A new paper in the Journal of Virology reports that dendritic cells (DCs) are more susceptible to infection by HIV-1 than its far less pathogenic retroviral sibling, HIV-2. The work is the product of collaboration between researchers at the NIH’s Vaccine Research Center and Oxford University in the UK. DCs act as immune system sentinels that capture pathogens as they first enter the body and transport them to lymph nodes in order to initiate immune responses by T cells and B cells. DCs are referred to as antigen-presenting cells for this reason.
The study authors point out that previous studies have shown that DCs can be susceptible to HIV-1 infection, but that infection of DC’s also leads to presentation of HIV antigens to HIV-specific CD4 T cells. They write: “this suggests that the infection of DCs by HIV-1 and subsequent processing and presentation of HIV-1 antigens on the surface of DCs is a double-edged sword. In order to induce an HIV-specific immune response, it is necessary for DCs to deliver appropriate signals to memory CD4+ T cells. However, in doing so, the intimate contact of DCs and T cells leaves HIV-1-specific CD4+ T cells susceptible to becoming infected by these HIV-1-carrying DCs. This could help to explain mechanistically how HIV-1-specific CD4+ T cells become preferentially infected in vivo.” However, although HIV-2 was extremely inefficient at infecting DCs, the researchers found that HIV-2-specific CD4 T cells were still more likely to be infected by HIV-2 compared to CD4 T cells targeting other pathogens, suggesting that transfer from DCs may not be the only means by which the virus preferentially infects HIV-2-specific CD4 T cells.
The findings may also suggest that HIV-1’s superior ability to target DCs contributes to the different courses of disease associated with HIV-1 and HIV-2 infection. Recent studies by the same researchers have shown that HIV-2-specific CD4 T cell responses are relatively preserved compared to the loss and dysfunction of HIV-1-specific CD4 T cells that occurs in progressive HIV-1 infection. Further investigations of the role of DCs in HIV-1 vs. HIV-2 infection may help shed light on the reasons for these differences. This area of research may also have implications for HIV-1 vaccines; although T cell-based candidates like the Merck Ad5 vaccine reliably induce HIV-specific memory CD4 T cells, it could be the case that HIV-1 infection of DCs (or other antigen-presenting cells such as macrophages) somehow prevents these CD4 T cell responses from being activated efficiently.
JVI Accepts, published online ahead of print on 3 October 2007
J. Virol. doi:10.1128/JVI.00976-07
Dendritic Cells Are Less Susceptible to HIV-2 Than HIV-1 Infection
Melody G. Duvall, Karin Loré, Hetty Blaak, David A. Ambrozak, William C. Adams, Kathlyn Santos, Christof Geldmacher, John R. Mascola, Andrew J. McMichael, Hilton C. Whittle, Sarah L. Rowland-Jones, and Richard A. Koup
HIV-1 infection of dendritic cells (DCs) has been documented in vivo, and may be an important contributor to HIV-1 transmission and pathogenesis. HIV-1-specific CD4+ T cells respond to HIV antigens presented by HIV-1-infected DCs and in this process become infected, thereby providing a mechanism through which HIV-1-specific CD4+ T cells could become preferentially infected in vivo. HIV-2 disease is attenuated with respect to HIV-1 and host immune responses are thought to be contributory. Here, we investigated the susceptibility of primary myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) to infection by HIV-2. We found that neither CCR5-tropic primary HIV-2 isolates nor a lab-adapted CXCR4-tropic HIV-2 could efficiently infect mDCs or pDCs, though these viruses could infect primary CD4+ T cells in vitro. HIV-2-exposed mDCs were also incapable of transferring virus to autologous CD4+ T cells. Despite this, we found that HIV-2-specific CD4+ T cells contained more viral DNA than memory CD4+ T cells of other specificities in vivo. These data suggest that either infection of DCs is not an important contributor to infection of HIV-2-specific CD4+ T cells in vivo, or that infection of DCs by HIV-2 occurs at a level undetectable in vitro. The frequent carriage of HIV-2 DNA within HIV-2-specific CD4+ T cells, however, does not appear to be incompatible with preserved numbers and functionality of HIV-2-specific CD4+ T cells in vivo, suggesting that additional mechanisms contribute to maintenance of HIV-2-specific CD4+ T cell help in vivo.
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