DCs, pivotal to adaptive immunity, are early targets of HIV. All lentiviruses can infect macrophage lineage cells in which they generate a persistent infection. HIV-1 has developed a broader tropism leading to preferential infection of CD4 þ T cells, which are progressively destroyed both as a direct viral cytopathic effect and a bystander induction of apoptosis in uninfected cells. 46 Studies in animal models have revealed that critical events to establishing systemic infection take place very quickly at the mucosal portal of entry. Following mucosal exposure to high doses of simian immunodeficiency virus (SIV), the virus can cross the mucosal barrier and it establishes within 3-4 h a small founder population of productively infected cells. 47, 48 Infection then expands locally before virus detection in the draining lymph node, and systemically throughout the secondary lymphoid organs. 49 In vivo, resting CD4 T cells are the initially infected cells in lymphoid tissues. 48 However, the first cells to be infected at the mucosa are the intraepithelial DCs, as shown in vivo in the genital tract of rhesus macaques 1 h after intravaginal inoculation of SIV, and infected DCs reach the draining lymph nodes 18-24 h after SIV exposure, much earlier than CD4 þ T cells. 50 As sentinels, DCs are crucial for the generation of antiviral immunity. They are the most potent antigen-presenting cell in the immune system owing to their superior capacity for acquiring and processing antigens for presentation to T cells and their potential to express high levels of the co-stimulatory molecules that drive T-cell activation and polarization. 51 Thus, they effectively link the innate recognition of viruses to the generation of the appropriate type of adaptive immune response. DCs are a heterogeneous family, including langherans cells in the epidermis, interstitial DCs found in all peripheral tissues, myeloid DCs and plasmacytoid DCs found in the blood. Their heterogeneity resides at several levels, including anatomical location, phenotype and function. 52 DCs express a large repertoire of PRRs and, in response to signals from these receptors, they are activated and migrate to the T-cell area of regional lymph nodes where mDCs present virus-derived epitopes to CD4 þ or CD8 þ T cells. 53 DCs have a prominent role in promoting viral dissemination. Viruses, including HIV, have evolved Figure 2 HMGB1-mediated cross talk between DCs and NK cells is pivotal to DC maturation and further induction of adaptive immunity. The disruption of an epithelial barrier allows invasion of microbial pathogens, which elicit an innate response at the site of infection (1). Neutrophils and macrophages infiltrate the site of tissue infection and release alarmins, including HMGB1 (2). HMGB1 recruits iDCs, resulting in an increase in local mobilization of iDCs (3). Functional DC maturation requires a cross talk with NK cells, which involves HMGB1 expressed at NK-DC synapse (4). Immature to mDC conversion allows DCs to migrate to secondary lymphoid organs (5) and contributes to the enhanced uptake, processing and presentation of microbial antigens to naïve T cells, thus polarizing a Th1 response (6) . This T-cell response involves IL-12 and IL-18 released by mDCs. Cognate interaction between NK cells and DCs may also lead to the selective killing of DCs that are not appropriate for antigen presentation to T cells (7). This editing process, which involves TRAIL, allows NK cells to control the quality of DCs, thus regulating adaptive immunity different strategies to evade DC antiviral activity and to propagate and persist in DCs. HIV-1 replication in DCs is usually weakly productive, and the frequency of HIV-1infected DCs in vivo is much lower than that of HIV-1-infected CD4 þ T cells. 54 However, DCs do not need to be productively infected to transmit the virus to CD4 T cells and to spread it in an infectious form. Analysis of conjugates between DCs and T cells revealed the recruitment of HIV and its receptors CD4, CCR5 and CXCR4 to DC-T cell junction, thus facilitating transmission of HIV during the formation of an infectious synapse in the absence of antigen-specific signaling. 55 This process, known as 'trans-infection', takes place when part of the virus evades classical degradation pathways, being maintained in endosomal acidic compartments, thus retaining viral infectivity for long periods and promoting efficient HIV transfer to CD4 T cells. 56, 57 Trans-infection ability may be restricted to mDCs that display a greater ability to capture incoming virions, retain them in an infectious form in large vesicles within the cells, and transmit them to target CD4 þ T cells, 58, 59 thus augmenting viral dissemination in the lymphoid tissues and significantly contributing to HIV disease progression. Therefore, the viral dissemination that mDCs potentially mediates in vivo is powerful, as viral transmission through trans-infection does not rely on antigen presentation, many CD4 þ T cells being exposed to mDCs-exposing virus.