Why AIDS Was Pinned to HIV, but CFS Remains a Mystery

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DISCOVER

M A G A Z I N E

The Crux

A Tale of Two Viruses: Why AIDS

Was Pinned to HIV, but Chronic

Fatigue Remains a Mystery

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

virology.ws

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

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

(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

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

(http://bit.ly/zJkSGS) 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 in 1959

(http://bit.ly/xYHOq4), who noted that females were more

frequently affected, and suggested that a virus might be

involved.

In the 1980s 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

(http://bit.ly/xhQJiT).

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 developed.

Another problem is that in contrast to their excellent work on

AIDS, the CDC has stumbled when tackling CFS

(http://bit.ly/usLskj).

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.