Human T-Cell Leukemia Virus Linked to AIDS

Journal article

By: Jean L. Marx

Date: May 20, 1983

Source: Marx, Jean L. "Human T-Cell Leukemia Virus Linked to AIDS." Science. (May 20, 1983): 20, (4599) 806-809.

About the Author: Jean Marx is a regular contributor to the journal of Science, and is also the author of A Revolution in Biotechnology.

INTRODUCTION

Cells are the building blocks of all living organisms. The lifespan of cells partially depends on the functioning of organs. In a gradual process, the old cells perish and new ones are made. However, cells that lose the ability to die and continue to multiply at an abnormal rate give rise to the medical condition commonly known as cancer. A similar abnormal condition of blood cells is termed blood cancer, or leukemia. This disease afflicts human beings because of sudden mutations in blood cells or through a certain viral infection.

A virus known as the Human T-cell Leukemia Virus (HTLV) causes T-cell leukemia—a rare form of blood cancer that particularly affects T-cells. T-cells protect the body by tagging an outside object entering the body as foreign. Subsequently, the body would act against such foreign objects. In 1981, scientists pointed out that even if a person carries this virus from birth, the disease manifests only in adulthood. It is, therefore, called Adult T-cell Leukemia (ATL). In the early 1980s, doctors treating some patients suffering from sexually transmitted diseases found that these patients also had high fever, sore throat, headaches, pneumonia, and swollen lymph nodes—symptoms indicating a suppressed immune system that was, at the time, thought to be caused by lack of T-cells. Research showed that this immune suppression could be transmitted from one person to another, and it was later termed the Acquired Immune Deficiency Syndrome (AIDS).

Further research on patients with ATL suggested a link between HTLV and AIDS. The American scientist Robert Gallo, along with his team from the National Cancer Institute (NCI) found a strong connection between HTLV infected people and those having AIDS. According to a report published by Gallo and his team, an important observation was that T-cells in patients showed abnormal behavior in both the diseases, and that the modes of viral transmission were similar. The team also discovered a single virus causing leukemia and suppression of the immune system in cats.

The following article excerpt was published in the journal Science in 1983, and discusses Robert Gallo's findings. The article, as its name suggests, reports that AIDS can be caused by the Human T-Cell Leukemia Virus.

PRIMARY SOURCE

Patients with the new immune disease show evidence of infection by human T-cell leukemia virus. Does the virus cause the disease?

Five reports in this issue of Science suggest a possible link between the serious new disease, acquired immune deficiency syndrome (AIDS) and human T-cell leukemia virus (HTLV), which has been associated with a rare type of human cancer. Investigators at the Harvard University School of Public Health, the National Cancer Institute, and the Pasteur Institute have fond evidence of HTLV infection in patients with AIDS or at high risk of developing the syndrome. The evidence includes isolation of the virus itself from a few patients, detection of the viral DNA in T cells from two cases, and also a much higher incidence of antibodies against HTLV in AIDS patients than in controls.

It is still too early to tell whether HTLV actually causes AIDS. The disease is characterized by immune suppression, which results in high susceptibility to opportunistic infections by agents that do not usually cause serious illnesses in healthy people but can prove devastating to individuals with defective immune responses. HTLV may be just another of these opportunistic pathogens, a consequence rather than a cause of AIDS. Max Essex of the Harvard group says, "I definitely do not want anyone to get the impression that we have proof of cause. What we do have is a good lead."

A good lead is much needed. Since AIDS first became manifest in 1981, more than 1350 cases have been reported to the Centers of Disease Control (CDC). The mortality rate may be 70 percent or higher, and the number of cases continues to grow by four to five per day. Epidemiological studies strongly suggest that AIDS is caused by an infectious agent, although other possibilities have not been conclusively ruled out. Efforts to identify the infectious agent have proved frustrating.

According to Robert Gallo of the National Cancer Institute (NCI), there are a number of reasons for taking a close look at HTLV as a possible cause of AIDS. First is the prevalence of HTLV in the Caribbean area and in Africa. The Caribbean area, especially Haiti, and equatorial Africa have been suggested as possible sources of the putative AIDS agent.

In the United States, Haitian immigrants constitute the third largest group of AIDS patients. The largest group consists of homosexual and bisexual men who have been extremely active sexually, and the second largest includes users of illegal intravenous drugs. Hemophiliacs are a fourth group with increased risk of AIDS.

AIDS has apparently spread among homosexuals by sexual contact and among drug users by contaminated needles. It is believed to have been transmitted to hemophiliacs by way of the blood clotting factor preparations that they must take. But the Haitians have always been a puzzle, because the vast majority deny both homosexual practices and drug use and they have not been exposed to clotting factor preparations. The identification of a causative virus in the Haitian population could help clear up this mystery.

Secondly, HTLV primarily infects T cells. As Gallo puts it, "HTLV is extraordinarily T-cell tropic." The primary AIDS defect also seems to be in the T lymphocytes, which are reduced in number in the patients and abnormal in composition. The helper T cells, which are needed to activate certain immune responses, including antibody production by the B-lymphocytes, are very low in number, whereas the killer-suppressor cells are much less affected. The loss of helpers, while the activities of suppressor T cells remain more or less intact, could produce the profound suppression of the immune response that is characteristic of AIDS.

A third point of similarity is mode of transmission. As noted previously, AIDS spreads by intimate contact and through blood products. "Everything we know about HTLV suggests that intimate contact is needed for transmission," Gallo remarks. He points out that the viral envelope, which is required for infectivity, is very fragile. It tends to come off when the virus buds from infected cells, thus rendering the particles incapable of infecting new cells. Gallo speculates that direct cell-to-cell contact may be required for the spread of HTLV.

Finally, there are the precedents for a virus causing both a leukemia and immunosuppression. This is true for feline leukemia virus, which has been studied for many years in the Essex laboratory. "More cats are killed as a result of feline leukemia virus causing immunosuppression than by feline leukemia virus causing leukemia," Essex says.

The virus generally impairs T-cell responses in the animals. Previous attempts to demonstrate an effect on antibody production had failed, but the Essex group now finds that natural infection by feline leukemia virus suppresses the antibody response to an antigen that normally requires the cooperation of helper T cells to elicit antibody production. Feline leukemia virus also has a preference for infecting T cells and produces primarily T cell leukemias. The antibody response may be deficient, Essex speculates, because of a problem with the helper T cells.

Previous failures to demonstrate a viral effect on antibody production may be attributable to the differing responses of cats to naturally occurring and laboratory-induced infections. The natural infections are more effective at suppressing the immune response of cats than infections induced by such laboratory methods as directly injecting the virus.

HTLV is one of the retroviruses, which have RNA as their genetic material. In infected cells, the RNA is copied into DNA, which may then become integrated into the DNA genome of the host cell and bring about the cell's cancerous transformation. To determine whether AIDS patients showed signs of infection by HTLV the Gallo group looked for viral DNA in the patients' T cells.

They detected the viral DNA in the cells of two of 33 patients, but did not find it in T cells from any of 25 healthy homosexual males. They were able to isolate infectious HTLV particles form the T cells of one of the two individuals who were positive for viral DNA and also from two additional patients. This is from a total of about 20 patients whose T cells were used in attempts to isolate HTLV. In addition, a French group, under the direction of Luc Montagnier of the Pasteur Institute in Paris, has isolated a related virus from the T cells of a homosexual male with lymphadenopathy, a condition that may be a mild form of AIDS or a forerunner of the full-blown disease.

There is more than one type of HTLV. About 35 isolates of the virus have been made throughout the world. Roughly 25 of these have been characterized and most are of the type designated HTLV-I, which was originally isolated by the Gallo group. A second type of the virus, which is designated HTLV-II, has been isolated from the cells of a patient with hairy cell leukemia.

The NCI workers have characterized one of their three HTLV isolates from AIDS patients and it is HTLV-I. The virus isolated by the French group is neither HTLV-I nor II, but represents a third variant of the virus. Although the members of the HTLV family are distinguished on the basis of structural variations in one of the internal proteins of the viral particle, they have other features in common, including their preference for infecting T cells and the rather unusual properties of their enzyme for copying RNA into DNA.

Gallo suggests that logistical problems might explain why viral DNA could be detected in the cells of so few AIDS patients. "If infection leads to a decline in the population of infected cells, you may not be able to find them by the time you get frank disease," he explains. In fact, the NCI workers could not detect integrated viral DNA in T cells from blood samples taken at a later date from the two patients who had earlier given positive results. The same problem might affect attempts to isolate the virus itself. Lymphocytes from the spleen or lymph nodes might be a better source of virus than the peripheral blood cells used for the NCI studies. The French workers isolated their virus from lymph node cells….

If HTLV does cause AIDS then there must be a way of maintaining the immunosuppressed state even after the virus is no longer detectable. The immune systems of the patients do not appear to recover.

Simply finding HTLV or the DNA in AIDS patients does not mean that the virus caused the disease. "From our data it could be an opportunistic infection," Gallo concedes. "But Essex's data argue that it is more than opportunistic."

Essex and his Harvard and CDC collaborators detected antibodies against membrane-associated antigens of HTLV in at least 25 percent of 75 AIDS and 23 lymphadenopathy patients. Another 10 percent or so would be positive if the investigators used a somewhat less stringent criterion for a positive antibody test.

In contrast, only one of 81 homosexual controls who had been matched for age, race, and place of residence with 36 of the AIDS patients had the antibodies. The one positive individual was a friend, but not a sex partner, of one of the patients. Only two of an additional 305 controls, including homosexuals who had visited a venereal disease clinic, healthy blood donors, kidney dialysis and chronic hepatitis patients, had the antibodies. "The message is that 25 to 40 percent of AIDS cases have the antibodies and 1 percent or less of control groups do," Essex says.

Other attempts to identify differences in viral exposures between AIDS patients and controls have not turned up such a large discrepancy between the two groups. Nevertheless, some 50 percent of the patients did not have the antibodies, either because the test was not sensitive enough to detect them or because their immune systems failed to make the antibodies—or because they had not been infected by HTLV.

Militating against the possibility that HTLV causes AIDS, Gallo says, is the relatively short period of time required for the immune deficiency disease to develop. CDC officials have reported the latency period of AIDS to be several months to a year. The T-cell leukemia caused by HTLV may require years, if not decades, to develop after infection by the virus.

Perhaps more disconcerting than the discrepancies in the latency periods of the two conditions is the apparent lack of AIDS in southern Japan, an area where the rate of HTLV infection is very high. Some 25 percent of the population there have antibodies against the virus, compared to 4 to 5 percent in Haiti and 1 percent in the United States.

Either AIDS exists in that part of Japan but has not been diagnosed, which seems unlikely especially in view of the publicity AIDS has received during the past year, or the Japanese may respond differently to the infection. Another possibility, Gallo points out, is that a change occurred in the HTLV family in Africa or Haiti that conferred a new capability for immune suppression on the virus. Comparison of the nucleotide sequences of the DNA of viral isolates form the various sources may help to clarify this issue.

Why some people might develop AIDS as a consequence of HTLV infections while others get leukemia is unclear. It might be an as yet undetermined difference in the infecting HTLV or in the host response to the infection. It might depend on the site at which the viral DNA integrates in the genome of infected cells.

In any event, there are now a number of approaches that may be taken to clarify the relation between HTLV and AIDS. A prospective study of high-risk individuals to see whether HTLV infection precedes or follows development of AIDS is a possibility. Another is to look at people who have other types of immune suppression, children with congenital immunodeficiency diseases or kidney transplant patients, for example, to see if they too have an increased number of HTLV infections.

If HTLV does eventually prove to be the cause of AIDS, then a specific test for the early diagnosis of the condition may be feasible. Especially desirable is an assay for the AIDS agent in blood. The possibility that the condition may be transmitted in blood products has naturally generated a great deal of concern. Ultimately a vaccine may be developed to protect high-risk individuals. But that all awaits firm proof of the cause of AIDS.

SIGNIFICANCE

Gallo's above-mentioned report is one of the first scientific papers to be published on AIDS. In the early 1980s, considerable medical research was conducted to assimilate the root causes for AIDS. This was a period when no one was aware that infection with the Human Immunodeficiency Virus (HIV) eventually leads to AIDS.

Although Gallo's research indicated HTLV (or HTLV-I, as it is commonly known) as the most promising virus for causing AIDS, this was soon proven false. Further research revealed specific differences between HTLV I and the virus that actually causes AIDS. Researchers found that although the modes of transmission of both the viruses were similar, HTLV I was not as easily transmitted as the AIDS-causing virus. Moreover, while HTLV caused an abnormal increase in the number of T-cells, the AIDS-causing virus degenerated the defense mechanism. It was also found that HTLV maintained its genetic make-up, unlike the actual virus.

At the time, a team of French scientists, led by Luc Montagnier from the Pasteur Institute, also worked on isolating the AIDS virus. As mentioned above, they found that HTLV and the AIDS-causing virus had similar genetic make-up. However, the similarity ended there because both the viruses were found to operate inside the cell in distinct ways. Montagnier wanted the AIDS virus to be called HTLV III (due to its similarity to HTLV I and II), but the team termed it Lymphoadenopathy Associated Virus (LAV). At the same time, Gallo and his team published more papers in Science declaring HTLV III (now known as Human Immunodeficiency Virus or HIV) to be the cause of AIDS. This caused a legal conflict between the American and French scientists. The issue was resolved in 1987 by proclaiming both Gallo and Montagnier as co-discoverers of the AIDS virus, in an agreement signed by the respective scientists, then U.S. President Ronald Reagan (1911–2004) and French Prime Minister Jacques Chirac.

Although it reaches an erroneous conclusion, Gallo's report is considered a highly significant paper by scientists, as it instigated exhaustive research and competition among scientists to find the cause of AIDS. Several viruses were initially and incorrectly linked to AIDS. For example, a New York Times article published in August 1985, stated that scientists assumed the Hepatitis B virus to be the basis of AIDS.

Since the 1980s, both HIV infection and AIDS have become a worldwide pandemic. There is also a common misconception that HIV and AIDS are identical conditions. Although HIV does eventually lead to AIDS, only when the numbers of the HIV virus are sufficient in the body to cause the symptoms characteristic of immune system compromise is AIDS diagnosed. According to a 2004 paper titled 'Human retroviruses in Leukemia and AIDS: reflections on their discovery, biology and epidemiology' by Abraham Karpas, ninety percent patients who are tested HIV positive develop AIDS in less than ten years. Medical research has also proved that HIV is a far more destructive virus compared to HTLV. The above-mentioned report suggests that only about one percent of those infected by HTLV eventually develop leukemia.

According to the United Nations, as of 2005, the number of people reportedly living with AIDS is 40.3 million.

FURTHER RESOURCES

Books

Gallo, Robert C. Virus Hunting: AIDS, Cancer, and the Human Retrovirus: A Story of Scientific Discovery. New York: Basic Books, 1993.

Web sites

Avert.org. "HIV & AIDS Statistics." 〈http://www.avert.org/statindx.htm〉 (accessed March 14, 2006).

Cambridge Journals Online. Karpas, Abraham. " Human Retroviruses in Leukemia and AIDS: Reflections on Their Discovery, Biology and Epidemiology." 〈http://journals.cambridge.org/〉 (accessed March 14, 2006).