Abstract
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.
Highlights
Dendritic cells (DCs) are key regulators of immunity given their pivotal role in initiating and shaping adaptive immune responses against a vast array of pathogens and cancers [1,2,3]
We found that complement-opsonization of the virus is able to relieve SAMHD1 restriction in DCs, thereby initiating strong maturation and co-stimulatory capacity of the cells and PLOS Pathogens | DOI:10.1371/journal.ppat
HIV-C caused a significantly higher productive infection (p
Summary
Dendritic cells (DCs) are key regulators of immunity given their pivotal role in initiating and shaping adaptive immune responses against a vast array of pathogens and cancers [1,2,3]. The virus is spontaneously surrounded by covalently linked C-fragments and opsonized HIV-1 particles accumulate already during the acute phase of infection [6, 7]. These structures interact with the abundant CR3 and CR4 on DCs and not via DC-SIGN/gp120 as shown earlier by our group [9]. Laguette et al [17] identified SAMHD1 as dendritic- and myeloid cell-specific HIV-1 restriction factor, which was counteracted, if the accessory protein Vpx encoded in the SIV or HIV-2 genome was incorporated into viral particles [17,18,19]. Phosphorylation of SAMHD1 on residue T592 was shown to negatively regulate its HIV-1-restricting ability without reducing cellular dNTP levels [20,21,22,23]
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