Mannose receptor is an HIV restriction factor counteracted by Vpr in macrophages

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.

Vpr Is a VIP: HIV Vpr and Infected Macrophages Promote Viral Pathogenesis

“…Combined, these findings demonstrate that HIV replication is significantly enhanced by cell-to-cell transmission between macrophages and T cells, which explains the earlier observation that the presence of macrophages boosts viral burden in lymphoid tissues [81]. Cell-to-cell spread from macrophages is restricted by mannose receptor (MR), which binds to mannose residues of HIV Env [89]. This restriction is alleviated by the viral accessory protein Vpr [14,88], a process that is described in greater detail in the Vpr section below.…”

“…Transmission via synapses is resistant to neutralization by antibodies [86], meaning it may be particularly difficult to inhibit by an antibody-based HIV vaccine. This form of transmission mediates the spread of HIV from macrophages to CD4 + T cells [87], which is much more efficient than infection of CD4 + T cells by cell free virus [88,89]. In addition, phagocytosis of infected CD4 + T cells by macrophages leads to greater infection of macrophages than does incubation with cell-free virus [90].…”

“…One group found that MR binds HIV on the plasma membrane of macrophages and transfers virions to CD4 + T cells, a process known as trans-infection [121]. It was recently demonstrated that this interaction also enhances cis-infection of MR-expressing macrophages [89]. This activity is analogous to that of DC-SIGN, which enhances trans-infection by DCs [122] and members of the Siglec family, which enhance both trans-and cis-infection of DCs and macrophages [123,124].…”

“…Given its role in enhancing HIV infection, it was somewhat surprising that several groups have observed that infection by HIV or SIV decreases MR expression and MR-mediated phagocytosis [72,75,125,126]. It was recently revealed that this is because, after a productive HIV infection has been established, MR continues to bind Env, which restricts HIV spread [89]. Downmodulation of MR is mediated simultaneously and independently by two HIV accessory proteins: Nef [127] and Vpr [89].…”

“…It was recently revealed that this is because, after a productive HIV infection has been established, MR continues to bind Env, which restricts HIV spread [89]. Downmodulation of MR is mediated simultaneously and independently by two HIV accessory proteins: Nef [127] and Vpr [89]. The effects of Vpr on MR and the implications for HIV pathogenesis are discussed in more detail in a separate section below.…”