p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway

Abstract

Macrophages are a major target cell for HIV-1, and their infection contributes to HIV pathogenesis. We have previously shown that the cyclin-dependent kinase inhibitor p21 inhibits the replication of HIV-1 and other primate lentiviruses in human monocyte-derived macrophages by impairing reverse transcription of the viral genome. In the attempt to understand the p21-mediated restriction mechanisms, we found that p21 impairs HIV-1 and simian immunodeficiency virus (SIV)mac reverse transcription in macrophages by reducing the intracellular deoxyribonucleotide (dNTP) pool to levels below those required for viral cDNA synthesis by a SAM domain and HD domain-containing protein 1 (SAMHD1)-independent pathway. We found that p21 blocks dNTP biosynthesis by down-regulating the expression of the RNR2 subunit of ribonucleotide reductase, an enzyme essential for the reduction of ribonucleotides to dNTP. p21 inhibits RNR2 transcription by repressing E2F1 transcription factor, its transcriptional activator. Our findings unravel a cellular pathway that restricts HIV-1 and other primate lentiviruses by affecting dNTP synthesis, thereby pointing to new potential cellular targets for anti-HIV therapeutic strategies.

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

“…It is tempting to speculate that HLTF could exert additional functions, because we report here that the protein is expressed in nondividing macrophages. Cell cycle-related proteins, for instance, the cyclin/ Cdk inhibitor p21, which was first thought to be only dedicated to the control of cell cycle progression, were later on identified in macrophages as a repressor of HIV-1 replication (75,76). Our experiments did not demonstrate a rescue of Vpr-deleted HIV-1 replication in HLTF-silenced macrophages.…”

Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

“…During viral entry, HIV-1 replication is dependent on the activity of a host cell ribonucleotide reductase (RNR) that contains nonheme iron, which is important for its enzymatic activity (52). Recently, expression of p21 was shown to downregulate the expression of the RNR2 subunit, which decreased the intracellular deoxynucleoside triphosphate (dNTP) pool and impaired HIV-1 and simian immunodeficiency virus (SIV) reverse transcription (53). Expression of p21 inhibited RNR2 transcription by repressing the E2F1 transcription factor which activates RNR2 transcription (53).…”

COMMD1/Murr1 Reinforces HIV-1 Latent Infection through IκB-α Stabilization

“…Although latent HIV-1 infection affected the expression of several host factors in four sets of latently HIV-1-infected cells and the respective parental cells, most of these effects were dependent on the cell type. Interestingly, p21 was induced in all latently HIV-1-infected cell lines and was previously reported as an HIV-1 restriction factor in hematopoietic stem cells and macrophages (51,52). Therefore, on the basis of this concept, reevaluation of host factors by knockdown screening might clarify the effect of host factors on HIV-1 latency and improve our understanding of the roles of HIV-1 host factors.…”