Abstract
HIV-1 Vpr is necessary for maximal HIV infection and spread in macrophages. Evolutionary conservation of Vpr suggests an important yet poorly understood role for macrophages in HIV pathogenesis. Vpr counteracts a previously unknown macrophage-specific restriction factor that targets and reduces the expression of HIV Env. Here, we report that the macrophage mannose receptor (MR), is a restriction factor targeting Env in primary human monocyte-derived macrophages. Vpr acts synergistically with HIV Nef to target distinct stages of the MR biosynthetic pathway and dramatically reduce MR expression. Silencing MR or deleting mannose residues on Env rescues Env expression in HIV-1-infected macrophages lacking Vpr. However, we also show that disrupting interactions between Env and MR reduces initial infection of macrophages by cell-free virus. Together these results reveal a Vpr-Nef-Env axis that hijacks a host mannose-MR response system to facilitate infection while evading MR's normal role, which is to trap and destroy mannose-expressing pathogens.
Highlights
Vpr is a highly conserved HIV accessory protein that is necessary for optimal replication in macrophages (Balliet et al, 1994) but its mechanism of action is poorly understood
Because we had previously determined that Vpr functions in macrophages to counteract a macrophage specific restriction factor that targets Env, we reasoned that Env-binding proteins selectively expressed by macrophages were potential candidate restriction factors
We found that mannose receptor (MR), which is highly expressed on macrophages and has been previously shown to bind Env (Trujillo et al, 2007; Fanibunda et al, 2008; Lai et al, 2009), was significantly decreased by wild-type HIV 89.6 but not by 89.6 vpr-null (Figure 1C and D, p
Summary
Vpr is a highly conserved HIV accessory protein that is necessary for optimal replication in macrophages (Balliet et al, 1994) but its mechanism of action is poorly understood. Studies using human lymphoid tissue (HLT), which are rich in both T cells and macrophages, have found that loss of Vpr decreases virus production (Rucker et al, 2004) but only when the virus strain used is capable of efficiently infecting macrophages (Eckstein et al, 2001) These studies provide evidence that Vpr enhances infection of macrophages and increases viral burden in tissues where macrophages reside. Previous work by our group demonstrated that Vpr counteracts an unidentified macrophage-specific restriction factor that targets Env and Env-containing virions for lysosomal degradation (Mashiba et al, 2014; Collins et al, 2015). This restriction could be conferred to permissive 293T cells by fusing them with MDM to create 293T-MDM heterokaryons.
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