Science - USA (2022-02-25)

SCIENCE science.org 25 FEBRUARY 2022 • VOL 375 ISSUE 6583 830-A

By Scott B. Biering

T

he Flaviviridae are a fam-

ily of medically impor-

tant viral pathogens that

include dengue virus se-

rotypes 1 to 4 (DENV1 to

DENV4) as well as Zika virus (ZIKV),

West Nile virus (WNV), and yellow fever vi-

rus (YFV). Together, these mosquito-borne

human pathogens impose a tremendous

global disease burden (ranging from non-

severe to potentially fatal cases) with dev-

astating economic effects ( 1 ). Almost half

of the world’s population lives within the

tropical and subtropical habitats of the

Aedes mosquito vectors that transmit these

viruses. As global temperatures continue

to climb, the habitats of Aedes will expand

further, resulting in even more people being

at risk for flavivirus infection. Thus, the de-

velopment of therapeutics and vaccines to

treat or prevent severe flavivirus infections

is urgently needed.

There are currently no flavivirus thera-

peutics available, and the lone licensed

dengue vaccine, Dengvaxia, is approved

only for individuals with preexisting

DENV immunity because of the risk of

predisposing DENV-naïve recipients to se-

vere disease, presumably from antibody-

dependent enhancement (ADE) ( 2 , 3 ). This

risk of vaccine-induced ADE is a problem

for all current dengue vaccine candidates

because they target the envelope (E) pro-

tein, making the production of a vaccine

challenging. Targeting other viral proteins

that contribute to severe disease is now a

major avenue of investigation ( 4 ). Further,

a pan-flavivirus therapeutic or vaccine di-

rected to a conserved viral protein critical

for disease is highly attractive given the

prevalence of multiple flaviviruses in many

Aedes-endemic areas. Previous work from

my team’s laboratory and others has impli-

cated the flavivirus nonstructural protein 1

(NS1) as such a target ( 5 , 6 ).

NS1 is well conserved among flaviviruses,

exhibiting 20 to 40% identity and 60 to 80%

similarity. This protein is essential for viral

replication as an intracellular dimer and is

secreted from infected cells as a

hexamer containing lipid cargo

( 7 , 8 ). Secreted NS1 circulates in

the blood of infected individu-

als, where it is used clinically for

diagnosis and as a biomarker of

disease severity ( 9 ). NS1 also

functions as a virulence factor through in-

teractions with immune cells, leading to the

secretion of proinflammatory and vasoac-

tive cytokines as well as interactions with

endothelial cells, which result in endothe-

lial barrier dysfunction and vascular leak

( 5 , 6 , 10 – 12 ). A cytokine storm and vascular

leak are hallmarks of severe DENV infec-

tion ( 13 ). My colleagues and I have shown

that multiple flavivirus NS1 proteins can

trigger vascular leak independently of viral

infection ( 14 ). Further, immunization and

passive transfer of anti-NS1 antibodies pro-

tects mice from lethal flavivirus challenge,

making NS1 a promising target for thera-

peutic intervention against pan-flavivirus

infection with no risk of ADE ( 5 , 15 , 16 ).

In 2021, we published a proof of concept

for achieving pan-flavivirus protection, re-

porting the structural basis of protection

of a pan-flavivirus anti-NS1 monoclonal

antibody (mAb) 2B7 ( 17 ). This antibody was

isolated from mice immunized with DENV2

NS1 as part of an immunology course taught

at the University of California, Berkeley, by

P. Robert Beatty in conjunction with the

laboratory of Eva Harris more than 20 years

ago. Today, our laboratory and many others

frequently use 2B7 as a molecular tool to

study DENV. As the role of flavivirus NS1 in

promoting pathogenesis became apparent,

we investigated whether 2B7 could protect

against lethal vascular leak syndrome in

our mouse model and found that it did ( 17 ).

To investigate the mechanism by which 2B7

inhibits NS1 pathogenesis, we teamed up

with Janet Smith, an expert NS1 structural

biologist at the University of Michigan,

to resolve a crystal structure of NS1 com-

plexed with 2B7. We reasoned that visual-

izing the interaction between NS1 and 2B7

could elucidate why 2B7 was protective and

potentially how NS1 contributes to disease.

Structures of DENV NS1 in complex with

2B7 revealed the possibility that 2B7 may

inhibit two domains of NS1 at once.

Flavivirus NS1 has three domains, includ-

ing the amino-terminal β-roll, the wing do-

IMMUNOLOGY

One antibody to treat them all

Conserved flavivirus protein holds potential as target for

versatile vaccines and therapies

Division of Infectious Diseases and Vaccinology, School of

Public Health, University of California, Berkeley, Berkeley,

CA 94720, USA. Email: [email protected]

FINALIST

Scott Biering

Scott Biering

received

undergraduate

degrees from

the University

of California, Los Angeles, and

a PhD in microbiology from

the University of Chicago. He is

currently a postdoctoral scholar

at the University of California,

Berkeley, in the laboratory of

Eva Harris. His present research

investigates the role of viral

proteins like flavivirus nonstruc-

tural protein 1 (NS1) and SARS-

CoV-2 spike (S) in inducing viral

pathogenesis and promoting

viral dissemination. http://www.science.

org/doi/10.1126/science.abn9651

PRIZE ESSAY

PHOTO: COURTESY OF SCOTT BIERING