HIV-1 Vpr Redirects Host Ubiquitination Pathway

Abstract

HIV-1 modulates key host cellular pathways for successful replication and pathogenesis through viral proteins. By evaluating the hijacking of the host ubiquitination pathway by HIV-1 at the whole-cell level, we now show major perturbations in the ubiquitinated pool of the host proteins post-HIV-1 infection. Our overexpression-and infection-based studies of T cells with wildtype and mutant HIV-1 proviral constructs showed that Vpr is necessary and sufficient for reducing whole-cell ubiquitination. Mutagenic analysis revealed that the three leucine-rich helical regions of Vpr are critical for this novel function of Vpr, which was independent of its other known cellular functions. We also validated that this effect of Vpr was conserved among different subtypes (subtypes B and C) and circulating recombinants from Northern India. Finally, we establish that this phenomenon is involved in HIV-1-mediated diversion of host ubiquitination machinery specifically toward the degradation of various restriction factors during viral pathogenesis. IMPORTANCEHIV-1 is known to rely heavily on modulation of the host ubiquitin pathway, particularly for counteraction of antiretroviral restriction factors, i.e., APOBEC3G, UNG2, and BST-2, etc.; viral assembly; and release. Reports to date have focused on the molecular hijacking of the ubiquitin machinery by HIV-1 at the level of E3 ligases. Interaction of a viral protein with an E3 ligase alters its specificity to bring about selective protein ubiquitination. However, in the case of infection, multiple viral proteins can interact with this multienzyme pathway at various levels, making it much more complicated. Here, we have addressed the manipulation of ubiquitination at the whole-cell level post-HIV-1 infection. Our results show that HIV-1 Vpr is necessary and sufficient to bring about the redirection of the host ubiquitin pathway toward HIV-1-specific outcomes. We also show that the three leucinerich helical regions of Vpr are critical for this effect and that this ability of Vpr is conserved across circulating recombinants. Our work, the first of its kind, provides novel insight into the regulation of the ubiquitin system at the whole-cell level by HIV-1.

Coexpression Network Analysis of Benign and Malignant Phenotypes of SIV-Infected Sooty Mangabey and Rhesus Macaque

“…Based on the gene expression phenotypes, these pathways are classified into three different groups: (1) the MAL + phenotypes that are only observed in RMs; (2) the mixed phenotypes (MAL + /BEN + ) present in both RMs and SMs; and (3) the BEN + phenotypes that are solely present in SMs ( Fig 3 ). There are eight enriched pathways in the MAL + group, including the protein ubiquitination pathway, p53, granzyme A signaling, gramzyme B signaling, Mitotic roles of polo-like kinase, Glucocorticoid receptor signaling, oxidative phosyphorylation and mitochondrial dysfunction pathways [ 38 – 43 ]. Another enriched pathway (i.e., granzyme A signaling pathway) is also observed at three time points of SIV infection in RMs.…”

HIV infection results in clonal expansions containing integrations within pathogenesis-related biological pathways

“…Viral integrations were consistently detected in genes represented in numerous biological pathways, and these integrations exhibited specific clonal expansion only during in vivo infection. The accessory genes of HIV are known to broadly alter the internal composition of infected cells by hijacking normal phosphorylation (36) and ubiquitin processes (37), mediating viral gene transcription (38), and suppressing immune surveillance and detection (39). These data indicate that cells containing viral integrations within genes relevant to these pathways have a higher frequency of expansion, especially during in vivo infection, indicating preferential IS expansion.…”

Network of MicroRNAs Mediate Translational Repression of Bone Morphogenetic Protein Receptor‐2: Involvement in HIV‐Associated Pulmonary Vascular Remodeling

“…Ubiquitinylated degradation of BMPR2 by SMURF and viral K5 ubiquitin ligases have been reported previously. 28,29,56 Considering the overall reduction of ubiquitination process under HIV infection, 57 the miRNA pathway may play an alternative role in the observed BMPR2 downregulation in response to HIV-1 and cocaine exposure. In extension to our previous findings, in the present study we demonstrate the role of miRNAs in regulating the translation expression of BMPR2 independent of its mRNA degradation in HPASMCs when exposed to cocaine and HIV-1 protein Tat.…”