Polyamine-Linked Cholesterol Incorporation in Rift Valley Fever Virus Particles Promotes Infectivity

Abstract

Viruses rely on an array of cellular metabolites to replicate and form progeny virions. One set of these molecules, polyamines, are small aliphatic molecules, which are abundant in most cells, that support virus infection; however, the precise roles of polyamines in virus infection remain incompletely understood. Recent work demonstrated that polyamine metabolism supports cellular cholesterol synthesis through translation of the key transcription factor SREBP2. Here, we show that the bunyavirus Rift Valley fever virus (RVFV) relies on both cholesterol and polyamines for virus infection. Depletion of cellular cholesterol or interruption of cholesterol trafficking negatively impacts RVFV infection. Cholesterol is incorporated into RVFV virions and mediates their infectivity in a polyamine-dependent manner; we find that the virus derived from polyamine-depleted cells lacks cholesterol within the virion membrane. Conversely, we find that virion-associated cholesterol is linked to the incorporation of spermidine within the virion. Our prior work demonstrated that polyamines facilitate pH-mediated fusion and genome release, which may be a consequence of cholesterol depletion within virions. Thus, our work highlights the metabolic connection between polyamines and cholesterol synthesis to impact bunyavirus infection. These data demonstrate the connectedness between cellular metabolic pathways and reveal potential avenues of therapeutic intervention.

Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs Urea Cycle

“…Polyamines are important for replication of various viruses. In recent years the Mounce group demonstrated that polyamines ensure infectivity of virions either by direct incorporation into the virus particle [55] or by incorporation of cholesterol [56] thus conferring binding of virions to the cell surface and concomitant virus entry [55,57,58]. During polyamine exhaustion, non-infectious viral particles can be formed, as shown for Bunyaviruses [59].…”

Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle

“…Polyamines are important for the replication of various viruses. In recent years, the Mounce group demonstrated that polyamines ensure the infectivity of virions either by direct incorporation into the virus particle [ 59 ] or by incorporation of cholesterol [ 60 ], thus conferring binding of virions to the cell surface and concomitant virus entry [ 59 , 61 , 62 ]. During polyamine exhaustion, non-infectious viral particles can be formed, as shown for Bunyaviruses [ 63 ].…”

Natural hosts and animal models for Rift Valley fever phlebovirus

“…In addition to inhibiting viral entry, translational arrest and autophagy are also considered integral components of host defense against RVFV ( 86 , 87 ). Cholesterol can be incorporated into RVFV particles and enhance RVFV infectivity in a polyamine-dependent manner ( 88 ). Studies have found that a high-cholesterol diet can lead to liver cholesterol accumulation, and it mainly affects cerebral vessels among the vascular effects, with up-regulation of LDLr and LRP1 detected in cerebral vessels ( 89 ).…”