An efficient mode of HIV-1 illness of CD4 lymphocytes occurs in

An efficient mode of HIV-1 illness of CD4 lymphocytes occurs in the context of infectious synapses where dendritic cells (DCs) enhance HIV-1 transmission to lymphocytes. R5 and X4 HIV-1 strains to autologous lymphocytes was analyzed using an infection system. By using this model we observed a strong enhancement of lymphocyte IgG2a Isotype Control antibody (APC) illness with R5 but not with X4 viruses. This lack of DC-mediated enhancement in the propagation of X4 viruses was proportional to CXCL12 production by mMDDCs. When CXCL12 activity was inhibited with specific neutralizing antibodies or small interfering RNAs (siRNAs) the block Proparacaine HCl to mMDDC transfer of X4 viruses to lymphocytes was eliminated. These results suggest that CXCL12 production by DCs resident in lymph nodes represents an antiviral mechanism in the context of the infectious synapse that could account for the delayed appearance of X4 viruses. HIV-1 strains that use CCR5 for access (R5 Proparacaine HCl strains) are responsible for most transmission events and predominate in both early and chronic phases of illness (36 37 while later on phases of disease are characterized by the frequent emergence of variants that use both CCR5 and CXCR4 (R5X4 dual-tropic strains) or CXCR4 only (X4 strains). About half of the individuals infected with B clade HIV-1 switch coreceptor use from CCR5 to CXCR4 and the emergence of X4 viruses is associated with accelerated CD4+ T-cell decrease and fast progression to AIDS (40). The R5-to-X4 switch is associated with mutations in residues located within the V3 region of gp120 which tend to increase the overall positive charge of the V3 loop (15). Because only a limited Proparacaine HCl quantity of mutations are required for this phenotypic switch (38 46 the emergence of X4 variants would be likely to take place on multiple occasions throughout illness. Furthermore there is evidence that X4 HIV-1 strains are present as small viral populations in individuals in whom R5 HIV-1 isolates predominate (11) and the fast emergence of X4 HIV-1 isolates following treatment with potent CCR5 antagonists (47) stretches that observation. Moreover CXCR4 expression is definitely more common than CCR5 manifestation (5 6 Therefore the failure of X4 HIV-1 to increase during natural illness is an apparent paradox suggesting the presence of selective pressures influencing tropism development but the mechanisms governing such selection are not fully recognized. Myeloid and plasmacytoid dendritic cells (PDCs) represent the two main subsets of DCs that have been explained in humans. Despite posting common antigens their functions and tasks Proparacaine HCl in HIV-1 illness are radically different. DCs are the most potent antigen-presenting cells (4 44 Immature DCs (iDCs) migrate specifically to sites of swelling to capture pathogens and pathogen-associated antigens which are processed into antigenic peptides and offered on major histocompatibility complex class II molecules. Once triggered by pathogen encounters DCs mature and migrate to the T-cell areas of secondary lymphoid organs where they interact with and activate resting T cells and initiate adaptive immune reactions (4 27 PDCs are located in blood and secondary lymphoid organs but they can be recruited to sites of swelling and are thought to play an important part in innate immune responses to different types of viruses by generating alpha interferon (IFN-α). Certain subsets of DCs residing in the peripheral mucosae are the 1st immunocompetent cells to encounter lentiviruses (21 39 Successful illness of a host by HIV-1 requires the dissemination of disease from sites of initial illness at mucosal surfaces to T-cell zones in secondary lymphoid organs where myeloid DCs enhance the illness of CD4+ T cells by HIV-1 (10 33 34 On the other hand PDCs inhibit HIV-1 replication in T cells by secretion of IFN-α and yet-unidentified soluble factors (19). The molecular basis underlying DC-T-cell spread of HIV-1 remained unclear until the C-type lectin DC-SIGN (DC specific ICAM-3-grabbing nonintegrin) (18) was recognized. DC-SIGN is highly indicated on DCs present in mucosal cells and binds to disease via interaction with the HIV-1 envelope glycoprotein gp120. DC-SIGN efficiently captures.