Abstract
The Bunyaviridae comprise a large family of RNA viruses with worldwide distribution and includes the pathogenic New World hantavirus, Andes virus (ANDV). Host factors needed for hantavirus entry remain largely enigmatic and therapeutics are unavailable. To identify cellular requirements for ANDV infection, we performed two parallel genetic screens. Analysis of a large library of insertionally mutagenized human haploid cells and a siRNA genomic screen converged on components (SREBP-2, SCAP, S1P and S2P) of the sterol regulatory pathway as critically important for infection by ANDV. The significance of this pathway was confirmed using functionally deficient cells, TALEN-mediated gene disruption, RNA interference and pharmacologic inhibition. Disruption of sterol regulatory complex function impaired ANDV internalization without affecting virus binding. Pharmacologic manipulation of cholesterol levels demonstrated that ANDV entry is sensitive to changes in cellular cholesterol and raises the possibility that clinically approved regulators of sterol synthesis may prove useful for combating ANDV infection.
Highlights
Hantaviruses are a genera of the Bunyaviridae family that includes a large number of human pathogens
Hantaviruses found in the Americas, the so called New World hantaviruses, including Andes virus (ANDV) from Argentina and Chile, can cause a lethal hemorrhagic fever known as hantavirus pulmonary syndrome (HPS) while the Old World hantaviruses from Europe and Asia are associated with Hemorrhagic Fever with Renal Syndrome (HFRS) [1,2,3,4,5]
We found that four genes, encoding components of a complex involved in regulation of cholesterol synthesis and uptake, were critical for Andes virus infection
Summary
Hantaviruses are a genera of the Bunyaviridae family that includes a large number of human pathogens. Unlike other members of the Bunyaviridae family, ANDV and the other hantaviruses are not transmitted by arthropod vectors but instead infect humans directly by aerosolized excreta from infected rodents. Entry into host cells by the membrane enveloped hantaviruses depends upon the viral glycoproteins GN and GC, which form a heterodimeric complex on the virion surface following cleavage of a polyprotein precursor [6,7,8]. ANDV must utilize host cell molecules and pathways during the virus life cycle for replication to occur. Identifying pathways rather than individual molecules that are needed for virus replication could lead to the development of multiple therapeutic targets. Pathways used in common by multiple viruses within a family would represent ideal candidates for therapeutic development
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