HHV-6, the other virus that causes AIDS

[James Scutero]

The Journal of Experimental Medicine/Volume 181/April 1995 1303-1310

Infection of gamma/delta T Lymphocytes by Human Herpesvirus 6: 
Transcriptional Induction of CD4 and Susceptibility to HIV Infection
by Paolo Lusso, Alfredo Garzino-Demo, Richard W. Crowley and Mauro S. 
Malnati

Discussion

     Although the role of gamma/delta T cells in the strategic 
organization of the immune system has only recently started to be 
unraveled, increasing evidence indicates that these cells represent an 
essential component of the protective response against specific 
microorganisms. In this study, we documented that HHV-6, a T-
Lymphotropic herpesvirus, can productively infect gamma/delta T 
lymphocytes, inducing important phynotypic and cytopathic changes. 
Moreover, we found that gamma/delta T cells can recognize and kill HHV-
6-infected target cells, suggesting that gamma/delta T cells may play a 
protective role against infection by HHV-6 in vivo. Thus, by directly 
attacking gamma/delta T cells, HHV-6 may seek to escape the immune 
control of the host and thereby establish persistent infection. 
Previous studies have elucidated that HHV-6 is an immunotropic 
herpesvirus that can infect and kill several critical elements of the 
immune system. These biological properties suggest that infection with 
HHV-6 may have broad immunosuppressive  effects, although direct in 
vivo evidence for such action has not yet been provided. Nevertheless, 
accumulating clinical evidence indicates that HHV-6 may be associated 
with severe pathology, such as pneumonitis, encephalitis, and bone 
marrow suppression, in patients subjected to immunosuppressive regimens 
after bone marrow or organ transplantation and in patients with AIDS. 
In HIV-infected patients, however, HHV-6 has been suggested to play a 
more substantial pathogenetic role. Diverse clinical and experimental 
observations indicate that HHV-6 may contribute, directly or 
indirectly, to the destruction of CD4+ T cells, a pathological hallmark 
of AIDS, and thereby expedite the course of the disease. In vitro, HHV-
6 can coinfect individual CD4+ T cells with HIV, accelerating the 
kinetics of HIV expression and cell death. This synergistic effect may 
be due to multiple mechanisms, including the transactivation of the 
regulatory sequences contained in the long terminal repeat of HIV, the 
release of HIV-activating cytokines and the expansion of the range of 
cells susceptible to HIV by inducing de novo expression of the CD4 
receptor. In this study, we found that gamma/delta T cells, after HHV-6 
infection, are induced to express CD4 on their surface membrane, thus 
becoming susceptible to productive infection by HIV-1. Given the 
potential role of HHV-6 in AIDS, it is tempting to speculate that this 
virus might contribute, directly or indirectly, to the gamma/delta T 
cell abnormalities that have been described in patients infected with 
HIV. 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 are an important cause of 
morbidity and mortality in AIDS.
     We found that polyclonal gamma/delta T cells induce lysis of both 
autologous and heterologous target cells infected by HHV-6, as 
previously demonstrated for NK cells. Unlike gamma/delta T cells, 
however, polyclonal NK cells were not productively infected in vitro by 
HHV-6, despite rapid internalization of the virions. Because of 
polyclonal NK cells efficiently recognize and kill HHV-6 infected 
targets, we hypothesized that active recognition of the target might 
induce resistance to HHV-6 infection in the NK effectors. Consistent 
with this concept, productive HHV-6 infection was documented in NK 
clones lacking the ability to kill HHV-6-infected targets, but not in 
clones with a high lytic activity against infected cells. In the 
present study, uncloned gamma/delta cells were readily infected by HHV-
6, in spite of their ability to kill infected targets. Whether 
gamma/delta T and NK cells receive different activatory signals from 
infected targets or display a different repertoire of reactive events 
(e.g., cytokine secretion, membrane alterations) remains to be 
established. We observed that gamma/delta T cells maintained their 
cytolytic activity against infected cells for several days after 
exposure to HHV-6. the subsequent loss of cytotoxic ability coincided 
with the early stages of extracellular virus production (day 4 after 
infection), at a time when the cellular DNA and protein synthesis 
machineries start to be overtaken by the herpesvirus. The lytic effect 
against K562 started to decrease even at an earlier time after 
infection (day 2), suggesting that the functional impairment induced by 
HHV-6 in gamma/delta T cells is generalized and not specific for the 
recognition and/or killing of virus-infected cells. In another 
herpesvirus system, HSV-1, a rapid loss of killing ability has been 
documented after exposure of CTL, NK, or LAK cells to infected targets. 
Direct infection by HSV-1 has been proposed as a possible mechanism for 
such functional impairment in CTL and LAK cells. However, when cell-
free HSV-1 was used, the killing ability of CTL's was lost only at 
exceedingly high MOI levels. Cell-free virus inocula were also used in 
our experiments with HHV-6, but not at similar MOI levels. However, the 
fact that uninfected gamma/delta T (this report) and NK cells display a 
significant level of cytotoxic activity in vitro against HHV-6-infected 
targets suggests that HHV-6, at variance with HSV-1, is not able to 
promptly disarm cytolytic effectors. Further studies are needed to 
elucidate whether herpesviruses exploit common mechanisms for impairing 
the function of antiviral effector cells and thereby elude the immune 
surveillance of the host.
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-James M. Scutero, original proponent of misc.health.aids
 misc.health.aids WWW homepage: http://www.panix.com/~jscutero