M A G A Z I N E
A Tale of Two Viruses: Why AIDS
Was Pinned to HIV, but Chronic
Fatigue Remains a Mystery
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
(http://bit.ly/x5WHir) 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 (http://bit.ly/w4sHj2)
fallen apart (http://bit.ly/xhQJiT) 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
The first inklings of the disease now called AIDS surfaced in
Los Angeles in the summer of 1981. The 5 June 1981 issue
(http://1.usa.gov/x97mzV) of Morbidity and Mortality
Weekly Report described 5 homosexual men with
Pneumocystis carinii pneumonia (abbreviated PCP),
normally only observed in individuals with weakened
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
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
(http://bit.ly/zJkSGS) was isolated from a patient at risk for
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
(http://bit.ly/xYHOq4), who noted that females were more
frequently affected, and suggested that a virus might be
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 (http://1.usa.gov/zzgs3q).
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
(http://1.usa.gov/zT9NKI) in the blood of a substantial
fraction of CFS patients.
A second laboratory (http://1.usa.gov/x47VLE) 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 retracted
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
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,
In contrast, AIDS was readily identifiable and easily
diagnosed once a blood test for HIV was developed.
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
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
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
But that never stopped a good scientist.