Biology subjects

Dash, C.

Publications and source records attributed to Dash, C..

3 recordsLinked to original sources

bioRxiv2022

HIV-1 preintegration complex preferentially integrates the viral DNA into nucleosomes containing trimethylated histone 3-lysine 36 modification

HIV-1 DNA integration into the host chromosomes is carried out by the preintegration complex (PIC). The PIC contains the viral DNA, virally encoded integrase enzyme and other critical viral/host factors. The PIC-associated viral DNA is preferentially integrated into gene bodies of actively transcribing genes. Here, we identify a biochemical mechanism underlying the preference of PIC-mediated viral DNA integration (PIC-VDI). Specifically, we observed that the PIC-VDI into human chromatin is preferred over the genomic DNA. Surprisingly, nucleosome core particles without any histone modifications were not preferred for PIC-VDI when compared to the analogous naked DNA. However, PIC-VDI was markedly enhanced with nucleosomes containing the trimethylated histone 3 lysine 36 (H3K36me3), an epigenetic mark linked to HIV-1 DNA integration preference. Interestingly, we observed that nucleosomes with flanking linker DNA promoted PIC-VDI in the presence of LEDGF/p75. We also discovered that nucleosomes with linker DNA and H3K36me3 served as the optimal substrate for PIC-VDI. Mapping of the integration sites within these substrates identified preference of specific regions of the nucleosome core DNA for integration. Finally, we provide biochemical and genetic evidence that histone H1 protein, that condenses the chromatin, negatively regulates HIV-1 DNA integration, consistent with the integration preference for open chromatin structure. Collectively, these results identify the role of specific chromatin marks that drive HIV-1 integration preference and define the optimal substrate requirement for efficient DNA integration by the PIC.

microbiology↗

bioRxiv2021

HIV-1 Mutants that Escape the Cytotoxic T-Lymphocytes are Defective in Viral DNA Integration

ABSTRACT HIV-1 replication is durably controlled in certain untreated HIV-1-infected individuals expressing particular human leukocyte antigens (HLA). These HLAs tag infected cells for elimination by presenting specific viral epitopes to CD8+ cytotoxic T-lymphocytes (CTL). In individuals expressing HLA-B27, CTLs primarily target the capsid protein (CA)-derived KK10 epitope. Selection of CA mutation R264K helps HIV-1 escape the CTL response but severely diminishes virus infectivity. Here we report that the R264K mutation-associated infectivity defect arises primarily from impaired viral DNA integration. Strikingly, selection of the compensatory CA mutation S173A or depletion of host cyclophilin A largely rescues the R264K-associated integration and infectivity defects. Collectively, our study reveals novel mechanistic insights into the fitness defect incurred by an HIV-1 variant escaping a CA-directed CTL response.

microbiology↗

bioRxiv2020

Phycobilins as potent food bioactive broad-spectrum inhibitor compounds against Mpro and PLpro of SARS-CoV-2 and other coronaviruses: A preliminary Study

In the twenty first century, we have witnessed three corona virus outbreaks; SARS in 2003, MERS in 2012 and ongoing pandemic COVID-19. To prevent outbreaks by novel mutant strains, we need broad-spectrum antiviral agents that are effective against wide array of coronaviruses. In this study, we scientifically investigated potent food bioactive broad-spectrum antiviral compounds by targeting Mpro and PLpro proteases of CoVs using in silico and in vitro approaches. The results revealed that phycocyanobilin (PCB) showed potential inhibitor activity against both proteases. PCB had best binding affinity to Mpro and PLpro with IC50 values of 71 m and 62 m, respectively. In addition, in silico studies of Mpro and PLpro enzymes of other human and animal CoVs indicated broad spectrum inhibitor activity of the PCB. Like PCB, other phycobilins such as phycourobilin (PUB), Phycoerythrobilin (PEB) and Phycoviolobilin (PVB) showed similar binding affinity to SARS-CoV-2 Mpro and PLpro

microbiology↗