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Imam, H.

Publications and source records attributed to Imam, H..

2 recordsLinked to original sources
bioRxiv2022

The potent broadly neutralizing antibody VIR-3434 controls Hepatitis B and D Virus infection and reduces HBsAg in humanized mice

Background & AimsChronic hepatitis B is a major global public health problem, and coinfection with hepatitis delta virus (HDV) worsens disease outcome. Here, we describe a hepatitis B virus (HBV) surface antigen (HBsAg)-targeting monoclonal antibody (mAb) with the potential to promote functional cure of chronic hepatitis B and D to address this unmet medical need. MethodsHBsAg-specific mAbs were isolated from memory B cells of HBV vaccinated individuals. In vitro neutralization was determined against HBV and HDV enveloped with HBsAg representing eight HBV genotypes. Human liver-chimeric mice were treated twice weekly with a candidate mAb starting three weeks post HBV inoculation (spreading phase) or during stable HBV or HBV/HDV coinfection (chronic phase). ResultsFrom a panel of human anti-HBs mAbs, VIR-3434 was selected and engineered for pre-clinical development. VIR-3434 targets a putative conserved, conformational epitope within the antigenic loop of HBsAg and neutralized HBV and HDV infection with >12,000-fold higher potency than Hepatitis B Immunoglobulins in vitro. Neutralization was pan-genotypic against strains representative of HBV genotypes A-H. In the spreading phase of HBV infection in human liver-chimeric mice, a parental mAb of VIR-3434 (HBC34) prevented HBV dissemination and intrahepatic HBV RNA and cccDNA increase. In the chronic phase of HBV infection or co-infection with HDV, HBC34 treatment decreased circulating HBsAg by >1 log and HDV RNA by >2 logs. ConclusionsThis in vitro and in vivo characterization identified the potent anti-HBs mAb VIR-3434, which reduces circulating HBsAg and HBV/HDV viremia in human liver-chimeric mice. VIR-3434 is currently in clinical development for treatment of patients with chronic hepatitis B or D. Lay summaryChronic infection with hepatitis B virus places approximately 290 million individuals worldwide at risk for severe liver disease and cancer. Currently available treatments result in low rates of functional cure or require lifelong therapy that does not eliminate the risk of liver disease. We isolated and characterized a potent, human antibody that neutralizes hepatitis B and D viruses and reduces infection in a mouse model. This antibody could provide a new treatment for patients with chronic hepatitis B and D. HighlightsO_LIIdentification of a human mAb VIR-3434 that potently neutralizes HBV and HDV C_LIO_LIVIR-3434 targets a conserved, conformational epitope of the HBsAg antigenic loop C_LIO_LIVIR-3434 treatment blocks intrahepatic HBV spread in human liver-chimeric mice C_LIO_LIVIR-3434 treatment reduces circulating HBsAg and HDV RNA in co-infected mice C_LIO_LIData have enabled clinical development of VIR-3434 against chronic hepatitis B/D C_LI

microbiology↗
bioRxiv2017

Exosomes from Nef expressing monocytic cells restrict HIV-1 replication in infected cells through the assembly of stress granules

Exosomes are membranous vesicles secreted from almost all types of cells, carry proteins and nucleic acids and function as vehicles for intercellular communication. Cells infected with HIV-1 or expressing the viral Nef protein secrete more exosomes than uninfected cells or those not expressing this protein. We used stably transfected, Nef-expressing U937 human monocytic cells and exosomes purified from these cells to study their effects on HIV-1 infected and uninfected CD4+ T-cells. The Nef exosomes inhibited virus production from HIV-1 infected CD4+ T-cells, but caused activation induced cell death in uninfected bystander cells. Mutations in its conserved Arginine residues and in the secretion-modification-region failed to secrete Nef into exosomes. Cell lines expressing these mutant Nef proteins did not deliver it to the target CD4+ T-cells, and exosomes prepared from these mutant Nef-expressing cells also did not inhibit virus production. Nef exosomes inhibited virus production by inducing the assembly of stress granules in HIV-1 infected cells, which sequestered increased amounts of gag mRNA. This is a novel mechanism wherein we show the effects of exosomes on the assembly of stress granules and viral translational repression.

cell biology↗