Highlights d Potent nAbs were isolated from an asymptomatic donor with low plasma neutralization d RBD-specific nAbs target epitopes overlapping with known RBD antibody classes d NTD mutations in B.1.1.7 Spike confer neutralization resistance to NTD-specific nAbs d Most RBD-specific nAbs retain potent neutralization of the B.
HIV-1 must replicate in cells that are equipped to defend themselves from infection through intracellular innate immune systems. HIV-1 evades innate immune sensing through encapsidated DNA synthesis and encodes accessory genes that antagonize specific antiviral effectors. Here, we show that both particle associated, and expressed HIV-1 Vpr, antagonize the stimulatory effect of a variety of pathogen associated molecular patterns by inhibiting IRF3 and NF-κB nuclear transport. Phosphorylation of IRF3 at S396, but not S386, was also inhibited. We propose that, rather than promoting HIV-1 nuclear import, Vpr interacts with karyopherins to disturb their import of IRF3 and NF-κB to promote replication in macrophages. Concordantly, we demonstrate Vpr-dependent rescue of HIV-1 replication in human macrophages from inhibition by cGAMP, the product of activated cGAS. We propose a model that unifies Vpr manipulation of nuclear import and inhibition of innate immune activation to promote HIV-1 replication and transmission.
The antiviral cytokine interferon (IFN) activates expression of IFN-stimulated genes (ISGs) to establish an antiviral state. Myxovirus resistance 2 (MX2/MxB) is an ISG that inhibits the nuclear import of HIV-1 and interacts with the viral capsid and cellular nuclear transport machinery. We identified the myosin light chain phosphatase (MLCP) subunits MYPT1 and PPP1CB as positively-acting regulators of MX2, interacting with its N-terminal domain (NTD). We demonstrated that serine phosphorylation of the NTD at positions 14, 17 and 18 suppresses MX2 antiviral function, prevents interactions with the HIV-1 capsid and nuclear transport factors, and is reversed by MLCP. Importantly, NTD serine phosphorylation also impedes MX2-mediated inhibition of nuclear import of cellular karyophilic cargo. We additionally found that IFN treatment reduces levels of phosphorylation at these serines and outline a homeostatic regulatory mechanism where repression of MX2 by phosphorylation, together with MLCP-mediated dephosphorylation, balances the deleterious effects of MX2 upon normal cell function with innate immunity against HIV-1.
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