NEW YORK NATIVE/May 22, 1995

THE T-CELL KILLER

HHV-6 May Not Even Need HIV to Destroy The Cells That Prevent

Opportunistic Infections

by Neenyah Ostrom

What sets off the cascade of events that results in the

destruction of the immune systems of "AIDS" patients? Although the

putative causal agent of the syndrome, HIV, is believed to orchestrate

the immune system's collapse, no one has been able to explain how it

does it. Meanwhile, another virus, Human Herpes Virus 6 (HHV-6), has

been found to kill immune system cells directly-including T-cells, the

loss of which is the agreed-upon hallmark of the syndrome-without any

mystery or putative indirect mechanisms that have been attributed to

HIV. Now, new research from Robert Gallo's National Cancer Institute of

Tumor Cell Biology reveals that HHV-6 infection is required for HIV to

be able to infect some T-cells.

Not only is HHV-6 able to infect and kill these T-cells that HIV

is unable to infect, these are the very T-cells that are meant to

defend against HHV-6 infection. Therefore, HHV-6 is able to elude

detection by the immune system by killing these cells.

Furthermore, these particular T-cells killed by HHV-6 are also the

ones that protect against specific types of bacteria, including the

Mycobacterium that causes tuberculosis.

In other words: According to this new research, HHV-6 is not only

able to elude detection by the immune system by killing the cells that

are meant to defend against the virus, but HHV-6 infection may also be

the driving force behind the tuberculosis epidemic that is sweeping the

inner cities of the nation.

This research from the National Cancer Institute italicizes the

public health tragedy that has been allowed to develop, as billions

have been spent unsuccessfully to fight HIV, and very little attention

has been paid to HHV-6. HHV-6 is a treatable infection, when it is

caught early; it can be controlled by the readily-available drugs

foscarnet and ganciclovir, as well as the experimental (and presumably

less toxic) drug Ampligen.

But because of the power of the HIV lobby in doling out grant

monies, nearly all the anti-"AIDS" research in the U.S. has focused

(unsuccessfully) on HIV and on developing (ineffective) anti-HIV drugs.

A collaboration between Paolo Lusso from Gallo's NCI lab and

others at the National Institutes of Health examined the "potential

role of HHV-6 in AIDS," which is described in their new research

report.(1)

These investigators found that the HHV-6 infects a particular

subset of T-cells that is "involved in the protective immune response

against specific microorganisms"-including HHV-6 itself.

HHV-6 (Variant A) is not only able to infect this subset of T-

cells, infection by HHV-6 results, in laboratory studies, in "massive

cell death."

In addition to infecting and killing these T-cells, HHV-6

radically alters them: It causes them to secrete the cell surface

protein that turns them into CD4 (T4) cells.

This, according to Lusso and colleagues, renders these T-cells

newly "susceptible to productive infection by HIV-1."

In other words: HIV is incapable of infecting these T-cells unless

HHV-6 has infected them first. (Because of the damage HHV-6 is capable

of causing without HIV, one is tempted to say: So what?)

This subset of T-cells has only recently been described, and is

called "gamma/delta T-cells."

"These results demonstrate that gamma/delta T-cells can be

directly targeted and killed by a herpesvirus and may have implications

for the potential role of HHV-6 in AIDS," Lusso and colleagues

reported.

This finding raises the question: What is the primary

immunosuppressive infection in "AIDS" patients? Is HHV-6 simply

loosening the jar's lid so that HIV can remove it?

Or is HHV-6 actually the primary infection that destroys the

immune systems of "AIDS" patients?

And if it is, what is this virus doing in other people with active

HHV-6 infections-like Chronic Fatigue Syndrome patients?

Lusso is joined in this investigation by NCI colleagues Alfredo

Garzino-Demo and Richard W. Crowley, as well as Mauro S. Malnati from

the National Institute of Allergy and Infectious Diseases. Their study

is published in the April issue of the Journal of Experimental

Medicine.(2)

Lusso and colleagues' investigation delves into an arcane and

newly-discovered pocket of immunology. It has recently been discovered,

they note, that there are two distinct lineages, or families, of T-

cells. One is called alpha/beta; the other is called gamma/delta. These

two families of T-cells respond to challenges by infectious agents in

different ways, which have not yet been entirely elucidated.(3)

The gamma/delta T-cells appear to be capable of responding to

viruses, bacteria, and protozoa. In addition, in the laboratory, these

T-cells are activated by proteins created in response to an infection-

i.e., by the host response, not simply the invading organism itself.

Lusso and colleagues hypothesize that, in living organisms (as

opposed to in the laboratoy), these cells' response "to microorganisms

may be, at least in part, secondary to the effects that the infection

induces in the host, suggesting a possible role of gamma/delta T-cells

in the regulation of the immune response and/or in self-reactive immune

phenomena."(4)

In other words: Because these cells react to an organism's

response to infection, they may play a role in regulating such immune

responses to invaders such as bacteria and viruses.

Additionally, it is primarily the gamma/delta T-cells; so, by

killing those cells, HHV-6 can elude attack by the immune system.

Lusso and co-authors point out that HHV-6 was the first "T-

lymphotropic human herpesvirus" to be discovered. Unlike its close

relative HHV-7, HHV-6 is quite deadly to the cells it infects, not only

T-cells but also natural killer (NK) cells, B-cells, and monocytes.

Lusso and co-authos put this all into perspective this way:

" In all these cell types, HHV-6 induces dramatic

cytopathic changes, suggesting that it may act as an

immunosuppressive agent in vivo. Moreover, a series of

positive viral interactions has been documented between HHV-6

and HIV, the causative agent of AIDS, leading to the hypothesis

that HHV-6 may accelerate the natural course of HIV

infection in coinfected patients. This concept has been corroborated

by the recent demonstration that HHV-6 infection is active and

widespread in terminal AIDS patients. Diverse anomalies of

both the cellular and humoral arms of the immune system have

been reported in patients with AIDS, including gamma/delta T-cell

alterations. In this study, we have investigated the susceptibility

of gamma/delta T-cells to infection by HHV-6 and the interactions

between HHV-6 and HIV in gamma/delta T-cells.(5)"

In their laboratory studies, Lusso and colleagues separated out a

population of gamma/delta T-cells (contamination by alpha/beta T-cells

was estimated to be less than one percent) and exposed them to HHV-6.

After three days, there were signs that the T-cells were infected.

After four to seven days, "a growing proportion of gamma/delta T-cells

exibited the typical HHV-6 induced cytomorphological changes,

consisting of size enlargement, refractile appearance, and loss of

blastic shape with the acquision of an evenly rounded cellular

profile," according to Lusso et al. "Eventually, the viral cytopathic

effect induced widespread cell destruction, resulting in the extinction

of the cultures at day 10-12 after infection."(6)

In about 12 days, then, HHV-6 infection resulted in the total

destruction of the cell cultures into which the virus was introduced.

Before killing the infected gamma/delta T-cells, HHV-6 decreased

the ability of those cells to kill invaders. This loss of function in

the T-cells occurred in two to four days.

In other words: Not only does HHV-6 kill these T-cells, it

destroys the immune system mechanism that is supposed to kill other

invaders.

Gamma/delta T-cells do not ordinarily have the CD4 protein on

their surfaces. HHV-6 infection, however, causes them to express

this cell surface protein. After nine days of infection, more than 70

percent of the gamma/delta T-cells were expressing the CD4 protein,

according to Lusso and colleagues.

HIV uses the CD4 cell protein to infect T-cells. Gamma/delta T-

cells are generally resistant to HIV infection. When Lusso and

colleagues exposed the HHV-6 infected gamma/delta T-cells (which were

producing the CD4 protein) to HIV, however, "they became susceptible to

productive infection by HIV-1," they found. When the cells were treated

with a substance that inhibited the production of the CD4 protein, HIV

was no longer able to infect the cells, "conclusively demonstrating

that the HHV-6 induced CD4 was essential for infection of gamma/delta

T-cells by HIV-1."(7)

In other words, HIV couldn't even infect these T-cells unless HHV-

6 already had infected them and begun the process of causing their

"extinction."

The infection of gamma/delta T-cells by HHV-6 is particularly

diabolical, since those cells help to defend against invasion by the

virus. By infecting these cells, Lusso and colleaues write, "HHV-6 may

seek to escape the immune control of the host and thereby establish

persistent infection." They note that HHV-6 "can infect and kill

several critical elements of the immune system," suggesting the virus

"may have broad immunosuppressive effects."(8)

And, in what may be an even more sinister development, Lusso and

colleagues suggest that it is HHV-6, not HIV, that is driving the

tuberculosis epidemic.

While HHV-6 has been shown to be associated with potentially life-

threatening conditions such as encephalitis, pneumonitis, and bone

marrow suppression, in "AIDS" patients, "HHV-6 has been suggested to

play a more substantial pathogenetic role," according to Lusso and co-

workers.

For instance, "Diverse clinical and experimental observations

indicate that HHV-6 may contribute, directly or indirectly, to the

destruction of CD4-positive T-cells, a pathological hallmark of AIDS,

and thereby expedite the course of the disease."(9)

In particular, "Damage to gamma/delta T lymphocytes could

predispose patients to infection by specific microorganisms that these

cells help to control, including some (e.g. Mycobacteria [that causes

tuberculosis]) that are in important cause of morbidity and mortality

in AIDS."

Lusso, along with Gallo, has previously suggested in the medical

literature that HHV-6 may play a more primary role in causing "AIDS"

than is generally appreciated.

In the March 5, 1994, issue of The Lancet, Lusso and Gallo wrote

an editorial that accompanied a research report by Medical College of

Wisconsin researchers Konstance K. Knox and Daniel R. Carrigan. Knox

and Carrigan noted that "HHV-6 has been proposed as a cofactor in the

pathogenesis of AIDS." They decided to evaluate "the frequency of

active HHV-6 infections in patients who died with AIDS."(10)

Knox and Carrigan found that 100 percent (34 of 34) of the autopsy

tissues from "AIDS" patients tested were positive for HHV-6 infection,

compared to only nine of 34 positive for cytomegalovirus infection.(11)

Knox and Carrigan found HHV-6 infections in the lungs, kidneys,

livers, spleens, and lymph nodes of the patients studied. They

suggested that HHV-6's ability to infect lymphocytes could not only

help spread infection throughout the body, but also contribute to the

destruction of lymphocytes in "AIDS" patients: "An HHV-6 infected

lymphocyte within an area of inflammation could transfer infection to

other lymphocytes newly recruited into the lesion which, when combined

with immunosuppressive result of CD4 lymphocyte destruction by the HHV-

6 infection, could perpetuate inflammation and lead to significant

systemic consumption of lymphocytes."(12)

In their accompanying editorial, Lusso and Gallo point out "That

HHV-6 could contribute to the striking depletion of CD4 T-cells seen in

patients with AIDS was suggested by us more than five years ago. We

made this proposal after observing that HHV-6, unlike cytomegalovirus

or other putative cofactors in AIDS, shares with HIV a primary tropism

for CD4 T-cells and can productively coinfect with HIV individual

target lymphocytes, causing accelerated cytopathic changes..."(13)

Because of all the destruction HHV-6 is known to be able to

inflict on the immune system, Lusso and Gallo suggest that "it may have

detrimental effects on the immune sytem and expedite progression of the

disease [AIDS]."(14)

Is HHV-6 merely "expediting" the progression of "HIV disease," as

these HIV investigators suggest?

Or, as HHV-6 researchers like Knox and Carrigan have been showing,

is HHV-6 infection more primary to "AIDS" than has been previously

acknowledged?

REFERENCES

1. Lusso, Paolo, Afredo Garzino-Demo, Richard W. Crowley, and Mauro S.

Malnati; "Infection of Gamma/Delta T Lymphocytes by Human Herpesvirus

6: Transcriptional Induction of CD4 and Susceptibility to HIV

Infection"; Journal of Experimental Medicine 181:1303, April 1995.

2. Ibid.

3. Lusso et al., op cit.

4. Lusso et al., op cit.

5. Lusso et al., op cit.

6. Lusso et al., op cit.

7. Lusso et al., op cit.

8. Lusso et al., op cit.

9. Lusso et al., op cit.

10. Knox, Konstance Kehl and Donald R. Carrigan; "Disseminated Active

HHV-6 Infections in Patients With AIDS"; The Lancet 343:577, March 5,

1994.

11. Ibid.

12. Knox and Carrigan, op cit.

13. Lusso, Paolo and Robert C. Gallo; "Human Herpesvirus 6 in AIDS";

The Lancet 343:555, March 5, 1994.

14. Ibid.

Reprinted from, and with permission from, AIDS Authority