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(Journal of Leukocyte Biology. 2006;80:984-993.)
© 2006 by Society for Leukocyte Biology

Type I interferon production in HIV-infected patients

Anne Hosmalin*,{dagger},{ddagger},§,1 and Pierre Lebon§

* Institut Cochin, Département d'Immunologie, Paris, F-75014, France;
{dagger} INSERM U567, Paris, F-75014, France;
{ddagger} CNRS, UMR-S 8104, Paris, F-75014, France; and
§ Université Paris 5, Faculté de Médecine René Descartes, UM3, Paris, F-75014, France

1 Correspondence: Institut Cochin, Département d'Immunologie, 27, rue du Fg St. Jacques, Bat Gustave Roussy 8eme etage, Paris 75014, France. E-mail: hosmalin{at}cochin.inserm.fr


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ABSTRACT
 
Type I IFNs display multiple biological effects. They have a strong antiviral action, not only directly but also indirectly through activation of the immune system. They may also have actions that are deleterious for the host. The cells that produce type I IFN are mostly plasmacytoid dendritic cells (pDC), but this depends on the viral stimulus. The migration and distribution of pDC into lymphoid organs, driven by chemokine interactions with their ligands, determines interaction with different cell types. In HIV infection, IFN production in vitro is impaired during primary infection and later in association with opportunistic infections. Circulating pDC numbers are decreased in parallel. These parameters may be used to help assess the prognosis of the disease and to monitor treatment.

Key Words: plasmacytoid dendritic cells • innate immunity • adaptive immunity • immune therapy • vaccination • primary infection • virus


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INTRODUCTION
 
IFN can protect from viral infection [1 ]. Human type I IFNs comprise 13 subtypes of IFN-{alpha}, in addition to IFN-ß, -{omega}, -{delta}, -{tau}, and -{kappa}. These different IFNs share the same IFN-{alpha}/-ß receptor. IFN-like molecules or type III IFNs with similar properties also include limitin (mouse), IL-28A or IFN-lambda2, IL-28B or IFN-lambda3, and IL-29 or IFN-lambda1; they share a distinct class II cytokine receptor [2 3 4 5 6 ].


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ANTIVIRAL ROLE OF TYPE I IFN
 
Antiviral role of type I IFN in vivo
The antiviral role of type I IFN was shown in vivo: anti-interferon sera administration increased dramatically the susceptibility to acute challenges with lymphocytic choriomeningitis, encephalomyocarditis, herpes simplex, maloney sarcoma, vesicular stomatitis, Newcastle disease, and influenza viruses. Mice impaired for the IFN-{alpha}/-ß receptor were extremely susceptible to acute challenges with vesicular stomatitis, Semliki Forest, vaccinia, or the noncytopathic lymphocytic choriomeningitis WE strain viruses [7 8 9 10 ]. IFN-{alpha} is currently widely used to treat viral hepatitis B and C [11 ]. A transitory peak of type I IFN was found in the plasma of SIV-infected macaques around day 10 postinfection, concomitant to the peak of plasma viral load [12 ]. In draining lymph nodes from rhesus macaques infected intravaginally by SIV mac-251 or -239, elevated IFN-{alpha} mRNA levels susceptible to have an antiviral activity were found too late to prevent viral replication and dissemination, whereas pro-inflammatory cytokine mRNA susceptible to recruit potential targets for SIV were found earlier [13 , 14 ].When patients were studied during primary HIV infection, on average 2 months postinfection, type I IFN was not detectable in the plasma, at least by conventional methods in our hands [15 ].

The capacity of natural interferon producing cells (NIPC) within PBMC to produce IFN-{alpha} in vitro in response to stimulation by HSV-1 or other viral stimulation is impaired during chronic HIV infection in association with occurrence of opportunistic infections and Kaposi sarcoma [16 17 18 19 20 21 22 23 ]. Conversely, IFN-{alpha} production is higher in asymptomatic long-term survivors than in uninfected controls [24 ]. It is dramatically impaired during primary infection [15 ], adding another subclinical tendency toward immune deficiency to those that are already known during this stage, like low CD4 T cell counts [25 ]. This impairment was less pronounced after a follow-up of 1 year in untreated patients, but it was corrected in highly active antiretroviral therapy (HAART) treated patients [15 ]. This effect of HAART needs to be assessed in a larger cohort of patients. Primary infection is the stage in which a balance is set between viral replication and immune responses, depending on viral strain characteristics and host genetic factors [26 ]. The future evolution of these patients will tell whether the loss of IFN production in vitro during this stage is detrimental for the outcome of the disease. In chronically infected, progressive patients, reconstitution of IFN-{alpha} production, associated with protection from recurrent or opportunistic infection, was obtained by HAART [27 ]. Interestingly, this restoration occurred earlier than that of CD4 T cell counts [28 ]. Overall, a correlation seems to appear between high IFN-{alpha} production capacities and low HIV viral loads and high CD4 cell counts and lack of opportunistic infections [24 , 27 , 29 ]. These correlations can be related to the direct antiviral role of IFN-{alpha} or -ß on HIV-1 infected cells in different models using severe combined immunodeficient mice [30 31 32 33 ].

Type I IFN activation and mechanisms of action
HIV-1 stimulates plasmacytoid dendritic cells (pDC) through TLR7 [34 ] and apparently CD4 [35 ]. Induction of type I IFN by viruses can also be mediated through binding of viral RNA or DNA to TLR3, -8, or -9. Induction of type I IFN through TLR7, -8, and -9 is mediated by the adaptor molecule myeloid differentiation primary response protein 88 (MyD88), interferon regulatory factor (IRF)-7 and finally NF-{kappa}B activation. Induction of type I IFN by viruses can also be mediated through TLR-independent pathways, involving cytoplasmic sensors, like the retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene 5 (MDA5). This leads to IRF3 activation and finally NF-{kappa}B activation [36 ].

Type I IFNs induce or enhance the expression of many genes [37 ] through a cell transmembrane receptor composed of two subunits, IFNAR1 and IFNAR2. Binding of the receptors leads to a cascade of phosphorylation of kinases, JAK1 and Tyk2, and subsequently to the tyrosine phosphorylation of signal transducers and activators of STAT1 and STAT2. These activated STAT form a complex with IRF9, ISGF3, which translocates to the nucleus and binds to DNA sequences of IFN-stimulated genes (ISG) containing IFN-stimulated response elements (ISRE). More than 100 ISG are transcribed, and their products are involved in the different properties of interferons such as antiviral, antiproliferative, apoptosis, and immunomodulatory properties. The main ISG encode for the protein kinase stimulated by ds RNA (PKR), the 2’-5'oligoadenylate synthetases (OAS), and the myxovirus resistance GTPase (MX), but also the ISG 20. PKR is a serine threonine kinase, which, in the presence of dsRNA, phosphorylates substrates, among which the subunit {alpha} of the eukaryotic initiation factor 2-{alpha} (eIF2{alpha}) stops protein translation. OAS, in the presence of dsRNA, synthesizes 2'5' oligoadenylates, which activate endogenous cytoplasmic RNase L (RNase L) and lead to the degradation of viral and cellular mRNA. PKR and OAS are also involved in cellular apoptosis. MxA, from the dynamin family, inhibits the RNA polymerase of influenza viruses and more generally appears to detect viral infection by sensing nucleocapsid-like structures and trapping them into specific subcellular compartments to make them unavailable for the generation of new virus particles [36 , 38 ].

The antiviral activity of type I IFN can also be mediated by different actors of the immune system [3 , 36 ]. Indeed, type I interferons amplify their own expression through induction of IRF-7 [39 ] and through accumulation of plasmacytoid dendritic cells (pDC) [40 ]. They activate the lytic potential and proliferation of NK and {gamma}{delta} T cells and NO synthesis by macrophages. They also enhance lysis of infected cells by cytotoxic T cells or T helper type 1 cells, as well as IFN-{gamma} production by T lymphocytes [41 ]. During LCMV infection, the activation of CD8 T cells depends on their ability to respond to type I IFN [42 43 44 45 ]. Type I IFN increase class I MHC expression on all cell types, perhaps counteracting the effect of HIV Nef [46 , 47 ], and thus potentially increasing recognition and lysis by specific CD8+ T lymphocytes. In addition, cross-presentation by DC is enhanced through the action of virally-induced type I IFN [48 ], and this presentation pathway is probably crucial so as to enhance viral antigen presentation while avoiding autoimmune recognition [49 50 51 52 53 ]. Conversely, high levels of type I IFN inhibit IL-12 expression and IL-12 activation of NK cell IFN-{gamma} production [41 ]. STAT1 has a critical role in many of these effects [36 ].

Role of type I IFN on HIV replication in vitro
Type I IFNs inhibit the replication of HIV-1 [54 55 56 ], especially when cells are pretreated by IFN before infection; this effect acts on the integration and the reverse transcriptase activity of the virus [57 , 58 ]. When cells are treated by IFN after infection, the antiviral effect is less pronounced [57 , 59 ]. IFN is supposed to block the association of RNAs to polyribosomes and inhibit viral particle assembly through posttranslational modification of viral proteins. A weak but continuous production of IFN-ß by the PBMC of healthy donors or of HIV+ patients, after transduction by a retroviral vector encoding for IFN-ß, protects them from HIV-1 infection; blockade of viral infection using this mechanism seems to occur at a very early stage of HIV-1 replication [60 ]. HIV-1 induces directly the synthesis of the MxA gene [61 ] and of the 2-5A synthetase [62 ] but not of other interferon-inducible genes [61 ]. The direct induction of the 2-5A synthetase makes HIV-infected cells resistant to another viral infection, particularly vesicular stomatitis virus (VSV) infection and may play a role in the control of HIV protein synthesis. Indeed in vitro, HIV-1 production is strongly inhibited by transfection of the 2-5A synthetase gene [63 ]. 2’-5' Oligoadenylates and analogs can inhibit the reverse transcriptase activity of HIV-1 [62 ].

Viral escape to the effects of type I IFN
Viruses have the genetic capacity to downmodulate IFN production or inhibit responses to IFN [36 , 64 ]. Inhibition of IFN induction in infected cells occurs through viral proteins that block the activation of IRF-3 after interaction with ds RNA, preventing the activation through TLR3 or TLR-independent sensors such as RIG-I and MDA 5 [36 , 64 ]. Some strains of RSV and measles inhibit IFN production by pDCs, although the molecular mechanisms involved are unknown [64 ]. Inhibition of the response of infected cells to IFN has recently been demonstrated in the case of cytomegaloviruses and involves specific targeting and degradation of STAT-2 [64 ]. No evident inhibition of IFN induction by HIV was reported. A sequence in the 5' HIV-1 long terminal repeat (LTR) contains a binding site for transcription factors of the IRF family. IRF-1 is produced early upon virus entry in CD4+ T cells and before expression of Tat. IRF-1 activates HIV-1 long terminal repeat (LTR) transcription and also cooperates with Tat in amplifying virus gene transcription and replication. IRF-1 is mostly expressed under the action of IFN-{gamma} in activated T cells and not under the action of type 1 IFN [65 ]. The HIV-1 transactivating response (TAR) RNA can activate the 2-5A synthetase and PKR [66 ]. However, HIV induces the expression of the RNase L inhibitor, which antagonizes the binding of 2’-5'A oligoadenylates to RNase L [67 ]. PKR can be activated by HIV through binding to the ds RNA region TAR of the LTR [68 ]. The transactivating protein Tat and the cellular TAR RNA binding protein (TRBP) also bind to TAR and to PKR and behave as inhibitors of the autophosphorylation of PKR during viral infection, therefore inhibiting its action on the eIF2{alpha} substrate and on protein synthesis. TRBP is part of a Dicer complex and is required for RNA interference; it is perhaps diverted by HIV-1 [69 70 71 ]. Moreover, PKR can phosphorylate HIV Tat and enhance its capacity to transactivate the LTR [72 ]. TAR and Tat, therefore, participate actively in viral escape to the effects of type I IFN.


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ADVERSE ROLES OF TYPE I IFN IN VIRAL INFECTION
 
All the effector mechanisms of the immune system that reduce viral replication have mirroring adverse effects on the host. Type I and type II IFNs induce a cytotoxic activity in antigen presenting cells. HIV itself, like other viruses, induces a cytotoxic activity in monocytes [73 ], DC [74 ], and CD4 T cells themselves [35 ] against infected CD4 T lymphocytes but also against uninfected cells. TRAIL mediates at least in part the cytotoxicity of monocytes, in a type I IFN-dependent way [75 ]. In vitro, HIV-1 gp120 induces in CD4 T lymphocytes both sensitivity to TRAIL directly and TRAIL expression indirectly, through the stimulation of CD4, which induces type I IFN secretion by pDC [35 ]. These cytotoxic mechanisms, as well as those stimulated in NK cells [76 ] or bystander T cells, can be responsible for the high susceptibility to apoptosis of uninfected CD4 T cells that are found in HIV-infected patients [77 ]. Indeed, TRAIL neutralization in HIV-1 infected Hu-PBL-NOD-SCID mice inhibits human CD4 T cell apoptosis induced by HIV-1 infection [78 ]. Moreover, soluble TRAIL is found in the plasma of HIV-1 infected patients and is decreased by HAART in correlation with viral load [75 ]. In addition, in the SCID-hu Thy/liv mouse model and in thymus organ cultures, HIV-1 induces pDC to secrete type I IFN, which in turn up-regulates MHC class I molecule expression on most thymocytes [79 ]. This may lead to thymic selection of dysfunctional CD8+ T lymphocytes [80 ].

Early work has suggested a deleterious effect of high concentrations of IFN-{alpha} (i.e., inhibition of T cell proliferation, inhibition of chemokine production) and even proposed immunization against this cytokine as a therapeutic approach against AIDS [81 , 82 ]. A dichotomy may exist between positive and negative effects of IFN-{alpha} in the early vs. late stages of the disease. IFN-{alpha} has been shown to be potentially beneficial on HIV viral loads during early stages of infection, but not later [83 ]. In chronic lymphocytic choriomeningitis virus (LCMV) infection, administration of anti-IFN serum inhibits pathogenesis [84 ]. During acute LCMV infection in mice, while type I IFN activate effector CD8 T cell responses, they also prevent renewal of the DCs [85 ] and drive the early attrition of CD8 T cells [86 , 87 ]. Besides their effects in viral infections, type I IFN can enhance autoimmunity; particularly, the high levels of type I IFN found in the sera of systemic lupus erythematosus induce differentiation of monocytes into DC and probably exacerbate the pathogenesis of the disease [88 , 89 ]. How the outcome of the balance between negative and positive effects of IFN on antiviral immune responses is regulated needs further investigation but it may depend on the kinetics, levels and anatomical location of IFN release.


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PLASMACYTOID DENDRITIC CELLS AND OTHER CELL TYPES RESPONSIBLE FOR TYPE I IFN PRODUCTION
 
The major human peripheral blood mononuclear cell subset that was responsible for the production in vitro of IFN-{alpha} in response to influenza, Sendai, and Newcastle disease viruses was first identified as an HLA-DR+, DC-related population lacking the markers for other cell lineages [90 , 91 ]. This population was nonadherent and stimulated allogeneic T cell proliferation poorly [92 ]. NIPC or IPC were eventually identified as plasmacytoid dendritic cells (pDC) [93 94 95 96 97 98 99 100 101 102 103 ]. They are present in lymph nodes, tonsils, and blood with a very low frequency and they produce 100 times more type I IFN per cell than monocytes.When they are depleted in vivo, the response to mCMV infection or to CpG or oligoribonucleotide injection is abolished [103 104 105 106 ]. In some infections, like LCMV infection, pDC are not the major population responsible for the early IFN-{alpha} response [104 ]. In humans, pDC produce IFN-{alpha} [107 ] after stimulation by live or inactivated HIV [108 , 109 ]. IFN-{alpha} in turn sustains pDC survival [110 , 111 ].

pDC counts are reduced during chronic as well as primary HIV-1 infection [22 23 24 , 27 , 112 113 114 115 116 ]. A correlation with plasma viral load [24 , 27 , 112 ] and/or with peripheral CD4 T cell counts [112 , 114 , 115 , 117 ] was found in most, but not all, studies [22 , 114 ]. A correlation with lymphoproliferative responses against HIV-1 p24 was found in one study [114 ]. In a pediatric study, pDC counts were found to be lower in viremic children with a history of decreasing CD4 T cell percentages compared with children with stable CD4 T cell counts [115 ]. The pDC count defect is already found at the onset of primary infection. Strikingly, at the onset of primary HIV infection and not at later time points in HIV or HCV [118 ] infection, the correlation between pDC counts and type I IFN production is lost [15 ], indicating loss of function in some pDC.

Why are circulating pDC numbers reduced in HIV patients? A central bone marrow precursor defect may be involved, as for T lymphocyte precursors in macaques [119 , 120 ]. pDC may also be destroyed in the periphery by the virus itself. Indeed, HIV infects pDC in vitro with cytopathogenicity [108 , 121 , 122 ], and infected pDC are found in the tonsils, thymus, and blood from HIV-infected patients [123 , 124 ]. pDC may also strive less because of lower IFN production [29 ] or defective interaction with CD4 T lymphocytes [124 ]. In any case, pDC probably home to lymph nodes during HIV infection [125 126 127 ]. In the SIV infection model, many activated DC were found in lymphoid tissues in primary or asymptomatic infection, but at the stage of AIDS only few activated CD83+ DC were found in the lymph nodes [127 ]. This finding was consistent with the lower capacity to up-regulate CD83, a terminal differentiation molecule, on spleen DC from late-stage HIV-infected patients [128 ].

Thus, the mechanisms responsible for the loss of circulating DC are not identified but may reflect different mechanisms, including homing to the lymphoid organs. This homing may help induce antiviral responses on one hand and hyperactivation of the immune system on the other; whereas a lack of DC activation in the lymphoid organs may reflect the failure of the immune system in AIDS.


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HOMING AND CELL INTERACTION
 
Compartmentalization is a key to understanding all biological responses, including immune responses. Type I IFN production will occur where the pDC are driven by viral stimulation, and relevant data must be sought not only in blood but also in lymphoid organs [129 130 131 ]. Migration of DC upon stimulation is selectively driven by the successive expression of different chemokine receptors and integrins [132 ]. Human pDC express L-selectin (CD62L), which probably drives their entry into the lymph nodes through high endothelial venules in the steady state, likewise to what has been demonstrated in mice [94 , 100 , 133 , 134 ]. During bacterial- or viral-driven inflammation, the expression of CXCR3 is required for pDC migration into the lymph nodes in a CXCL9- and E-selectin-dependent manner [135 ]. Plasmacytoid DC migration into inflamed tissues or tumors can also be mediated by CXCR4 and driven by SDF-1/CXCL12 [136 ]; by ChemR23, driven by chemerin [137 ]; and by CCR1, CCR2, and CCR5, receptors for inflammatory cytokines [102 ]. Once activated, pDC express CCR7, the receptor for the chemokines MIP3ß/CCL19 and SLC or 6Ckine/CCL212, which attract them into the T cell areas of secondary lymphoid organs [138 ]. In HIV infection, homing of pDC to the lymph nodes [125 ] would be consistent with the in vitro induction by HIV-1 of CCR7 expression and of migration toward CCL19 [139 ]. In mice, pDC differ from mDC in the in vivo response to TLR ligands, in terms of pattern and type I IFN requirement for activation and migration [140 ].

Human pDC have a successive chemokine expression pattern susceptible to attract other cell populations—first effector cells (cytotoxic T and NK cells and neutrophils), then effector memory T cells, then naive T and B lymphocytes—while they mature and putatively progress toward the T cell zones of the secondary lymphoid organs [141 142 143 144 ]. In addition, the cross-talk between mDC, pDC, monocytes, T and B lymphocytes, neutrophils, and NK cells in HIV infection needs to be explored [115 , 116 , 145 146 147 ]. The relations between pDC and the regulatory T cells that hinder antiviral effector responses as well as pathogenic hyperactivation of the immune system in HIV and SIV infections [148 149 150 151 152 153 154 ] will be interesting to study, because pDC can induce regulatory T cells [155 156 157 ]. Indeed, semi-mature pDC and mDC and FoxP3+CD4+ T cells were found in the lymph nodes from untreated HIV+ patients in higher proportions than in lymph nodes from treated HIV+ patients or from HIV– patients [158 ].

CCR5- and CXCR4-using HIV-1 isolates stimulate pDC maturation (up-regulation of CD83, CCR7, costimulation molecules, migration toward CCL19) and secretion of TNF-{alpha} and IFN-{alpha} [108 , 139 , 159 ]. In contrast, in response mostly to CCR5-using HIV-1 isolates, depending on the laboratories and probably on the concentration used, mDC undergo at least partial maturation but do not secrete either type I IFN nor bioactive IL-12 p70 [159 , 160 ]. However, when pDC and mDC are co-cultured with HIV, IFN and TNF-{alpha} secretion by pDC induces mDC maturation [139 ]. Virus replication is enhanced after pDC treatment with CD40L and antibodies against IFN-{alpha}, probably because of the reduction in IFN-{alpha} production [122 , 123 ]. HIV-1 infection is transferred from pDC as well as from mDC, most efficiently toward antigen-specific CD4+ T cells [161 ].


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PREDICTIVE FACTORS DURING HIV INFECTION
 
The results described above hint that pDC counts (when they will be standardized [15 ]) and/or in vitro type I IFN production might be used as predictive factors during HIV infection, as well as in other infections. Indeed, in dengue virus infection, children who developed hemorrhagic dengue fever had an early decrease in circulating pDC levels, which was not found in those who had more benign forms of the disease [162 ]. In tuberculosis, pDC count recovery correlates with successful antibiotic treatment [163 ]. Other predictive factors in HIV infection include: baseline levels of CD4 T cell counts and plasma HIV RNA; the nadir CD4 T cell count, as well as parameters such as CD4 T cell counts; proviral DNA load in peripheral blood mononuclear cells; anti-p24 lymphoproliferative response at the time of treatment interruption; and immunologic setpoint activation, as measured by median density of CD38 molecules on CD4 and CD8 T cells [164 165 166 167 168 169 ]. However, these factors are not completely predictive of disease progression in at least three circumstances.

The first circumstance is the decision to treat by HAART early during acute or primary infection. Here, the putative restoration of type I IFN production under HAART [15 ] adds an additional argument, together with the reduction of CD8 T cell oligoclonality [170 ] and the increase in specific CD4 responses [171 , 172 ], for the use of HAART to preserve the immune system while viral populations are homogeneous, thus preventing virus spreading. However, there is limited durability [173 ], early resistance induction [169 , 174 ], long-term drug-associated toxicity, and lack of adherence [26 ].

The second circumstance is to evaluate HAART success: a recovery in pDC counts, at least partial, or in type I IFN production, was obtained in several studies but not all [22 ], through HAART during chronic infection [27 , 117 ] and probably during primary infection [15 , 175 ]. This recovery sometimes correlated with a recovery in CD4 T cell counts and/or a decrease in viral load [27 , 113 , 117 ]. pDC count recovery was earlier and more pronounced than CD4 count recovery [28 , 117 ].

The third circumstance is the counseling of patients who request HAART interruption because of side effects. One study on patients with primary HIV-1 infection with undetectable viral loads under HAART showed that pDC count recovery during HAART correlated with the ability to control spontaneously replication after treatment interruption [175 ]. This pilot study needs further confirmation in large cohorts of chronically infected patients [167 ]. pDC counts, in addition to baseline viral load and other predictive factors, might help in counseling the patients on their risk of viral replication rebound.


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Type I IFN administration or stimulation as therapy against HIV infection
 
IFN-{alpha} is currently being tested in clinical trials, particularly during primary HIV infection, where it might supplement defective production [15 ] and where promising results were obtained [176 ], as formerly in asymptomatic chronic infection [83 ]. Type I IFN production might also be stimulated by TLR ligands, if pDC can still respond. More interestingly, it might be stimulated by CpG or imiquimod analogs for antiviral protection at the mucosal level [177 178 179 180 ]. However, caution must be exercised to avoid hyperactivation of the mucosal immune system that would increase viral replication [181 ]. Finally, IFN-{alpha} is a strong adjuvant in vaccination [182 ]. It induces the differentiation of monocyte-derived DC for cell therapy [183 , 184 ]. CpG oligonucleotides can stimulate not only pDC, but also B cells [185 ], for systemic and mucosal vaccination; indeed they induce strong local T cell immune responses in the genital tract and cross-clade protection [186 , 187 ]. Therefore, type I IFN administration or stimulation may have strong potential in future immune therapies against HIV.


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CONCLUSION
 
Correlative data indicate that type I IFN produced by pDC have a role in the control of HIV infection, although pathogenicity may also be induced [188 189 190 191 192 193 194 195 196 ]. The role of homing into lymphoid organs and of interactions with other cell types still needs intensive studying during this infection. Plasmacytoid DC counts and/or of type I IFN production tests in vitro might be used as predictive factors during HIV infection, to evaluate HAART success or to counsel patients who want to interrupt HAART about their risk of viral rebound. Immune therapy and vaccination can use either IFN-{alpha} itself or its induction by TLR ligands to obtain better viral replication control and stimulation of antigen-specific immune responses. The mechanisms of viral escape to the effects of type I IFN need to be understood further to lead to better targeted therapies.


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ACKNOWLEDGEMENTS
 
The authors thank Michaela Müller-Trutwin (Pasteur Institute, Paris), Stéphanie Louis, Michelina Nascimbeni, Concepción Marañón, Miriam Lichtner, Sandrine Kahi, Leyla Develioglu, Isabelle Kamga, Aurélie Teissonnière, Ludovic Fery, Laurent Chorro, Seckou Diocou, Guillaume Hoeffel, and Jérôme Pacanowski (all from the Antigen Presentation by Dendritic Cell Team, Cochin Institute, Paris) and Martine Sinet (INSERM E0109, Le Kremlin-Bicêtre, France), as well as all members of the Dendritic Cells Workgroup from the Agence Nationale de la Recherche contre le SIDA et les hépatites virales (ANRS, Actions coordonnées 19 and 31), for stimulating discussions; and Marc Dalod (Centre d’Immunologie de Marseille, Luminy, Marseille, France), Rémi Cheynier and Stéphanie Beq (both from the Pasteur Institute, Paris) for greatly improving the manuscript. Work sponsored by the ANRS and Sidaction.

Received March 4, 2006; revised May 3, 2006; accepted July 5, 2006.


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