Dendritic cells and their role in HIV pathogenesis
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HIV and Dendritic Cells


the role of dendritic cells in sexual HIV-1 transmission

DC are professional antigen presenting cells that sample the environment at sites of pathogen entry. Sentinel immature DC develop into mature effector DC upon activation by microorganisms, and migrate to the draining lymph nodes where they stimulate naïve Th cells. HIV-1 has been proposed to make use of this migratory process, being captured by the DC and delivered to the lymph node where the virus is transmitted to CD4+ T cells. The lymph node then becomes the principal site of virus production.

DC can capture HIV through several receptors, of which DC-SIGN is the best studied example. After capture, the virus dissociates from DC-SIGN and resides in an unidentified non-lysosomal compartment (box A, figure below). After T cell encounter, HIV is recruited to the site of T cell interaction. This so-called 'infectious synapse' depends on strong cell-cell adhesion mediated by ICAM-1—LFA-1 interaction (box B). The precise composition of the synapse is largely unknown.


dendritic cell-mediated HIV-1 capture and subsequent transfer to T cells


Thesis outline (Oct 2006):
Download my complete PhD thesis (3.5 MB PDF) [here]

Chapter 1: general introduction on HIV-1 and DC
See above or for long version [my thesis]

Chapter 2: Dendritic cell-mediated HIV-1 transmission to T cells of LAD-1 patients is impaired due to the defect in LFA-1
[Retrovirology PDF]
In this chapter, I describe our research on the importance of strong DC-T cell interaction through ICAM-1—LFA-1 binding. We have previously identified ICAM-1 on DC as a crucial factor for HIV-1 transmission [read PDF]. ICAM-1 binds LFA-1 on T cells, an integrin responsible for adhesion and signaling at the immunological synapse. To corroborate the importance of the ICAM-1—LFA-1 interaction, we made use of LFA-1 negative leukocytes from Leukocyte Adhesion Deficiency type 1 (LAD-1) patients. It is shown in Chapter 2 that DC-mediated HIV-1 transmission to LAD-1 T cells is impaired in comparison to healthy controls. Furthermore, HIV-1 transmission to T cells from a unique LAD-1 patient with a well characterized LFA-1 activation defect was impaired as well, demonstrating that activation of LFA-1 is crucial for efficient transmission.


In Chapter 3 and 4, our research on the different cell types involved in transmission is described.

Chapter 3: Differential susceptibility of naïve, central memory, and effector memory T cells to dendritic cell-mediated HIV-1 transmission
[Retrovirology PDF]
Several T cell subsets can be identified in humans: naïve T cells (TN) that initiate an immune response to new antigens, and memory T cells that respond to previously encountered pathogens. The memory T cell pool comprises central memory (TCM) and effector memory cells (TEM), which are characterized by distinct homing and effector functions. The TEM cell subset, which can be further divided into effector Th1 and Th2 cells, has been shown to be the prime target for viral replication after HIV-1 infection, and is abundantly present in mucosal tissues. In Chapter 3, transmission experiments to these different T cell types were performed. We found that co-receptor expression on the respective T cell subsets is a decisive factor for transmission. Accordingly, CCR5-using (R5) HIV-1 was most efficiently transmitted to TEM cells. This highly efficient R5 transfer to TEM cells suggests that mucosal T cells are an important target for DC-mediated transmission. This may contribute to the initial burst of virus replication that is observed in these cells. In contrast, CXCR4-using (X4) HIV-1 was preferentially transmitted to TN cells, which are considered to inefficiently support HIV-1 replication. These results indicate that DC may play a decisive role in the susceptibly of TN cells to X4 tropic HIV-1.

Chapter 4: Opposing roles of blood myeloid and plasmacytoid dendritic cells in HIV-1 infection of T cells: transmission facilitation versus replication inhibition
[Blood PDF] [editorial]
In this chapter, the DC were the subject of variation. In humans, 2 main DC types are identified: CD11c+ myeloid DC (MDC) and CD11c- CD123+ plasmacytoid DC (PDC). MDC include Langerhans cells, dermal DC and interstitial DC. They have been associated with HIV-1 capture and sexual transmission, whereas PDC play an important role in the innate immune responses to different types of viruses, including HIV-1. To compare the influence of MDC and PDC on HIV-1 infection of T cells, we isolated donor-matched MDC and PDC from peripheral blood, activated them by adding different maturation-inducing compounds, and co-cultured them with T cells and HIV-1. It was found that MDC enhance HIV-1 infection through capture of the virus and subsequent transmission to T cells, and that differently matured MDC subsets have different HIV-1 transmission efficiencies. These differences were not due to soluble factors, viral capture differences or the expression of integrins ICAM-1, -2, -3 or LFA-1. In contrast, regardless of their state of maturation, PDC inhibit HIV-1 replication in T cells through the secretion of IFN-alpha and an additional, unidentified small molecule. In this chapter, we thus show that the two main types of DC have opposing roles in HIV-1 infection of T cells.


The last part of the thesis is dedicated to two studies on microbicides.

Chapter 5: Lactoferrin prevents dendritic cell-mediated HIV-1 transmission by blocking the DC-SIGN—gp120 interaction
[Journal of Virology PDF]
[Watch item on Dutch current affairs programme '1Vandaag' (2006)]
Given the important role of MDC in sexual HIV-1 transmission, the possibility of preventing this process was explored in chapter 5. Proteins from milk and serum were tested for their ability to block DC-mediated HIV-1 transmission, and bovine lactoferrin (bLF) turned out to be the most potent inhibitor. bLF binds strongly to DC-SIGN, thus preventing virus capture and subsequently transmission. Interestingly, the bovine protein is a much more efficient inhibitor of transmission than human LF (hLF). Since bLF is non-toxic and easy to purify in large quantities, it forms an interesting candidate microbicide against HIV-1. Another advantage of bLF is its ability to block HIV-1 replication in T cells. This broad spectrum of activity underscores the usefulness of bLF as a microbicide to prevent HIV-1 transmission, and research on such usage of bLF seems justified.

Chapter 6: Histatin 5-derived peptide with improved fungicidal properties enhances HIV-1 replication by promoting viral entry
[Journal of Virology PDF]
The development of microbicides can also have unexpected and potential dangerous side-effects, as shown in Chapter 6. We have tested the antiviral properties of variants of an antimicrobial peptide from saliva (Histatin 5). This peptide inhibits Candida albicans, an opportunistic fungus that causes 'oropharyngeal candidiasis' in a majority of HIV-infected patients progressing towards AIDS. The peptide variants are more amphipatic versions of the active domain of Histatin 5 (Dh-5), and displayed increased fungicidal activity. Although Dh-5 inhibited HIV-1 replication, none of the peptide variants was more effective in this respect. In contrast, three out of four derivatives significantly increased HIV-1 replication by promoting the envelope-mediated cell entry process. Most likely, the derivatives affect membranes, thereby facilitating fusion of viral and cellular membranes.

Chapter 7: Microbicides to prevent sexual HIV-1 transmission (general discussion)
See [my thesis]
Finally, I have put the main findings of the thesis in perspective with recent literature on microbicide development. In the absence of an effective HIV-1 vaccine, we have to consider alternatives to slow the virus from spreading.

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