Abstract
Pathogenic bacteria and their microbial products activate dendritic cells (DCs) at mucosal surfaces during sexually transmitted infections (STIs) and therefore might also differently shape DC functions during co-infection with HIV-1. We recently illustrated that complement (C) coating of HIV-1 (HIV-C), as primarily found during the acute phase of infection before appearance of HIV-specific antibodies, by-passed SAMHD1-mediated restriction in DCs and therefore mediated an increased DC activation and antiviral capacity. To determine whether the superior antiviral effects of HIV-C-exposed DCs also apply during STIs, we developed a co-infection model in which DCs were infected with Chlamydia spp. simultaneously (HIV-C/Chlam-DCs or HIV/Chlam-DCs) or a sequential infection model, where DCs were exposed to Chlamydia for 3 or 24 h (Chlam-DCs) followed by HIV-1 infection. Co-infection of DCs with HIV-1 and Chlamydia significantly boosted the CTL-stimulatory capacity compared to HIV-1-loaded iDCs and this boost was independent on the opsonization pattern. This effect was lost in the sequential infection model, when opsonized HIV-1 was added delayed to Chlamydia-loaded DCs. The reduction in the CTL-stimulatory capacity of Chlam-DCs was not due to lower HIV-1 binding or infection compared to iDCs or HIV-C/Chlam-DCs, but due to altered fusion and internalization mechanisms within DCs. The CTL-stimulatory capacity of HIV-C in Chlam-DCs correlated with significantly reduced viral fusion compared to iDCs and HIV-C/Chlam-DCs and illustrated considerably increased numbers of HIV-C-containing vacuoles than iDCs. The data indicate that Chlamydia co-infection of DCs mediates a transient boost of their HIV-specific CTL-stimulatory and antiviral capacity, while in the sequential infection model this is reversed and associated with hazard to the host.
Highlights
Dendritic cells (DCs) play a pivotal role in the defense against invading pathogens
We found that long-term exposure (24 h) of iDCs to Chlamydia induced significant up-regulation of CD83, CD86, and HLA-DR compared to untreated iDCs (Figure 1A)
A reduced maturation of DCs was observed upon co-infection with HIV-C and Chlamydia (HIV-C/ChlamDCs) and this maturation was comparable to that when iDCs were exposed to HIV-C only (Figure 1B, CD83—left panel, CD86—middle panel, HLA-DR—right panel)
Summary
Dendritic cells (DCs) play a pivotal role in the defense against invading pathogens. DCs reside in the peripheral tissue, where they capture antigens and transport them to lymph nodes to present them to naive T cells. DCs play a key role in shaping the adaptive immune response. Of all new HIV-1 infections, 60–90 % are caused by sexual transmission [1, 2]. Since HIV-1 transmission occurs at mucosal surfaces, DCs are amongst the first cells to encounter the virus [3]. HIV-1 spontaneously activates the classical complement (C) pathway [4], even in seminal fluid [5], through direct binding of C1q to the viral surface. C-opsonized HIV (HIV-C) is accumulating at mucosal sites during early HIV-1 infection [6, 7]
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