason why we do
not understand this disease is because it is extraordinarily complex.
But that never stopped a good scientist.


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