Complement-Opsonized HIV-1 Overcomes Restriction in Dendritic Cells.

DCs express intrinsic cellular defense mechanisms to specifically inhibit HIV-1 replication. Thus, DCs are productively infected only at very low levels with HIV-1, and this non-permissiveness of DCs is suggested to go along with viral evasion. We now illustrate that complement-opsonized HIV-1 (HIV-C) efficiently bypasses SAMHD1 restriction and productively infects DCs including BDCA-1 DCs. Efficient DC infection by HIV-C was also observed using single-cycle HIV-C, and correlated with a remarkable elevated SAMHD1 T592 phosphorylation but not SAMHD1 degradation. If SAMHD1 phosphorylation was blocked using a CDK2-inhibitor HIV-C-induced DC infection was also significantly abrogated. Additionally, we found a higher maturation and co-stimulatory potential, aberrant type I interferon expression and signaling as well as a stronger induction of cellular immune responses in HIV-C-treated DCs. Collectively, our data highlight a novel protective mechanism mediated by complement opsonization of HIV to effectively promote DC immune functions, which might be in the future exploited to tackle HIV infection.

Co- but not Sequential Infection of DCs Boosts Their HIV-Specific CTL-Stimulatory Capacity.

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.