Role of the Fas/FasL pathway in HIV or SIV disease.

Abstract

Human immunodeficiency virus disease involves progressive destruction of host immunity leading to opportunistic infections and increased rates for malignancies. Both depletion in immune cell numbers as well as defects in their effector functions are responsible for this immunodeficiency The broad impact of HIV reflects a similarly broad pattern of cell depletion including subsets that do not express viral receptors or support viral replication. Indirect cell killing, the destruction of uninfected cells, is due partly to activation of the Fas/FasL system for cell death. This death-signaling pathway is induced during HIV disease and contributes significantly to viral pathogenesis and disease.

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BioMed Central
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Retrovirology
Open Access
Review
Role of the Fas/FasL pathway in HIV or SIV disease
Bhawna Poonia, C David Pauza and Maria S Salvato*
Address: Institute of Human Virology, University of Maryland, School of Medicine, 725 W Lombard Street, Baltimore, MD 21201, USA
Email: Bhawna Poonia - bpoonia@ihv.umaryland.edu; C David Pauza - cdpauza@ihv.umaryland.edu;
Maria S Salvato* - msalvato@ihv.umaryland.edu
* Corresponding author
Abstract
Human immunodeficiency virus disease involves progressive destruction of host immunity leading
to opportunistic infections and increased rates for malignancies. Both depletion in immune cell
numbers as well as defects in their effector functions are responsible for this immunodeficiency The
broad impact of HIV reflects a similarly broad pattern of cell depletion including subsets that do
not express viral receptors or support viral replication. Indirect cell killing, the destruction of
uninfected cells, is due partly to activation of the Fas/FasL system for cell death. This death-signaling
pathway is induced during HIV disease and contributes significantly to viral pathogenesis and
disease.
Background
Changes in CD4 cell count and viral RNA burden are the
most commonly used markers for HIV disease progres-
sion. However, evidence has existed for several years that
many patients with HIV disease experience a broad loss of
leukocyte subsets without an apparent preference for
depleting CD4 T cells [1-3]. Effects on cell types other than
CD4 T cells were documented in macaques after showing
substantial B cell loss during acute SIV infection [4] and in
humans by showing depletion of γδ T cells [5] that are
CD4 negative. Many other examples confirmed that the
profound impact of HIV on "non-CD4" leukocyte popu-
lations must depend on indirect mechanisms, as opposed
to direct cell killing that occurs when HIV or SIV infects
and destroys susceptible CD4+ cells. Uninfected CD4+
cells can also be destroyed by indirect mechanisms. Since
both direct and indirect mechanisms are driven by viral
burden, it has been difficult to distinguish their contribu-
tions to CD4+ T cell depletion and progressing disease.
This technical obstacle has blocked efforts to explore new
therapies that target indirect mechanisms.
Besides depletion of immune cells due to cell death, HIV
infection is also characterized by defects in effector cell
functions. T cell exhaustion or low HIV-specific T cell cyto-
toxicity has been attributed to loss of zeta chains [6] or to
high levels of PD-1 or CTLA-4 on the surface of T cells
[7,8]. During chronic HIV infection this immune dysfunc-
tion can result from interactions with regulatory T cells
(Tregs) [9,10] that are exported to the periphery during
high thymic turnover [11]. Ultimately, Tregs contribute
not only to immune exhaustion but also to cell death via
the Fas/FasL apoptotic pathways (Fig. 1).
Mechanisms of indirect cell depletion in HIV infection
Despite overwhelming evidence for indirect cell deple-
tion, little is known about how it occurs in vivo. Cell loss
is accelerated during elevated viremia and a broad recov-
ery of leukocytes attends highly active antiretroviral ther-
apy (HAART) [12]. Some of these changes may be related
to release of sequestered lymphocytes from secondary
lymphoid tissues [13] as viral antigen declines during
therapy. HIV effects on bone marrow, thymus, and hemat-
Published: 15 October 2009
Retrovirology 2009, 6:91doi:10.1186/1742-4690-6-91
Received: 21 July 2009
Accepted: 15 October 2009
This article is available from: http://www.retrovirology.com/content/6/1/91
© 2009 Poonia et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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opoietic stem cells were also proposed as causes for gen-
eral leukocyte loss [14]. While HIV does indeed infect and
alter bone marrow and thymus, the kinetics for cell loss
during acute infection, the rates for recovery during
HAART and the durable repertoire defects in T and B cell
subsets after HAART [15,16] argue that these dynamic
changes occur within mature populations without an
overwhelming impact of declining stem cell output.
Therefore due to large expansions and contractions of
mature cell numbers, declining stem cells do not have a
measurable impact on leukocyte depletion in AIDS.
A process described as "chronic immune activation" or
"hyperactivation" occurs during HIV disease and is
Major mechanisms of leukocyte cell loss in AIDS
Figure 1
Major mechanisms of leukocyte cell loss in AIDS. Two models for cell death in AIDS are the direct and indirect killing of
leukocytes during disease progression. Direct killing, or killing of virus-infected cells, is presumed to be virus-mediated or to
occur via immune surveillance of virus-infected cells, most often by killer T cells. The virus-infected cells are predominately
memory T cells with the phenotype CD4+CD45RA- or CD4+CD45RA+Fas and are primarily killed by cytotoxic T cells in a
Fas-independent manner [52]. Indirect cell death, or killing of uninfected "bystander" cells, has also been documented in vivo. All
leukocytes, including uninfected bystander cells, can be activated, with up-regulation of Fas/FasL and other death mediators,
after contact with HIV-infected cells or HIV antigens such as soluble tat, gp120, vpr, and nef [20,24,38,39,49]. Thus HIV gene
expression contributes to both direct and indirect killing mechanisms. Contact with death ligands like FasL causes apoptosis of
activated cells through Fas/FasL signaling. Tregs are major effectors of bystander killing. The finding that HIV+ cells are less sus-
ceptible to Fas/FasL killing means that HIV+ cells become enriched when Fas-mediated apoptosis is the major death pathway.

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accompanied by higher expression of TNF superfamily lig-
ands and their receptors, e. g. Fas/FasL and TRAIL-DR5
[17-20]. Chronic activation coincides with "activation
induced cell death" (AICD) that was initially coined to
describe cell loss that occurs when lymphocytes are acti-
vated by viral antigen in the absence of appropriate cos-
timulation. AICD connects viral gene expression to a
general lymphocyte destruction, ultimately resulting in
reduced immune protection from HIV. It is now known
that both viral and host products can activate lym-
phocytes and induce death receptor expression. Secreted
HIV Tat protein has been shown to up-regulate FasL and
TRAIL in T cells or macrpophages, which can in turn
induce apoptosis in bystander cells, thereby providing a
mechanism of cell death in uninfected cells [21-23]. In
HIV disease, both antigen-specific and polyclonal activa-
tion have been observed [17,24,25]. This pan-activation
sensitizes the lymphocytes to apoptotic cell death that
occurs when the death ligand, usually cell-associated, con-
tacts a cell that is expressing death receptors.
Early investigators [26] proposed apoptotic death as an
important contributor to CD4 T cell depletion. They
observed that triggering through the T cell receptor failed
to induce proliferation of PBMC from HIV+ asympto-
matic donors; instead, CD4 cells in these cultures had fea-
tures consistent with Fas-mediated apoptosis [27]. We
confirmed this result in SIV-infected macaques [28]. Alter-
natively, signaling through the T cell receptor [29] can
activate the mitochondrial pathway for apoptosis, distinct
from the Fas-triggered caspase-8 death pathway [30]. Both
pathways are generally invoked in AICD (Figure 1). Since
antigen-specific memory T cells are more likely to express
Fas, cell killing can appear to be tied to antigen specificity.
Both the caspase 8 and the mitochondrial apoptosis
mechanisms tend to delete immune cells that respond to
antigen. Preferential apoptotic cell death of antigen-acti-
vated T cells could account for the lack of immune control
over opportunistic pathogens and an insufficiency of viral
immunity that fails to prevent viral persistence or pro-
gressing disease. Once the host environment is "set," and
after viremia triggers higher expression of FasL, every
encounter with antigen has the potential to drive cell
depletion among all lymphocyte compartments.
Role of Fas/FasL mediated cell death in HIV/SIV infections
Apoptosis is observed consistently among uninfected cells
in SIV+ macaques or HIV+ humans [31]. Chronic
immune activation drives cells into apoptosis [32] possi-
bly involving Fas/FasL interactions [33], and reflects an
exaggeration of the normal processes for homeostatic cell
regulation during HIV disease [34]. The roles of assassin
and victim are not always clear in these interactions. Acti-
vated CD4+ T cells can express FasL and become the effec-
tors of cell death including the destruction of resting B
cells [35], even as they also become targets for cell killing
and display high rates for apoptosis during disease.
Many studies have explored the mechanisms connecting
HIV/SIV antigen expression and apoptotic cell death.
Human macrophages express FasL after exposure to HIV
[36], creating a link between antigen presentation and
Fas/FasL-mediated apoptosis. HIV up-regulates FasL in
CD4 T cells [37,38] after they are exposed to soluble Tat,
gp120 [22] or Nef proteins [39]. Higher levels of FasL,
both cell-associated and in plasma, and Fas were observed
in specimens from HIV+ patients whose PBMC were espe-
cially susceptible to Fas-mediated cell death in vitro [40].
Cross-linking of CD4 by gp120 complexes or viral parti-
cles increased the susceptibility to apoptosis triggered by
FasL or TNF-α [41,42].
The patterns of CD4 T cell depletion appear to be antigen-
specific, as perturbation of the CD4 receptor repertoire is
significantly associated with higher plasma viremia [43].
This can be explained by an AICD mechanism or by virus
infection of antigen-activated cells as we proposed [44].
Less data are available to show whether CD8+ T cell or B
cell loss during HIV infection is antigen-specific, although
altered receptor repertoire have been reported in both
cases [45-47]. The γδ T cell population shows a specific
pattern of depletion in HIV disease [5], losing the critical
Vγ2-Jγ1.2+ subset that is required for pathogen and tumor
cell responses but few cells express CD4 and γδ T cells do
not support HIV replication. To the extent that antigen
stimulation is related to cell depletion, AICD may be
invoked as a mechanism for γδ T cell killing. Thus, AICD
is a mechanism that potentially links antigen stimulation
with expression of death ligand receptors, leading to spe-
cific cell depletion.
Neuronal cells that are depleted during chronic HIV infec-
tion comprise an important example of bystander deple-
tion since neuronal cells are not infected by HIV.
Neuronal cell loss has been attributed to interaction with
viral proteins such as gp120, vpr, nef, and tat, and to sol-
uble neurotoxic factors released by infected macrophages
[48]. The primary mechanism of neuronal depletion is
apoptosis via extrinsic Fas-related death receptors or
intrinsic mitochondrial pathways [48]. The fate of neuro-
nal cells during AIDS is reminiscent of the cell culture
studies previously mentioned documenting the apoptotic
destruction of uninfected cells exposed to viral proteins
[20,24,38,39,49].
Broadly acting immune stimulation during HIV or SIV
infection especially implicates the Fas death pathway
since activated T or B cells express Fas. Acute SIV infection
triggers rapid increases in Fas and FasL expression in
peripheral blood [50] as well as in thymus and other lym-

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phoid tissues [51]. During acute SIV infection, most T cells
express Fas [52] and there is abundant local expression of
FasL among intestinal lymphocytes [53]. Ablation of
intestinal lamina propria CD4+ cells during SIV infection
can be attributed in part, to the Fas/FasL mediated apop-
totic pathway but it is controversial whether apoptotic
death of uninfected cells exceeds virus-mediated killing of
infected cells. Detailed studies of viral burden and the ris-
ing proportion of SIV+ intestinal T cells argued that direct
depletion of infected cells accounts for the rapid cell loss
[52] without the need to invoke apoptotic killing of unin-
fected cells. These investigators stated that up to 60% of all
memory T cells were infected but that those cells were lost
within 4 days. They defined memory CD4+ cells as those
that were CD45RA- or CD45RA+CD95+, meaning that
Fas+ (CD95+) cells that are highly susceptible to apopto-
sis are included. Circulating lymphocytes and lym-
phocytes from lymph nodes and mucosa were sampled,
but lymphocytes were not sampled from the spleen or
liver, for example, so it is impossible to rule out margina-
tion as an explanation for lymphocyte loss. There is no
way to determine from the experimental design, whether
infected cells are being depleted faster than uninfected
cells.
Another recent publication from Mattapallil's laboratory
notes that early mucosal HIV/SIV infection (2-4 days after
inoculation) there are high level of infected CD4+ TH-17
T cells that are depleted during the course of infection
[54]. TH-17 cells are proinflammatory effectors of antivi-
ral immunity and are commonly suppressed by Treg, most
likely causing their depletion via the Fas pathway. Once
again it is not clear whether this depletion is due to migra-
tion or cell death in the category of direct depletion of
virus-infected cells or indirect depletion of uninfected
bystander cells. It is highly improbable that any one
mechanism will explain all events in AIDS pathogenesis.
Several important studies have implicated apoptosis in
uninfected cells as a major mechanism for leukocyte
depletion. Fas ligation was a probable cause of apoptosis
in T cells from SIV infected macaques [55]. However, cas-
pase-independent pathways for T cell apoptosis were
thought to drive cell death in other SIV infection studies
[56]. Cell loss, especially in gut-associated lymphoid tis-
sues, likely occurs by multiple mechanisms and we would
expect depletion of both CD4+ and CD4- cell subsets at
these loci of intense viral replication.
A recent publication describes gene expression profiles of
three stages of HIV infection: acute, chronic, and AIDS
[57]. The acute stage has high levels of FasL mRNA expres-
sion that diminishes during the chronic stage. This obser-
vation coincides with earlier published studies showing a
high level of PBMC-susceptibility to AICD during the
acute stage of SIV infection, and this susceptibility sub-
sides during the chronic stage [58].
Curiously, infected cells are more resistant to apoptosis
than uninfected cells [23,59]. The apoptosis resistance in
persistently infected lymphoid and monocytic cells was
shown to be independent of active viral production and
involved a modulation of the mitochondrial pathway
[60]. A consequence of this is that indirect cell killing
through apoptotic mechanisms like Fas/FasL will destroy
activated but uninfected cells while sparing the fraction of
infected cells. Such a process will tend to increase the pro-
portion of infected cells and diminish the proportion of
uninfected cells in a tissue heavily burdened by SIV or HIV
infection. Perhaps this mechanism contributes to the very
high proportions of infected cells noted in macaque intes-
tinal tissues after SIV infection [52] by removing unin-
fected cells and may help to reconcile apparent differences
between direct and indirect cell depletion models.
Substantial data have been accumulated on HIV induc-
tion of Fas or FasL, the susceptibility of PBMC from HIV
patients to apoptotic cell death and the reversal of these
conditions by HAART. When viremia was suppressed by
effective HAART, CD4 cells in PBMC had significantly
reduced apoptosis that correlated with increasing CD4
counts in blood even though lymphoid tissue FasL levels
were unchanged [61,62]. Similar findings have been
reported for HIV and SIV infections. However, the prob-
lem remains that susceptibility to apoptosis that is meas-
ured in vitro rises and falls with changes in viremia,
making it difficult to separate direct from indirect killing
mechanisms in terms of their contribution to disease pro-
gression. In murine systems, these problems are addressed
readily by the use of knock-out mutations eliminating Fas,
FasL or both molecules. For AIDS-related questions, the
initial studies are done most appropriately in nonhuman
primates using SIV or SHIV to establish persistent infec-
tion and then applying interventions to modulate the Fas/
FasL pathway.
Using a recombinant humanized anti-FasL monoclonal
antibody [63] we developed a protocol for treating rhesus
macaques to interrupt the Fas/FasL system. Animals
received a total of 5 injections given once per week of anti-
FasL beginning 2 weeks before SIV-inoculation and finish-
ing 2 weeks after virus inoculation. The pilot study
showed no effect of anti-FasL on plasma viremia, but
found increased virus-specific immunity and delayed dis-
ease among treated animals [64]. A larger study using
immunized macaques indicated that anti-FasL treatment
preserved memory T cells and antigen responses after SIV
infection, but was associated with decreased levels of Treg
cells [65]. In the two interventional studies, anti-FasL
delivered before and during the acute infection had a

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durable effect on immune status and disease many
months after treatment stopped. These changes were not
reflected in vRNA levels that were similar among treat-
ment and control groups, but were detected in the compo-
sition and activity of other T cell populations. This means
that uninfected effector cells must have been preserved by
the treatment.
Another indication of the importance for indirect cell kill-
ing comes from studies of "naturally-infected" macaques
i.e., sooty mangabeys infected with SIVsmm that maintain
plasma viremia, do not show high susceptibility to in vitro
apoptosis among PBMC and remain disease-free [66].
Here, apoptosis and immune activation were low and ani-
mals did not develop disease despite chronic viremia. The
observation of preserved CD4 T lymphocytes with regen-
erative capacity in spite of high levels of viremia, suggests
that virus alone cannot explain the massive loss of CD4
lymphocytes that occurs in pathogenic SIV and HIV infec-
tions [67] and indirect cell killing mechanisms may be
important.
We reported [68] that half of the 56 macaques tested
showed high levels of MHC-unrestricted cytolysis prior to
SIV inoculation and that animals from this group were all
rapid progressors. Subsequently, we found that MHC-
unrestricted cytolysis involves the Fas/FasL pathway [64]
and rapid progressors had higher baseline levels of cell
killing through this pathway. In corroboration of these
findings, high levels of lymph node cell apoptosis during
acute SIV infection also predict that animals will become
rapid progressors [69].
Reports showing lower levels of indirect cell killing/apop-
tosis among naturally-infected macaques despite similar
viremia [64,67,70], the correlation between apoptosis
and rapid progression [69] and intervention studies show-
ing disease-sparing after brief treatment with monoclonal
antibody against FasL [64,65]. These reports attest to
strong relationships between apoptotic killing of unin-
fected cells and pathogenesis. The in vitro and tissue stud-
ies on HIV agree with these findings. Disagreements
remain about the mechanisms for cell death, the roles for
viral proteins and the relative importance of Fas versus
non-Fas death pathways. In addition to direct infection
and cell destruction by viral cytopathic effects or antigen-
specific cytotoxicity, indirect cell killing mechanisms have
broad impact on host immune capacity and are important
in the pathogenesis of HIV/AIDS.
Significance of indirect cell killing for HIV vaccine/
therapeutics design
Knowing the role for uninfected bystander cell killing in
disease, it remains a challenge to apply this information
to treating HIV in man. An anti-Fas treatment during acute
infection would be difficult to deliver. Since it may not
modulate vRNA, the main marker for HIV therapy,
lengthy studies would be needed to document treatment
effects. The use of anti-retroviral therapy during this time
would obscure the impact of blocking FasL. A combina-
tion of anti-FasL plus active immunization during inter-
rupted HAART is conceivable, but unlikely to be pursued
given the treatment choices and durable virus suppression
achievable with available drugs. The most likely applica-
tion of this knowledge may come in the evaluation of pro-
phylactic or therapeutic vaccines. If we define viral
proteins that are responsible for inducing bystander cell
killing or identify particular motifs within these proteins
that trigger killing mechanisms, vaccine-elicited antibod-
ies may block these effects and preserve immunity even if
vRNA levels appear unchanged. For example, gp41 pep-
tide was shown to induce NKp44L on CD4+ T cells during
HIV infection, making them highly susceptible to NK
lysis. Immunizing against this peptide reduced ligand
expression on CD4 lymphocytes and decreased apoptosis
rates in SHIV-infected macaques [71] thereby indicating
its role in promoting bystander cell killing. Careful evalu-
ation of cellular apoptosis and tissue levels of Fas or FasL
will be important to evaluate vaccine trials. FasL bearing
CD4 lymphocytes were shown recently to kill antigen
expressing cells following plasmid immunization, result-
ing in both lower antigen expression and subsequent
decreases in antigen-specific cellular immunity [72]. Such
mechanisms may impact other biological therapies in
HIV/AIDS and appropriate inhibitors of Fas/FasL may be
required to properly implement new interventions.
Conclusion
HIV infection depletes a broad profile of leukocyte subsets
including many that do not express CD4 and are not sus-
ceptible to direct virus infection. Models for the loss of
non-CD4+ subsets including activation-induced cell
death, explain the antigen-specific pattern of cell loss and
frequently invoke Fas/FasL interactions as a principal
mediator of cell death. The role for FasL was tested in the
SIV/macaque model for AIDS using recombinant human-
ized monoclonal antibodies to neutralize this cell death
ligand. Treated macaques modulated SIV disease and
increased virus-specific immunity without consistent
reduction in vRNA burden. The status of animals treated
with anti-FasL was similar to natural SIVsmm infection of
sooty mangabeys that have no overt disease despite high
chronic viremia and show minimal apoptosis and
immune hyperactivation.
The Fas/FasL death pathway is an important component
of SIV or HIV disease. Whether this pathway for cell death
is driven by viral proteins, virus particles or induced host
factors remains unknown, although compelling examples
of each exist in literature. The capacity to control activa-

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tion of this cell death pathway may be important for the
ultimate success of preventive vaccine strategies. The mag-
nitude and duration of protective immunity, once viral
exposure has occurred, are key to controlling infection
and disease. Cell death pathways like Fas/FasL may be
exploited by HIV to reduce the level of protective immu-
nity and to establish a persistent infection with progress-
ing disease. There is a continuing need to understand
these mechanisms and develop effective interventions to
improve the impact of antiretroviral therapy.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
PB wrote the manuscript and approved its content. CDP
wrote the manuscript and approved its content. MSS
wrote the manuscript and approved its content.
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