It is widely believed that HTLV-1 enters cells in a manner similar to that of other retroviruses including the well-studied HIV-1. HTLV-1 infection of target cells is believed to require the two virally encoded envelope glycoproteins (Env), the surface subunit (SU) gp46 and the transmembrane subunit (TM) gp21, generated from the cleavage of a polyprecursor (gp61) in the Golgi apparatus 8 . As has previously been shown for the SU (gp120) and TM (gp41) of HIV-1 9 , the SU and TM of HTLV-1 are believed to function successively during the entry process. The gp46/SU, which does not contain a transmembrane region, is tethered to the cell surface through interactions with the gp21, and is involved in direct interactions with the cell surface receptors. Like the HIV-1 gp41, the gp21 of HTLV-1 contains a transmembrane region and a N-terminal hydrophobic fusion peptide that plays a crucial role in the fusion of the viral and cellular membrane during the final steps of HTLV-1 entry 10 11 . Earlier work showed that both the presence of certain mutations in the env gene and antibodies directed against gp46/SU partially or totally abolished HTLV-1 infection in vitro 12 13 . Infection was also reduced by exposure of target cells to a soluble recombinant protein containing soluble full-length SU, indicating that it could compete with the SU on the surface of the virus for the binding to yet unknown molecules at the cell surface 14 . Altogether, these experiments confirmed that the two Env glycoproteins play crucial role during HTLV-1 entry and indicated that, as for other retroviruses, this process depends on the expression of cellular receptor(s) at the surface of target cells. Interaction between gp46/SU and its cellular receptor(s) induces a conformational change that unmasks the fusion domain within the TM, allowing fusion between the viral and cellular membranes 15 .

Experimental demonstration that specific molecules function as a virus receptor often is a challenge 16 . This is illustrated by the fact that there are a great number of viruses, including certain retroviruses, for which no receptors have been identified. In addition, for certain viruses, it has been shown that more than one molecule may function as entry receptors. Some viruses use different receptors on different cell types, while others require the presence of both molecules on a given target cell to facilitate entry. In the case of HTLV-1, several peculiar features of the virus and its receptor(s) have considerably hampered research. First, free HTLV-1 virions are poorly infectious for most cell types and efficient infection of T cells requires a cellular contact 17 . Secondly, infected lymphocytes produce a limited amount of viral particles, amongst which 1 out of 10⁵ are actually infectious 18 . Lastly, the fact that molecules capable of binding and allowing HTLV-1 entry are expressed on nearly all available established cell lines has prevented the use of classical strategies such as the screening of a cDNA bank in receptor-negative cells.

Virus tropism, the ability of a virus to replicate in particular cells, depends on interactions between viral components and cellular factors at each step of the viral cycle from the initial entry to the ultimate release and transmission of virions. Here, we will focus on the cellular factors that allow HTLV-1 entry, which is determined by the distribution of the receptor molecule(s).

Although its ubiquitous nature considerably complicated its identification, several properties of the HTLV-1 receptor, in particular its expression pattern on primary cells, were characterized using indirect approaches. In 2003, two independent groups generated soluble SU proteins by generating recombinant SU-Ig-Fc fusion proteins containing either the full-length SU 22 or the N-terminal portion of SU (Receptor Binding Domain, see section 3.1) 40 . Their findings showed that the receptor was not present at the surface of resting CD4⁺ T cells but was rapidly upregulated upon activation. The receptor was also absent on naive T cells isolated from cord blood but could similarly be upregulated after stimulation by interleukin-7. Finally, it was reported that the SU-Fc could inhibit a mixed lymphocyte reaction 22 . This last property suggested that one of the molecules involved in the HTLV-1 receptor was a member of the immune synapse. Surface expression of the receptor was found to be not solely dependent on T cell activation. It could also be upregulated upon exposure to TGF-β, a potent negative regulator of the immune response 41 . The pattern of surface expression following exposure to TGF-β, as determined from binding of the soluble SU, was very similar to that observed after activation with PHA/IL-2, although with slightly slower kinetics. It depended on the TGF-β classical signalling pathway as it was abolished in the presence of Smad inhibitors. TGF-β not only triggered receptor expression at the cell surface but also increased the titer of lentiviral vectors pseudotyped with HTLV-1 Env in vitro, demonstrating that molecules capable of both binding and fusion were expressed 41 . TGF-β-treated T cells remained in a resting state, demonstrating that T cell activation per se was not required for receptor expression. This might constitute a strategy for the virus to increase its infectivity 42 as HTLV-1-infected CD4⁺ T cells are known to abundantly secrete TGF-β.

Over the years, several molecules were proposed as candidate HTLV-1 receptors. It was proposed that the HTLV-1 receptor is encoded by chromosome 17q23.2-23.5, which was questioned in later studies 38 43 . Most of the candidate receptors were identified as antigens against which specific antibodies could inhibit Env-mediated cell fusion 43 44 45 46 . It was later shown that some antibodies may inhibit this process through non-specific protein crowding, rather than directly competing for binding, making the results difficult to interpret 47 . Adhesion molecules, which strengthen and stabilize the cell-to-cell contact, can also augment cell fusion in a non-specific manner 48 . Most importantly, none of these molecules had demonstrated one fundamental property of the receptor, that is, the ability to bind the HTLV-1 SU. In contrast, as it could bind the 197-216 region of the SU, the heat shock cognate protein HSC70 was proposed as a receptor 49 . However, later studies showed that, while HSC70 modulates HTLV-1-induced syncytia formation, it was dispensable for HTLV-1 infection 50 , ruling out that this molecule was an entry receptor. The tetraspanin CD82 was also shown to bind the HTLV-1 Env protein but was excluded as an entry receptor on the fact that its overexpression inhibited, rather than enhanced, syncytia formation and HTLV-1 transmission 51 .

It was not until 2003 that work from Sitbon and Battini's laboratory identified a candidate that matched all the prerequisites to be a HTLV-1 receptor 2 . Furthermore, this group determined that this molecule interacted with both HTLV-1 and the related virus HTLV-2, believed to use a common entry receptor. After noticing that overexpression of either the HTLV-1 or HTLV-2 Env in cells prevented acidification of the culture medium, the authors hypothesized that the HTLV-1 receptor might be related to the proton-dependent lactate production. Based on their previous identification of the receptor binding domain (RBD) of HTLV-1 or HTLV-2, these authors further reported that the overexpression of either the H1-RBD (first 215 residues of the HTLV-1 SU) or the H2-RBD (178 residues of the HTLV-2) 40 52 53 altered glucose metabolism, which was consistent with the frequent use of metabolite transporters as entry receptors by retroviruses 16 . They focused on the ubiquitous glucose transporter 1 (GLUT1), which is upregulated in activated T cells, and found that overexpression of GLUT-1 in cells increased the level of binding of both the H1- or H2-RBD. In the absence of available GLUT1-negative cell lines, they used different approaches, in particular small interfering RNA (siRNA), to demonstrate that GLUT1 played a role in HTLV-1 entry. Down regulation of GLUT1 by siRNA both inhibited the binding of the H1- or H2-RBD and infection by retroviral vectors pseudotyped with either the HTLV-1 or -2 Env. Both were restored after cotransfection of GLUT1 but not GLUT3, a related glucose transporter. They later extended their findings by that identifying a specific residue in the HTLV-1 SU (Y114) of the H1-RBD that appeared critical to the interaction 52 , which interacted with the 6^th extracellular loop (ECL6) of GLUT1 54 .

Further data from other laboratories confirmed that GLUT1 plays a role in HTLV-1 entry. TGF-β, which had previously been shown to upregulate molecules capable of binding HTLV SU, induces GLUT1 at the surface of T cells 41 . Overexpression of GLUT1 in the bovine MDBK cell line, which is relatively resistant to HTLV-1 infection, increases two-fold the infectious titre of a HTLV-1 Env pseudotyped lentivirus vector 55 . A similar result was obtained in the NIH3T3 cell line, which is also poorly susceptible to infection by HTLV-1 pseudotyped vectors 1 . Antibodies raised against GLUT1 ECL1 (GLUT-IgY) block both Env-mediated fusion and infection. Furthermore, blocking interactions with GLUT1 ECL1, either by replacing the GLUT1 ECL1 with that of GLUT3, or by blocking with ECL1-derived peptides, inhibits HTLV-1-induced cell fusion, suggesting that ECL1 is critical for the receptor activity of GLUT1 1 . This confirmed earlier data showing that, although only the ECL6 was required for the binding of the H1-RBD to GLUT1, infection by HTLV-2-pseudotyped viruses also required residues located in ECL1 and ECL5 of this molecule 54 . This indicates that GLUT1 contains multiple functional determinants: those required for interactions with the RBD portion of the HTLV SU, located in ECL6, and others required for interactions of the entire Env, consisting of the full-length SU protein and the TM protein, located in ECL1 and ECL5. Thus, current data indicate that GLUT1 plays a role in HTLV-1 entry.

However, several studies suggested that the identification of GLUT1 was not the end of the story. The astrocytoma/glioblastoma U87 cell line, which expresses very low levels of GLUT-1 due to a transdominant negative mutation in one of the alleles of GLUT1 (GLUT-1 D5), is easily infected by HTLV-pseudotyped viruses 3 56 . Moreover, blocking interactions with GLUT1 by either siRNA-mediated down-regulation, or by incubating with GLUT-IgY blocking antibodies, has no effect on the level of infection with HTLV-Env-pseudotyped virus or HTLV Env-mediated fusion or infection in this cell line, suggesting that molecules other than GLUT1 might be involved 56 . An earlier study reported that overexpression of GLUT1 in a cell line (COS-7) increased cell-cell transmission, but did not increase the level of binding of the SU-Fc protein 57 . Similarly, more recent studies using clones of the U87 cell line that express different levels of GLUT1 have observed that the level of cell surface GLUT1 correlates with the titer of HTLV-1 Env pseudotyped viruses, but not with SU-Fc binding 58 . All these findings suggested that molecules other than GLUT1 are also involved in HTLV-1 entry, especially at the binding step.

Molecules of the HSPG family are composed of a core protein associated with one or more sulphated polysaccharide side chains called heparan sulfate glycosaminoglycans. Because of their highly negative charge, HSPG bind through electrostatic interactions to a plethora of proteins including growth factors and their receptors, chemokines, cytokines and numerous proteins of the extracellular matrix or the plasma, thereby playing a major role in mammalian physiology 59 . Pathogens, including many viruses, have been shown to hijack HSPG 60 . HSPG generally enhance infection by facilitating the attachment of the particles on target cells and/or allowing their clustering at the cell surface before specific interactions between viral proteins and their receptors that lead to fusion. For example, prior to interaction of the HIV SU (gp120) with CD4, the initial attachment of the virus to target cells involves specific interactions between gp120 and cellular HSPG 61 . Rarely, a specific role of HSPG in the fusion process has been observed, in particular with Herpes Simplex virus 62 .

The important role of HSPG in mediating attachment and entry has also been demonstrated for HTLV-1. Enzymatic removal of HSPG or inhibition of electrostatic interactions with dextran sulfate decreases the binding of full length soluble SU, Env-mediated syncytium formation and infection with pseudotyped viruses 7 . These initial findings, obtained in non-lymphoid cell lines expressing high levels of HSPG, were later confirmed in CD4⁺ T cells in Jones and Ruscetti's laboratory 6 . Although HSPG are barely detectable on quiescent T cells 63 , they are rapidly upregulated upon activation. In CD4⁺ T cells, HSPG augment both the binding of the SU-Fc and the infectious titer of pseudotyped viruses 6 . The importance of HSPG was suggested by studies showing that removing HSPG reduced binding and entry of HTLV-1 virus into CD4+ T cells and dendritic cells 4 6 and significantly reduced the level of HTLV-1 infection.

Other recent studies suggest another role for HSPG during cell-cell transmission of the virus. It was discovered that HTLV-1 virions are stored outside the cell, within a protective microenvironment enriched for specific components of the extracellular matrix, including lectins and HSPGs 64 . Following contact between T cells, these structures are rapidly transferred from infected to uninfected cells, ultimately resulting in infection of the target cell. This suggests that HSPG could play a broader role in HTLV-1 transmission by facilitating both the transfer of newly-formed virions from an infected T cells and the subsequent entry into the target T cell. The galactose-binding lectin Galactin-1, which has been shown to increase HTLV-1-Env mediated infection 65 , might also have a similar function.

Interestingly, HSPG are important for infection with HTLV-1 but not HTLV-2 66 , showing that these two viruses, initially considered to share the same receptor 67 , may share some but not all molecular determinants for entry. It has previously been reported that HTLV-1 SU has the ability to bind HSPG; this ability maps to the C-terminal region of HTLV-1 SU, located downstream the RBD and the proline rich region 66 . Interestingly, the Green laboratory has previously reported that the preferential tropism of HTLV-1 and HTLV-2 to transform CD4⁺ T cells or CD8⁺ T cells, respectively, is governed by Env 68 . The difference in the requirement of HTLV-1 and HTLV-2 two SU for HSPG might explain the different tropisms of the two retroviruses. Indeed, CD4⁺ T cells express a high level of HSPG and a lower level of GLUT1 whereas CD8⁺ T cells express a high level of GLUT1 but very few HSPG. In this model, the differences between HTLV-1 and HTLV-2 would be similar to what has been described in CD4-dependent and independent HIV-2 or SIV strains, which differ in their requirements for the binding receptor (CD4) but share similar fusion receptors 69 .

In 2006, the Hermine and Pique laboratories showed that Neuropilin-1 (NRP-1) also displayed properties expected for a HTLV-1 receptor 5 . This hypothesis was confirmed in a recent study 3 . NRP-1 is a 130 kDa single membrane spanning glycoprotein which acts as the co-receptor for Semaphorin 3a and VEGFA₁₆₅. NRP-1 was initially identified as a critically important factor in embryonic neuron guidance, and later shown to be a key player in the regulation of angiogenesis. In addition, Romeo and Hermine's laboratories were the first to demonstrate that NRP-1 is also involved in the regulation of the immune response 70 . NRP-1 is highly conserved amongst vertebrate species but there are no NRP-1 homologs in insects 71 . NRP-1 is mainly expressed in T cells and DC, which are targets of HTLV-1 in vivo. NRP-1 is highly expressed on plasmacytoid DC (pDC), which can be infected by cell-free virus in vitro 72 . Endothelial cells, in which HTLV-1 proviral DNA has been detected in vivo 25 , also express NRP-1 73 . NRP-1 is absent on resting T cells but is rapidly upregulated following activation 72 74 . In contrast with its relatively limited expression in vivo, NRP-1 is found in many tumor cells 73 and hence is expressed on an extremely broad range of established cell lines. Finally, NRP-1 plays a role in cytoskeletal rearrangement, a phenomenon that has been shown to be important for transmission of different retroviruses including HTLV-1 75 .

Ghez et al. reported that NRP-1 was able to directly interact with the HTLV-1 and -2 SU 5 . This interaction appeared functionally relevant since NRP-1 overexpression enhanced syncytium formation and the titer of HTLV-1 or -2 Env pseudotyped viruses whereas siRNA-mediated NRP-1 downmodulation had the opposite effect 5 . A strong polarization of NRP-1 and Env on either side of the interface between an infected cell and a target T cell was observed using confocal microscopy. This phenomenon was also observed with GLUT1, though GLUT1 was also found to colocalize at the membrane junction of two uninfected T cells, thus in an Env-independent manner. Both polarization and co-localization of the three molecules were particularly intense at regions where partial membrane fusion was taking place. It was also observed that GLUT1 and NRP-1 could form intracytoplasmic complexes in transfected cells, an association that was greatly enhanced in the presence of Env 5 .

The identification of three new molecules involved in the process of HTLV-1 entry allows one to revisit the HTLV-1 tropism paradox mentioned above. While HSPG usage appears to distinguish HTLV-1 and HTLV-2, their ubiquitous expression cannot explain the limited tropism of HTLV-1 in vivo. This is also the case of GLUT1, whose expression is ubiquitous as well. In contrast, the distinct pattern of NRP-1 expression in vivo and in vitro may explain the disparity between the in vivo and in vitro tropisms. In primary cells, NRP-1 is mainly expressed on endothelial cells, activated CD4⁺ T cells and DC, all of which have been observed to be infected in vivo. However, NRP-1 overexpression upon cell transformation renders it nearly ubiquitous among established cell lines. Moreover, the nrp-1 gene is strongly conserved between mammalian species and has no homolog in insects. These findings strongly favor the notion that the in vivo HTLV-1 tropism is mainly dictated by NRP-1 expression.

As was hypothesized previously, there is now definitive evidence that GLUT1 and NRP-1 bind to distinct regions of SU. Kim et al. determined that the minimal RBD is located within the first 183 amino terminal residues of the HTLV-1 SU 52 . Mutation of the tyrosine residue 114 completely abolished the binding of H1-RBD, suggesting it plays a critical role. However, the results of binding studies using RBD should be interpreted with caution, as they might not truly represent what occurs with the full length SU or the SU/TM complex in the native Env. Several lines of evidence suggest that this may be the case. For example, over expression of GLUT1 strongly increased binding of the H1-RBD 2 , but has little impact on the binding of full-length HTLV-1 SU 57 . It is thus possible that shortening the SU modifies its quaternary structure and mimics a conformational change resulting in an "active" form capable of binding directly to GLUT1, possibly by exposing the tyrosine residue 114 52 . It is tempting to speculate that the conformational change allowing the association to GLUT1 might be dependent on the initial SU binding to NRP-1. This would be analogous to what occurs for HIV, where SU (gp120) binding to CD4 induces a conformational change that allows binding to the co receptors, which facilitates fusion.

The HSPG-interacting SU region is located outside the GLUT1 and NRP-1 binding sites, and thus should not decrease its affinity to the other two molecules; this interpretation is consistent with the data showing that increasing cell surface levels of HSPG increases SU binding to receptor-expressing cells 6 7 . Blocking the ability of SU to interact with HSPG, either by enzymatic removal or incubation with a peptide mimicking the HSPG-binding domain of VEGFA₁₆₅ (exon-7 peptide), decreased the DC-mediated transfer of HTLV-1 to CD4+ T cells by 50%. Moreover, blocking both HSPG and NRP-1 interactions decreased HTLV-1 infection by 80% 4 72 . Thus, HSPG are important for the efficiency of HTLV-1 infection, likely by increasing and stabilizing the initial SU binding to NRP-1, a phenomenon already described for gp120 and CD4 76 .

In 2009, Lambert et al. found that the binding of the HTLV-1 SU to NRP-1 involved two distinct types of interaction: an indirect interaction mediated by HSPG and a direct interaction mediated by the amino-acids 90-94 of the SU 4 . Moreover, they identified a region of SU (aa 90-94) that is homologous in both sequence and function to the exon 8 domain of the NRP-1 ligand VEGFA₁₆₅, 77 . This demonstrates that the SU binds to NRP-1 using molecular mimicry of VEGFA₁₆₅. Interestingly, the aa 90-94 motif is conserved in the SU proteins of HTLV-2, HTLV-3 and related Simian T-Lymphotropic Viruses but not other retroviruses 4 and is the target of neutralizing antibodies 78 . Strikingly, Kim et al. showed that mutating either aa 94 (R) or 114 (Y), which inhibits direct interaction with NRP-1 or GLUT1 respectively, is equally efficient in preventing interference due to overexpression of the H1-RBD in target cells 52 . This reinforces the notion that the direct interaction of SU with both NRP-1 and GLUT1 is required for HTLV-1 entry.

In light of these data, it is possible to draw a model for HTLV-1 entry based on an analogy with HIV CD4/CXCR4 or CCR5 receptor complexes, and what is known about interactions of NRP-1 with its ligand VEGFA₁₆₅, HSPG, and receptor (Figure 1). During the initial binding phase, the SU would interact with HSPG via its C-terminal portion, allowing its attachment to the cell surface (Figure 1, step 1). This would enhance the local concentration of SU, and thus increase the probability of interactions with NRP-1. This notion is consistent with observations that removal of cell surface HSPG dramatically reduces the level of binding of the SU or virions to CD4⁺ T cells 6 , the titer of pseudotyped virus, and the infection of CD4⁺ T cells and DC. HSPG/SU complexes would then interact with the b domain of NRP-1, through both HSPG/NRP-1 interactions and direct SU/NRP-1 binding mediated by the 90-94 region of the SU (step 2). This binding to NRP-1 could trigger a conformational change within the SU, exposing the region necessary for GLUT1 binding including the critical Y114. Finally, the interaction of the SU with GLUT1 could trigger the fusion process necessary to HTLV-1 entry (step 3). In this model, NRP1, with the help of HSPG, is the primary binding receptor, while GLUT1 is the fusion receptor. This is consistent with the formation of NRP-1/Env/GLUT1 complexes and with the fact that GLUT1 over expression does not increase the level of HTLV-1 SU binding. This model applies to both primary CD4⁺ T cells and DC 4 72 . Recent data showing that HTLV-1 entry into primary astrocytes requires both NRP-1 and GLUT1 3 suggest that this view is true for these cells as well.

Whether this model is relevant for HTLV-1 entry in other types of cells remains to be investigated. A recent paper from Alkhatib's group showed that GLUT1, but not NRP-1, was involved in HTLV-1 entry into Hela cells 3 . Moreover, the same group was the first to show that HTLV-1 can efficiently enter into U87 cells, in which the surface level of GLUT1 is very low 56 . Low level of GLUT1 at the cell surface could be sufficient to promote fusion if the density of surface NRP1 is high, which is the case of the U87 cell line 3 . Indeed, it was shown that T cells expressing very low levels of CCR5 but high levels of CD4 were still competent for HIV envelope-mediated membrane fusion 79 . Alternatively, NRP-1 could function on certain cell types as both the binding and fusion receptor, as suggested for CHO cells 3 . Finally, one cannot exclude the possibility that, like HIV, HTLV-1 uses different fusion receptors on different cell types and other unidentified molecules could serve as fusion receptors for HTLV-1.

Other evidence supporting a NRP-1/GLUT1- complex comes from reports that a small intracytoplasmic protein called GLUT1CBP or PSD-95/Dlg/ZO-1 can bind both NRP-1 and GLUT1 via its PDZ domain 80 81 . Moreover, syndecans, the main members of the HSPG family, also contain a PDZ-binding motif at their C-terminus of their cytoplasmic domain 82 . Deletion of the PDZ-binding motif of GLUT1 was shown to preclude GLUT1 clustering at the plasma membrane 83 . GLUT1CBP could therefore act as a "bridge" to stabilize the entire tripartite receptor complex. It could also provide cues for cytoskeletal polarisation, since it can associate with several cytoskeletal proteins 80 (Figure 1, step 3). Altogether, this model not only reconciles nearly all of the recent data obtained on the HTLV-1 receptor but also appears to explain the in vivo tropism of the virus better than the GLUT1-only hypothesis.

Plasmacytoid DC (pDC), and to a lesser extent myeloid dendritic cells (myDC), constitutively express high levels of NRP-1, which is involved in the regulation of DC-T cell interactions at the immune synapse 70 . Shaking the commonly accepted idea that HTLV-1 could only be transmitted via cell to cell contact, it was recently found that free HTLV-1 virions could efficiently infect DC 72 . The contact of HTLV-1-infected DC with CD4⁺ T cells upregulates NRP-1 and HSPG within an hour followed by transmission of HTLV-1 to T cells and productive infection. This phenomenon appears to be dependent on both NRP-1 and HSPG expression on the target T cells 72 . Viral transmission may occur in cis (from virus produced from infected DCs) but also in trans (prior to infection of the DC), as has been previously shown for DC-mediated HIV infection. This raises the question of whether DC (in particular pDC) could constitute a reservoir for the virus. Several laboratories have reported detecting HTLV-1 sequences in DC in vivo 84 . It would be interesting to determine whether, in contrast to T cells, an active replication cycle takes place in pDC in vivo.

Targeting DC and interfering with NRP-1 signalling might have several other consequences on viral infection. HTLV-1 infection results in a depletion of myDC as well as pDC and an impairment of their IFNα-producing capacity 85 . Furthermore, the number of pDC is negatively correlated to the proviral load, suggesting a certain degree of impairment of the antiviral response. It is still not known whether this pDC decrease is due to true depletion or, as in HIV infection, to their migration into lymphoid tissues. Recent in vitro data demonstrated that cell-free HTLV-1 generates a pDC innate immune response by an induction of costimulatory molecules, production of massive levels of IFN-α, and rapid expression of the apoptotic ligand TRAIL. The role of NRP-1 in this process remains to be clarified. Furthermore, HTLV-1-stimulated pDC was shown to induce apoptosis of CD4⁺ T cells expressing DR5, transforming pDC into Interferon-producing Killer pDC (IKpDC) 86 . Interaction of HTLV-1 SU binding and NRP-1 in infected cells might by itself disturb DC-T cells interactions, and thus impair the immune response. This is consistent with previous reports that soluble HTLV-1 SU has an inhibitory effect on a mixed lymphocyte reaction 22 . This phenomenon might be of particular significance during primary infection when there is an active transcription of viral products including Env, which could thus dampen the primary antiviral response. Alternatively, IKpDC may reduce spreading of infection by killing infected T cells and allowing the emergence of few infected T cell clones in the infected host. Finally, infection of immature myDC might disturb T cell homeostasis and lead to an increased risk of autoimmune phenomena.