HIV-Infected Langerhans Cells Preferentially Transmit Virus to Proliferating Autologous CD4+ Memory T Cells Located within Langerhans Cell-T Cell Clusters

Abstract

Langerhans cells (LC) are likely initial targets for HIV following sexual exposure to virus and provide an efficient means for HIV to gain access to lymph node T cells. The purpose of this study was to examine the nature of the CD4+ T cell that becomes infected by HIV-infected LC. We infected human LC within tissue explants ex vivo and then, 3 days later, cocultured HIV-infected LC with different subsets of autologous CD4+ T cells. Using multicolor flow cytometric analyses of LC-CD4+ T cell cocultures, we documented that HIV-infected LC preferentially infected memory (as compared with naive) CD4+ T cells. Proliferating and HIV-infected CD4+ memory T cells were more frequently detected in conjugates of LC and autologous CD4+ T cells, suggesting that T cells become activated and preferentially get infected through cluster formation with infected LC, rather than getting infected with free virus produced by single HIV-infected LC or T cells. p24+ Memory CD4+ T cells proliferated well in the absence of superantigen; by contrast, p24+ T cells did not divide or divided only once in the presence of staphylococcal enterotoxin B, suggesting that virus production was rapid and induced apoptosis in these cells before significant proliferation could occur. These results highlight that close interactions between dendritic cells, in this case epidermal LC, and T cells are important for optimal HIV replication within specific subsets of CD4+ T cells. Disrupting cluster formation between LC and memory CD4+ T cells may be a novel strategy to interfere with sexual transmission of HIV.

To kill or be killed: how HIV exhausts the immune system

“…Langherans cells are likely initial targets for HIV following sexual exposure to virus and, following their infection, they were shown to preferentially transmit HIV to proliferating autologous memory CD4 þ T cells, further dying of apoptosis after antigenic stimulation. 125 The in vivo destruction of HIV-specific CD4 þ T-cell precursors may also occur in lymph nodes following HIV binding 126 and ligation of the homing receptor CD62L, as suggested. 127 Failure to detect HIV-specific CD4 þ T cells ex vivo might also be due to either their in vivo inhibition by high levels of viremia, 128 their anergy resulting from interaction with peripheral blood dendritic cells, 129 or their suppression by CD4 þ CD25 þ regulatory T cells 130,131 (Figure 1).…”

HIV-1 fusion peptide targets the TCR and inhibits antigen-specific T cell activation

“…Upon mucosal infection, DCs carry infective HIV virions attached to DC-SIGN molecules on their surface (40,41) and in cellular compartments that protect the virions (42). At the lymph nodes, the DCs loaded with HIV can interact with HIV-specific T cells (43,44), probably recruiting the HIV virions carried by the DCs to HIVspecific T cells (45). Once the virions reach the T cell membrane, FP might play 2 roles: mediating viral entry into the T cell (37) and, as indicated by our results, simultaneously inhibiting T cell activation.…”

HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production

“…After contact between DCs and T cells, HIV-1 is transferred to the latter in 2 phases, first from "caves" and then later from the cytosol. 5,[9][10][11][12] However, how HIV-1 manipulates DC biology to use the cell for viral transfer to T cells without marked cytopathic effects is still unclear. Viruses often shape their intracellular environment through alterations to host cell gene transcription, protein translation, and posttranslational modification, often initiating these changes by signaling through cell surface receptors or at subsequent stages in their replication cycle.…”