HHV-6: The T-Cell Killer

[James Scutero]

This article was posted with the permission of the publisher. 

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.
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-James M. Scutero, original proponent of misc.health.aids
 misc.health.aids WWW homepage: http://www.panix.com/~jscutero