Progressive loss of CD4+ T cells is a hallmark of HIV infection, but its mechanism remains poorly understood. In this issue of Blood, Stary and colleagues show that CD4+ T cells from viremic patients undergo apoptosis in response to death-inducing signals generated by TRAIL expressed on the surface of plasmacytoid dendritic cells.

HIV infection is characterized by progressive depletion of both infected and uninfected CD4+ T cells, which leads to the development of AIDS. Increased apoptosis is regarded as the primary cause of HIV-induced CD4+ T-cell loss, and multiple mechanisms have been brought forward to explain the immunopathogenesis of this apoptotic process.1  Whereas direct cytopathic effects affect the survival of infected CD4+ T cells, indirect mechanisms, such as activation-induced cell death, are likely to play a major role in the elimination of uninfected CD4+ T cells.2,3  Activation-induced cell death may involve an augmented responsiveness of CD4+ T cells to various inhibitory and death-inducing ligands such as PD-1L, CTLA-4, and FasL.4,5  Recent evidence points to an additional contribution of TNF-related apoptosis-inducing ligand (TRAIL).6 

Soluble TRAIL is elevated in the plasma of HIV-infected patients and CD4+ T cells from these patients are more sensitive to TRAIL-induced death signals. A possible source of TRAIL is plasmacytoid dendritic cells (pDCs), a professional interferon (IFN)–producing dendritic cell subset that usually plays a key role in antiviral immunity.6  In infected patients, pDCs release massive amounts of IFN-α in response to HIV, but cannot achieve the control of the infection. Rather, in vitro studies indicate that pDCs up-regulate TRAIL expression in response to HIV-induced IFN-α and thereafter acquire cytotoxic activity on bystander CD4+ T cells.6  Of note, the up-regulation of TRAIL expression by HIV-exposed pDCs is highly dependent on sensing viral single-stranded RNA through the intracellular sensor Toll-like receptor 7 (TLR7).6 

In this issue, Stary and colleagues sought to extend these in vitro findings to an in vivo setting and explored the presence of TRAIL-expressing killer pDCs in HIV-infected persons.7  They found that pDCs and CD4+ T cells from infected patients expressed TRAIL and its cognate receptor TRAIL-R1, respectively. TRAIL expression directly correlated with viremia, whereas there was an inverse correlation between TRAIL-expressing pDCs and CD4+ T cells. Remarkably, TRAIL-expressing pDCs were proximal to apoptotic CD4+ T cells in tissue sections from systemic lymph nodes. In vitro, pDCs from viremic patients, but not pDCs from aviremic or noninfected persons, triggered death of activated CD4+ T cells through a mechanism that required TRAIL and to a lesser extent IFN-α. This study clearly shows that TRAIL-expressing killer pDCs are present in vivo and likely play an important role in the loss of CD4+ T cells.

Stary and colleagues' findings also raise intriguing questions. For instance, it is remarkable that, although expressing comparable or higher surface levels of TRAIL, monocytes and myeloid dendritic cells (mDCs) from viremic patients do not have cytotoxic activity on activated CD4+ T cells. One possible interpretation is that monocytes and mDCs lack surface molecules with immunoregulatory activity required for TRAIL to deliver optimal cytotoxic signals to targeted CD4+ T cells. Another interesting aspect is the up-regulation of surface TRAIL-R1 but not TRAIL-R2, TRAIL-R3, and TRAIL-R4 by CD4+ T cells from viremic patients.7  What is the mechanism by which HIV selectively augments TRAIL-R1 expression? And why does TRAIL-R1 up-regulation occur on CD4+ T cells but not on other cell types such as monocytes? One possibility is that monocytes express constitutively high levels of TRAIL and are not susceptible to further up-regulation.

At any rate, the present work clearly suggests that HIV alters the responsiveness of CD4+ T cells to TRAIL-induced signals by perturbing the normal balance between death-inducing (R1 and R2) and regulatory (R3 and R4) TRAIL receptors on the surface of CD4+ T cells.7  Yet, the mechanism behind the establishment of this receptor imbalance remains puzzling. Furthermore, the expression of TRAIL and TRAIL-R1 by intestinal pDCs and CD4+ T cells, respectively, remains unknown. In both HIV-infected humans and SIV-infected macaques, CD4+ T cells undergo early and massive death in the intestinal mucosa.1,8,9  This mucosal catastrophe causes systemic leakage of intestinal antigens, which in turn promotes dysregulated systemic immune activation.1,2  Thus, a top future priority will be to address the presence, phenotype, and function of TRAIL-expressing killer pDCs and TRAIL-R1 CD4+ T cells in the intestinal mucosa of acutely and chronically infected HIV patients.

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

REFERENCES

1
Douek
 
DC
Roederer
 
M
Koup
 
RA
Emerging concepts in the immunopathogenesis of AIDS.
Annu Rev Med
2009
, vol. 
60
 (pg. 
471
-
484
)
2
Brenchley
 
JM
Price
 
DA
Schacker
 
TW
, et al. 
Microbial translocation is a cause of systemic immune activation in chronic HIV infection.
Nat Med
2006
, vol. 
12
 
12
(pg. 
1365
-
1371
)
3
Sodora
 
DL
Allan
 
JS
Apetrei
 
C
, et al. 
Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts.
Nat Med
2009
, vol. 
15
 
8
(pg. 
861
-
865
)
4
Fluur
 
C
De Milito
 
A
Fry
 
TJ
, et al. 
Potential role for IL-7 in Fas-mediated T cell apoptosis during HIV infection.
J Immunol
2007
, vol. 
178
 
8
(pg. 
5340
-
5350
)
5
Kaufmann
 
DE
Walker
 
BD
PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention.
J Immunol
2009
, vol. 
182
 
10
(pg. 
5891
-
5897
)
6
Hardy
 
AW
Graham
 
DR
Shearer
 
GM
Herbeuval
 
JP
HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFN-alpha.
Proc Natl Acad Sci U S A
2007
, vol. 
104
 
44
(pg. 
17453
-
17458
)
7
Stary
 
G
Klein
 
I
Kohlhofer
 
S
, et al. 
Plasmacytoid dendritic cells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patients.
Blood
2009
, vol. 
114
 
18
(pg. 
3854
-
3863
)
8
Veazey
 
RS
DeMaria
 
M
Chalifoux
 
LV
, et al. 
Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection.
Science
1998
, vol. 
280
 
5362
(pg. 
427
-
431
)
9
Brenchley
 
JM
Schacker
 
TW
Ruff
 
LE
, et al. 
CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract.
J Exp Med
2004
, vol. 
200
 
6
(pg. 
749
-
759
)