Primate Lentiviruses Modulate NF-κB Activity by Multiple Mechanisms to Fine-Tune Viral and Cellular Gene Expression

Abstract

The transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) plays a complex role during the replication of primate lentiviruses. On the one hand, NF-κB is essential for induction of efficient proviral gene expression. On the other hand, this transcription factor contributes to the innate immune response and induces expression of numerous cellular antiviral genes. Recent data suggest that primate lentiviruses cope with this challenge by boosting NF-κB activity early during the replication cycle to initiate Tat-driven viral transcription and suppressing it at later stages to minimize antiviral gene expression. Human and simian immunodeficiency viruses (HIV and SIV, respectively) initially exploit their accessory Nef protein to increase the responsiveness of infected CD4+ T cells to stimulation. Increased NF-κB activity initiates Tat expression and productive replication. These events happen quickly after infection since Nef is rapidly expressed at high levels. Later during infection, Nef proteins of HIV-2 and most SIVs exert a very different effect: by down-modulating the CD3 receptor, an essential factor for T cell receptor (TCR) signaling, they prevent stimulation of CD4+ T cells via antigen-presenting cells and hence suppress further induction of NF-κB and an effective antiviral immune response. Efficient LTR-driven viral transcription is maintained because it is largely independent of NF-κB in the presence of Tat. In contrast, human immunodeficiency virus type 1 (HIV-1) and its simian precursors have lost the CD3 down-modulation function of Nef and use the late viral protein U (Vpu) to inhibit NF-κB activity by suppressing its nuclear translocation. In this review, we discuss how HIV-1 and other primate lentiviruses might balance viral and antiviral gene expression through a tight temporal regulation of NF-κB activity throughout their replication cycle.

Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread

“…5), with the presence of vpu being specific to HIV-1 and some closely related simian lentiviruses (11). This has led to the notion that loss of Nefmediated CD3 down-regulation was facilitated by the acquisition of a vpu gene in a subset of primate lentiviruses, including HIV-1 (41,42). Vpu suppresses T cell activation by interfering with NF-κB to limit interferon-stimulated gene induction and innate immune responses (41,(43)(44)(45), in addition to antagonizing the restriction factor tetherin (46) and mediating CD4 degradation.…”

“…This has led to the notion that loss of Nefmediated CD3 down-regulation was facilitated by the acquisition of a vpu gene in a subset of primate lentiviruses, including HIV-1 (41,42). Vpu suppresses T cell activation by interfering with NF-κB to limit interferon-stimulated gene induction and innate immune responses (41,(43)(44)(45), in addition to antagonizing the restriction factor tetherin (46) and mediating CD4 degradation. By contrast, Nef stimulates IKKβ-mediated NF-κB activation to boost viral LTR activity and increase proviral transcription (43).…”

“…This creates an intriguing challenge for the virus of temporally balancing two opposing activities of Nef and Vpu to drive efficient viral transcription and replication while concomitantly suppressing antiviral responses and is comprehensively reviewed in ref. 41. The requirement to toggle T cell activation during different stages of the viral replication cycle likely explains why acquisition of vpu correlated with loss of Nef-mediated CD3 down-regulation (41); however, it does not explain why keeping CD3 should be better.…”

The involvement of human endogenous retroviruses K (HERV-K) in aging processes via induction of inflammation

“…In addition, primate lentiviruses, including HIV, boost NF-κB prote B activity to initiate viral transcription (Heusinger and Kirchhoff, 2017), leading to mild prolonged inflammation. The HIV infection also leads to accelerated aging detected by the epigenetic clock (Horvath and Levine, 2015).…”

The involvement of human endogenous retroviruses K (HERV-K) in aging processes via induction of inflammation

“…In addition, primate lentiviruses, including HIV, boost NF-κB prote B activity to initiate viral transcription (Heusinger and Kirchhoff, 2017), leading to mild prolonged inflammation. The HIV infection also leads to accelerated aging detected by the epigenetic clock .…”