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>> GOOD AFTERNOON.
WE'LL GET STARTED.
AS YOU CAN ALL TELL, IT'S
VIRTUALLY SPRINGTIME, SUMMERTIME
OUTSIDE AND IT'S ALSO
SOMETHING --
>> [INDISCERNIBLE]
>> HOW'S THAT?
THANK YOU.
OKAY.
SO IT'S SPRINGTIME, SUMMERTIME
AND THAT HAS MANY RECOLLECTIONS.
AND I'D LIKE TO BRIEFLY SHARE
ONE WITH YOU AS A SORT OF
UNUSUAL INTRODUCTION TO TODAY'S
TOPIC.
BUT I HOPE YOU'LL SEE WHERE I'M
GETTING.
SO THIS SYMBOL OF COURSE IS THE
BROOKLYN BRIDGE.
ONE OF THE TWO MOST FAMOUS
STRUCTURES IN BROOKLYN AND ONE
THAT HAS LASTED, AND THOSE OF
YOU WHO HAVE BEEN COMING TO THIS
COURSE REPEATEDLY HAVE HEARD
THIS SONG OVER AGAIN BUT IT'S
SORT OF THE METAPHOR THAT
SYMBOLIZES BRIDGING, BASIC
SCIENCE AND HUMAN HEALTH.
I'VE BEEN HANDING OUT WRONG
INFORMATION FOR SEVERAL WEEKS.
THAT'S ACTUALLY MANHATTAN ON THE
OTHER SIDE, NOT BROOKLYN.
AND THE TALLEST BUILDING IS THE
TRINITY CHURCH.
FOR THOSE WHO CALLED MY
ATTENTION TO IT, I STAND
ECTED.
OKAY.
NOW, THIS IS THE BASEBALL
SEASON, AND IT'S JUST STARTED.
AND IT'S VERY EXCITING AND THE
OTHER GREAT SYMBOL OF BROOKLYN
IS ABBOTT'S FIELD WHICH IS NOW A
GIANT HOUSING THING.
THERE'S A LITTLE PLAQUE ON THE
GROUND AND YOU TALK TO PEOPLE DO
YOU KNOW WHAT WAS HERE, NOBODY
HAS THE FAINTEST IDEA.
BUT THIS IS THE WORLD CHAMPION
BROOKLYN DODGERS IN 1955.
THE NEXT SLIDE SHOWS FOURF THE
BIG STARS AS JACKIE ROBINSON,
NEXT TO HIM IS DUKE SCHNEIDER
AND NEXT TO HIM IS PEE WEE RUIZ
AND NEXT TO HIM IS HARVEY ALTER.
[LAUGHTER]
I DON'T KNOW WHO THE FOURTH
PERSON IS.
MAYBE SOME EXPERTH CAN HELP ME
OUT.
WHY HOULD I BE SHOWING
BASEBALL PICTURES.
IT'S VERY SIMPLE.
BECAUSE THE MOST IMPORTANT
PERSON IN THE BASEBATHEME
ASIDE FROM THE PITCHER AND THE
COACH AND EVERYBODY ELSE IS THE
NUMBER 4 HITR BECAUSE SOMEBODY
IN THE FIRST THREE IS SUPPOSED
TO GET ON BASE AND THE NUMBER
FOUR HITTER IS THE GUY WHO HITS
THE HOME RUN.
SO TH IS A LONG TRACK IN A WAY
OF SAYING THAT TODAY WE HAVE TWO
NUMBER FOUR HITTERS.
AND THIS IS NO JOKE.
WE'RE REALLY VERY GRATEFUL TO
BOTH OF YOU FOR COMING.
AND I HOPE WE ALL WILL BENEFIT
FROM EXCITING NEW THINGS THAT
WE'RE GOING TO HEAR.
SO THE FIRST OF OUR SPEAKERS
TODAY IS JAKE LIANG HO GOT HIS
MEDICAL DEGREE AT HARVARD
MEDICAL SCHOOL.
AND IS HERE AT NIH AS THE CHIEF
OF THE LIVER DISEASE BRANCH.
JAKE HAS BEEN EXTREMELY
PRODUCTIVE IN LEADING A GROUP
THAT'S INVOLVED IN THE EXCITING
DEVELOPMENTS WITH HEPATITIS C
VIRUS.
WHICH WHO KNOWS, MAYBE THE FIRST
CHRONIC VIRUS INFECTION OF MAN
TO BE CURED BY DRU, WE'LL SEE.
WE'LL HEAR ABOUT IT.
AN ENORMOUS PROBLEM JAKE AND HIS
COLLEAGUES HAVE DONE OUTSIDING
WORK IN THE MOLECULAR, CELLULAR
AND ALSO AT THE CLINICAL LEVEL.
OUR SECOND SPEAKER IS HARVEY
ALTER WHO IS CHIEF OF THE
CLINICAL STUDIES AND ASSOCIATE
DIRECTOR OF RESEARCH IN THE
CLINICAL CENTER.
AND IN THE DEPARTMENT OF
TRANSFUSION IMMEDIATESON.
HARVEY IS FAMOUS BECAUSE AFTER
HIS GRADUATION FROM ROCHESTER
SCHOOL OF IMMEDIATE ISN'T HE
CAME TO NIH AS AN INVESTIGATOR,
AS A CLINICAL ASSOCIATE.
AND PLAYED A SIGNIFICANT
IMPORTANT ROLE IN THE DISCOVERY
OF AUSTRALIA ANTIGEN WHICH WAS
THE FIRST CLUE FOR THE
IDENTIFICATION OF HEPATITIS B
VIRUS.
NOW YOU MAY NOT THINK OF IT, BUT
IN THOSE DAYS IF SOMEBODY WENT
AND HAD TO HAVE A BLOOD
TRANSFUSION, THE CHANCES OF
GETTING HEPATITIS WERE VERY HIGH
PARTICULARLY IF YOU HAD MORE
THAN ONE TRANSFUSION.
AND THERE WAS SOME KNOWLEDGE
THAT THERE WERE AT LEAST TWO
MAJOR KINDS, ONE YOU GOT FROM
WATER AND CONTAMINATED FOOD AND
THAT TURNED OUT TO BE HEPATITIS
A OF COURSE.
AND THEN THERE WERE OTHERS THAT
WERE TRANSMITTED THROU LARGELY
BLOOD.
AND THE FIRST ONE IDENTIFIED WAS
HEPATITIS B.
AND MAR -- HARVEY PLAYED A
CRITICAL ROLE IN THAT AND
APPLIED THE KNOWLEDGE TO THE
BLOOD BANK WHOSE NAME YOU'LL
HEAR ELIMINATED A BIG PORTION OF
THIS POST TRANSFUSION HEPATITIS.
BUT HE WISELY RECOGNIZED THAT
THE WERE OTHER VIRUSES.
AND THEN PLAYED A IT CRITICAL
ROLE IN THE DESCRIPTION OF
SO-CALLED NON-A NON-B WHICH
TURNED OUT TOBE HEPATITIS C
VIRUS.
WHICH WE'LL HEAR MUCH MORE ABOUT
LATER.
NOW, IN RECOGNITION OF THESE
FINDINGS, HARVEY HAS RECEIVED
THE ALASKA AWARD ENUMERABLE
AWARDS FROM ORGANIZATIONS AROUND
THE WORLD AND MOST RECENTLY
RECEIVED A VERY PRESTIGIOUS
AWARD FROM CANADA.
AND SO HARVEY'S GOING TO TALK
ABOUT A NEW VIRUS ABOUT WHICH
MAYBE MANY OF YOU HAVEN'T HEARD.
THE ALPHABET HAS EXPENDED BEYOND
B TO E AND A LITTLE BEYOND.
BUT HE'S TOGETHER TO DISCUSSION
THE QUESTION OF E VIRUS AND ITS
RELATIONSHIP TO THE BLOOD BANK.
WHEN YOU THINK OF IT, THE BLOOD
BANK IS SOMETHING ON WHICH OUR
LIVES IN MEDICINE DEPEND.
THERE'S NO SUBSTITUTE.
YET, IT'S BEEN A LONG TIME
THERE'S ALWAYS THE QUESTION OF
DOES SOMETHING CREEP INTO THE
BLOOD BANK THAT CAN THEN CAUSE
EPIDEMICS AND SERIOUS ILLNESS
AMONG PEOPLE WHO GET
TRANUSIONS.
IS IT POSSIBLE TO PREDICT THAT?
OR IF YOU FIND SOMETHING, HOW DO
YOU FIND OUT WHETHER IT ACTUALLY
CAUSES DISEASE.
SO THESE ARE SOME OF THE
PROBLEMS THAT WILL BE DISCUSSED.
SO THANK YOU VERY MUCH, AND
JAKE, IF YOU WOULD AGAIN.
>> CAN YOU HEA ME?
OKAY.
THANKS FOR THAT KIND
INTRODUCTION, AND WHEN YOU
SHOWED THAT PICTURE OF BROOKLYN
BRIDGE I WASN'T SURE WHAT HE WAS
TRYING TO DO.
I THOUGHT HE WAS GOING TO TRY TO
SELL THE BROOKLYN BRIDGE BECAUSE
HE COULD DO THAT.
HARVEY ALSO IS PROBABLY MORE
APPROPRIATE TO TALK BIT BECAUSE
HE'S CLELY ONE OF THE PIONEERS
IN DISCOVERING HEPATITIS C VIRUS
BUT HE WAS KIND ENOUGH TO LET
TALK ABOUT HEPATITIS C AND TAKE
A NEW ADVENTURE ON HEPATITIS E.
WITHOUT FURTHER ADIEU, I CAME UP
WITH THIS TITLE PROBABLY BECAUSE
I FELT THAT SINCE THIS IS A
SERIES ON DEMYSTIFYING MEDICINE,
I SHOULD COME OUT WITH A
MYSTERIOUS TITLE AND THEN TRY TO
EXPLAIN IT.
IN THE SECOND, I THINK THIS IS
SOMETHING ACTUALLY SOMEHOW
INSPIRED ME WHAT I HAVE DONE
WHICH HOPEFULLY I'LL SHARE WITH
YOU MY THOUGHTS.
AS YOU HEARD, HEPATITIS C IS A
MAJOR PUBLIC HEALTH PROBLEM,
MORE THAN THREE MILLION AMERICAN
PEOPLE INFECTED WITH HEPATITIS
C.
AND GLOBALLY 170 PEOPLE INFECTED
WITH HEPATITIS C.
THIS IS NOT ONLY THE MAJOR CAUSE
OF CHRONIC LIVER DISEASE IN THE
WORLD BUT ALSO ONE OF THE HUMAN
VIRUSES HAS BEEN LOOKED
ETIOLOGICALLY.
IF YOU LOOK AT THE TREND IN THE
LAST DECADE OR SO -- 20 YEARS
AGO AND REALLY TOOK MANY YEARS
AFTER THAT WAS DISCOVERED IN
1989, AND THE VIRUS CLONED
MOLECULARLY BY MICHAEL AND HIS
COLLEAGUE -- OUR OWN HARVEY
ALTER AND BEN BRADLEY AT CDC,
THIS WOULD NOT HAVE BEEN
POSSIBLE.
THIS IS A MEMBER OF FLAVIVIRIDAE
FAMILY.
AND THERE ARE 30% SEQUENCE
VARIATIONS.
HIGH MUTATIONAL RATES CERTAINLY
IN THE BLOOD AND WHAT'S QUAD
QUASPECIES.
AND HIGH RATE OF CHRONICITY 70
TO 80% PEOPLE INFECTED WITH THIS
VIRUS WILL DEVELOP INTO CHRONIC
INFECTION DESPITE ACTIVE IMMUNE
RESPONSE.
ALSO ABOUT THIS INFECTION THAT
HAS A SILENT DISEASE PROGRESSION
MOST OF THE PEOPLE WITH THIS
INFECTION DON'T EVEN KNOW IT.
IF THEY DON'T HAVE END STAGE
LIVER DISEASE WILL THEY BECOME
SYMPTOMATIC.
I'M GOING TO COME BACK TO IT
ALTHOUGH MOST OF MY TALK TODAY
WILL NOT BE ON -- HOPEFULLY
YOU'LL GET SOME INKLING ON WHAT
WE DO.
THE VIRUS HAS EVOLVED WITH A
HOST WITH HUNDRED OF YEARS OR
FOR ONGOING INFECTIONS.
THE VIRUS FIRST INFECT THE HOST
THROUGH A SERIES OF HIGHLY
COORDINATED AND SEQUENTIAL
STEPS.
FIRST OF ALL VIRUS GAIN ENTRY
INTO THE CELLS BY INTERACTION
WITH VERY DIFFERENT POST DOCTOR
SO-CALLED ENTRY FACTORS.
AND THEN THE VIRUS IS THEN
RELEASED AND TRAFFIC THE AREA
OF, LET ME GET THIS WORKING, OF
ER IN WHICH THE -- TRANSLATED
INTO POLY PROTEIN.
AND THEN TOGETHER WITH MEMBRANE
DERIVED FROM THE ER FORMING THIS
SO-CALLED REPLICATED
INTERMEDIATE CONTRACTS IN WHICH
THE VIRAL REPLICATION OCCURS.
AND THEN MOST INFREQUENTLY
THROUGH ORGANELLE IN THE LIFER
CALLED LIPID DROPLETS THAT'S
WHERE THEY FIRST ASSEMBLE.
FROM THERE THE VIRUS IN COMPLEX
LIPO PROTEINS RELEASES INTO
CIRCULATION ALTERNATIVELY IT
COULD SPREAD TO THE ADJACENT
CELLS WITHOUT GOING THROUGH THE
CIRCULATION.
SO LET ME GO BACK TO MY TITLE.
SO WHAT IS ZERO DAY.
FOR THOSE OF YOU WHO KNOW WHAT
IT IS, LET ME PLAY IT OUT.
AND SO THERE ARE SEVERAL
MULTIPLE CHOICES.
IS IT YOUR BIRTHDAY, IS IT THE
DAY YOUR BANK ACCOUNT BALANCE IS
ZERO OR THE DAY YOU FEEL YOUR
LIFE IS A BIG ZERO I THINK THAT
MAY BE FAVORITE ANSWER FOR
DR. ALTER BUT I'LL ASK HIM
LATER.
RELATED TO THE ACADEMY AWARD
NOMINEE ZERO DARK 30.
OR SEPTEMBER 2011 OR IS THIS
WHAT GROUND ZERO IS NAMED.
THE LAST THREE IS CLOSE TO THE
ANSWER.
IN TODAY IT'S A CYBER SPACE
LINGO.
IT REFLECTS A VULNERABILITY IN
THE SOFTWARE OF A COMPUTER THAT
IS UNKNOWN BUT CAN BE EXPLOITED
BY HACKER TO BREAK INTO THE
SYSTEM.
THE MOST COMMON TECHNIQUE THAT
HACKING IS CALLED FUZZING.
FUZZING MEANS YOU INPUT RANDOM
DATA INTO APPLICATIONS THAT
FORCE THEM TO CRASH.
WHAT YOU DO IS YOU WOULD
DOCUMENT ALL THE CRASHES AND
TRYING TO FIGURE OUT WHERE THE
CRASH OCCUR AND EVENTUALLY TO
FOOL THE COMPUTER TO REVEAL THIS
VULNERABILITY FOR A WAY TO HACK
INTO THE COMPUTER.
THIS IS HOW MOST OF THE HACKERS
CAN HACK INTO VERY COMPLICATED
SOPHISTICATED COMPUTER SYSTEM.
AND ALTHOUGH I'M NOT A HACKER
BUT THIS CONCEPT IS INTRIGUING.
SO HOW CAN WE APPLY THIS
SO-CALLED ZERO DAY FOR HEPATITIS
C.
AGAIN ACTUALLY THIS IS NOT
REALLY NOT REALLY NEW.
SUCH A CONCEPTUALLY HAS BEEN
REALLY PROPOSED MANY YEARS AGO.
A NOBEL LAUREATE HAD MADE THE
STATEMENT THAT IN THE FACE OF
GREAT COMPLEXITY RANDOMNESS IS
NOT AN IRRATIONAL PROCESS.
SO HOW CAN THIS CONCEPT OF
HACKING RANDOMNESS INTRODUCE
HELP -- HEPATITIS C.
IF YOU INTRODUCE SO-CALLED
RANDOM PERTURBENS TO PERTURB THE
SYSTEM INTO VIRUS INFECTED CELLS
TO FORCE THE VIRUS TO PA HAVE
DIFFERENTLY JUST LIKE YOU FORCE
COMPUTERS BEHAVE DIFFERENTLY.
IN ORDER TO REVEAL THE SECRET
AND IDENTIFY ITS VULNERABILITY.
I THINK IN THE REST OF MY TALK,
I'M GOING TO SHARE WITH YOU
THREE VIGNETTES IN WHICH I'M
GOING TO APPLY THREE TYPE OF
PERTURBGUNS WITH PERHAPS BETTER
TREATMENT FOR THE VIRUS.
IT'S SMALL INTERFERENCE RNAs
MICRO RNAs AND CHEMICAL
PROBES.
AND INTERFERON FOR PROTURBENS.
THESE ARE HIGHLY USEFUL TOOLS
THAT YOU CAN SPECIFIC USING THIS
CONCEPT OF PERTURBAGENS
INITIATED AN ACV HOST
INTERACTIONS BY GENOME-WIDE
SIRNA SCREEN.
THIS WORK WAS DONE IN
COLLABORATION WITH HARVARD
MEDICAL SCHOOL INSTITUTE OF
CHEMISTRY IN CELL BIOLOGY WHO
HAD THE SCREENING FACILITY FOR
SIRNA.
YOU HAVE ARRAY POOLS OF SIRNA
REPRESENTING 20,000 HUMAN GENES
IN THE HUMAN GENOME AND THEM
TRANSECT IT INTO CELLS AND ONCE
YOU KNOCK OUT THESE GENES YOU
INFECT THE CELL WITH THE VIRUS
AND LATER YOU WILL HARVEST THE
CELLS.
THE CELLS YOU WILL USE EITHER
FOR STAINING FOR THE VIRAL
PROTEIN OR STAINING FOR NUCLEI
BY AUTOMATED IMAGING TECHNOLOGY.
THE SECOND STEP OR PART TO TAKE
THE FIRST STEP AND TRANSFER ON
TO NAIVE CELLS ASK THEN GO
THROUGH THE SAME PROCEDURE.
AS YOU CAN SEE PART ONE AND PART
TWO ACTUALLY LOOKING AT
DIFFERENT STAGES OF ROI CYCLES.
SO YOU THINK THIS TECHNIQUE WAS
ABLE TO IDENTIFY A WHOLE SERIES
OF WHAT WE CALL HOST FACTORS
THAT CAN FACILITATE INFECTIONS
OR HOST ANTI-VIRAL FACTOR THAT
CAN INHIBITOR HCV INFECTION.
THIS IS JUST IMAGE
REPRESENTATION OF THESE
STAINING.
AS YOU CAN SEE, THESE ARE THE
STAINING WITH THE VIRAL PROTEIN.
THIS IS A DNA WORKING THE
NUCLEI.
THIS IS THE POSITIVE CONTROL
THIS IS THE NEGATIVE CONTROL.
YOU CAN SEE THAT HOST FACTOR HAS
SIGNIFICANT DECREASE STAINING --
THESE CAN BE QUANTIFY BY
AUTOMATED IMAGE ANALYSIS AND
PROVIDE YOU WITH A DATABASE FOR
ANALYSIS, TO IDENTIFY WHAT'S
SO-CALLED HPF AND HAF.
SO USING THIS TECHNOLOGY AS WELL
AS COMBINING BIO -- HARVARD
MEDICAL SCHOOL WAS ABLE TO
GENERATE A COMPLICATED HCV
INTERACTION MAP AS SHOWN HERE.
I WON'T TAKE YOU THROUGH IT BUT
THE ONE NODE THERE WHICH
REPRESENTS THE GENE I TAKE ALPHA
CALLED CHUCK INHIBITORS WITH A
CAPITAL B KINASE ALPHA REPRESENT
A VERY CRITICAL INTERACTION
POINT OF HOW HCV INTERACTS WITH
THE HOST.
SO FRANK TOOK ON AN AMBITIOUS
PROCESS -- FIRST OF ALL WHAT HE
HAD DONE IS TAKE THIS OUT
WITH -- AS I MENTIONED WITH YOU
BEFORE SRNA WAS USED WITH A
POOL.
HE WANTED TO TEST WHETHER THESE
INDIVIDUALS SRLS WILL WORK.
INTERESTING YES INDIVIDUAL SRNA
WORK -- THEIR POTENCY KOAR LATE
VERY WELL WITH THE SILENCING
EFFICIENCY OF INDIVIDUAL SRNA.
SO IT'S VERY CONSISTENT INDEED
WITH THE SILENCING LEAD TO
DECREASE HCV REPLICATION.
FURTHERMORE HE OVEREXPRESSED THE
CELLS WITH EXPRESSION FACTOR
CONTAINING IKK ALPHA AND HE WAS
ABLE TO SEE SIGNIFICANT INCREASE
IN VIRAL PRODUCTIONS WITH HCV
INFECTED CELLS.
AND THE INFECTED VIRUS IN THE
CULTURE MEDIUM.
IN THE CONVERSE USING IKK ALPHA
MUTANT WHICH IS DEFICIENT IN THE
KINASE DOMAIN, THIS BEHAVES AS
NEGATIVE DOMINANT CONSTRUCT WAS
ABLE TO SIGNIFICANTLY DECREASE
THE VIRAL REPLICATION OF THE HCV
INFEBRUARIED -- INFECTED CELL AS
WELL AS INFECTED VIRUS.
AS YOU WELL KNOW N KAPPA B IS
ONLY A VERY IMPORTANT PATHWAY IN
MANY BIOLOGICAL FACETS.
THERE'S BEEN A LOT OF
PHARMACEUTICAL INDUSTRY IN
DEVELOPING ANDROGENS IN KAPPA B.
WE'RE ABLE TO GET SEVERAL OF
THESE DRUGS THAT ARE
SPECIFICALLY TARGETING IKK
COMPLEX.
TWO OF THE INHIBITORS WILL
TARGET, WERE ACTIVE AGAINST ALL
IKK.
I'LL TELL YOU THERE'S -- IKK.
BUT ONCE WE THOUGHT WILL TARGET
IKK BETA NOT IKK ALPHA.
SO TESTING THESE INHIBITORS SHOW
THAT THESE TWO INHIBITORS THAT
GENERAL IKK INHIBITOR WERE ABLE
TO SIGNIFICANT REDUCE BILE
PRODUCTION IN A DOSE DEPENDENT
MANNER WHEREAS THIS INHIBITOR
TARGETING IKK BETA ONLY HAD
KNOWN THE FACT IN PRIMARY HUMAN
HEPATOCYTE.
HE SAW THE SAME PHENOTYPE OF
THESE INHIBITOR IN SORT OF
BLOCKING HCV REPLICATION.
SO LET'S QUICKLY REVIEW KAPPA B
AND YOU'LL KNOW THAT IS
DISCOVERED BY BALTIMORE IN A
NOBEL WORK.
THIS WAS A PROCESS THAT IN
RESPONSE TO EXTERNAL STIMULI,
ACTIVATE THIS MASSIVE SWITCH N
KAPPA B SO-CALLED IKK COMPLEX
COMPOSED OF ALPHA, BETA AND
GAMMA.
PHOSPHORYLATION OF THIS COMPLEX
WILL THEN ACTIVATE THIS WHICH
WILL FURTHER PHOSPHORYLATE THIS
INHIBITOR OF IKK BETA HERE THAT
BASICALLY KEEPING THE NF KAPPA
COMPLEX DORMANT IN THE
CYTOPLASMA.
PHOSPHORYLATION OF IT K BETA
WILL LEAD TO DEGRADATION,
RELEASE THE N KAPPA B COMPLEX IN
THE NUCLEUS TO ACTIVATE N KAPPA
B RESPONSIVE GENES.
SO THIS IS IN A SHORT, IN A
SHORT HOW NF KAPPA B WORKS.
IN TERMS OF THE VIRUS, WHAT THE
VIRUS DID IS THAT THROUGH EITHER
RECEPTORS OR -- -- THAT WAS PART
OF THE ANTI-VIRAL RESPONSE
INVOLVING OTHER FACTORS SUCH
AS -- 7 AND 9 AND LEADS TO THE
INTRODUCTION OF THE INTERFERON
PATHWAY.
THE IKK BETA AND GAMMA ARE THE
ACTIVATORS OF THE N KAPPA B
COMPLEX.
IT'S ESSENTIAL FOR IKK ALPHA HAS
BEEN IMPLICATED IN MICHAEL
KAREN'S GROUP TO MEDIATED
SO-CALLED NON-CONICAL PATHWAY TO
N KAPPA B2 MOLECULE.
SO TO EXPLORE THIS FURTHER WE
SAY GO AHEAD AND KNOCK OUT ALL
THE KAPPA B PATHWAY AND SEE WHAT
THE EFFECT ON HCV REPLICATION.
LO AND BEHOLD WHEN HE DID THE
FOLLOWING EXPERIMENT, HE SAW
THAT KNOCKING OUT ALL OF THE --
LEAD TO INCREASE KAPPA INFECTION
WHICH YOU WOULD EXPECT BECAUSE
THESE ARE INNATE AND -- IF YOU
KNOCK IT DOWN IT WOULD GO UP.
AROUND IKKA ALPHA LEADS TO
SIGNIFICANT REDUCTION OF
REPLICATION.
THE REASON IKK ALPHA AND OTHER
KAPPA B COMPONENTS HAVE AN
IMPOSING FACTOR ON HCV
PROPAGATION.
SO HOW COULD THIS BE.
FURTHERMORE, I SAY SINCE I CAN
OVEREXPRESS IKK ALPHA THAT CAN
LEAD TO THE PHENOTYPE OR
INCREASE REPLICATION.
IF WE KNOCK DOWN THE DOWN
STREAM, IF INDEED IKK ALPHA IS
MEDIATED THROUGH THIS, WE SHOOT
SEE ANY OVER EXPRESSION IN IKK
ALPHA.
AND ACTUALLY THIS IS NOT WHAT HE
SAW WHEN HE DID THE FOLLOWING
EXPERIMENT.
WHEN HE TREAT THE CELLS WITH --
AGAINST F KAPPA B ONE AND TWO,
HE STILL COULD SEE THE INCREASE
BY REPLICATION AS A RESULT OF
IKK ALPHA EXPRESSION.
SO IT SUGGESTS THAT IKK ALPHA IS
GOING THROUGH SOME OTHER
PATHWAYS TO THE CLASSICAL AND
KAPPA B PATHWAYS.
SO THEREFORE THE EFFECTIVE IKK
ALPHA WITH COMPLICATION IS
INDEPENDENT IN KAPPA B.
THERE'S ALSO A LOT OF DATA THAT
WENT INTO PROVING THIS BECAUSE
WE SHOW THEM THAT THIS IS INDEED
A KAPPA B.
I'M NOT GOING TO YOU THEM BUT
YOU'LL READ ABOUT IT IN A COUPLE
MONTHS THAT THIS PATHWAY IS
INDEED INDEPENDENT OF KAPPA B.
SO WHAT DOES IKK ALPHA ACT IN
THE HCV LIFE CYCLE.
I SHOWED THIS TO YOU BEFORE.
VARIOUS DIFFERENT ASSAYS HAVE
BEEN DEVELOPED IN THE LAST FEW
YEARS.
REALLY LOOK AT SPECIFIC STEP OF
THE VIRAL LIFE CYCLE, THE HCVPP
AND THE BINDING ASSAY.
THE ENTRY IS TO THE SINGLE CYCLE
INFECTION ASSAY TO LOOK AT THE
EARLY STEPS -- LOOKING AT
TRANSLATION, REPLICATION ASSAY
LOOKING AT REPLICATION AND
FINALLY THE HCV CC ASSAY CAN
LOOK AT THE COMPLETE VIRAL LIFE
CYCLE.
SO APPLYING THESE TECHNIQUES
SHOW THAT IKK ALPHA ACTUALLY ACT
ON THE ASSEMBLY PROCESS.
AS WE JUST REMIND YOU THAT THE
PROCESS -- SO A WHAT DOES THIS
MEAN.
PATHOLOGICALLY, HCV INFECTION IS
ASSOCIATED WITH A PATHOLOGICAL
HALLMARK OF STEATOSIS.
WHAT YOU SEE HERE IN THE SAMPLE
OF HCV INFECTED -- THIS IS
SIMILAR TO ANOTHER DISEASE WE
SEE VERY COMMONLY SO-CALLED
NON-ALCOHOLIC FETAL HEPATITIS IN
WHICH THE PRIMARY INJURIOUS --
THE LIPID DROPLET IS INVOLVED IN
THE HCV INFECTION.
THIS PHENOMENA HAS BEEN
DESCRIBED IN VARIOUS DIFFERENT
CELL CULTURE MODELS.
HCV INFECTOR CELLS AS HAS BEEN
SHOWN TO HIGH LEVEL LIPID
DROPLETS WAS SHOWN HERE.
THIS IS A CORE STAINING AS YOU
CAN SEE THAT.
THERE'S INCREASE LIPID DROPLETS
AND -- WELL WITH HCV CORE
PROTEIN.
THEN YOU TREAT THE CELLS WITH
IKK ALPHA, YOU CAN SEE THAT THE
LIPID DROPLET WAS SIGNIFICANTLY
REDUCED ALTHOUGH YOU CAN SEE THE
CORE THERE.
BUT NO LONGER -- WITH THE CORE
OF THE LIPID DROPLETS.
THIS SUGGESTS THAT HCV INFECTION
INDUCED LIPID DROPLET FORMATION
AND CO-LOCALIZES WITH HAD.
CV CORE.
IKK ALPHA MEDIATES THE FACT THAT
HCV LIPID DROPLET FORMATION.
SO TO FURTHER EXPLORE THE FACT
THAT IKK ALPHA AND LIPID DROPLET
FORMATION OVEREXPRESS WILD TYPE
IKK FAL AWE THAT CAN INCREASE
HCV REPLICATION.
OVER EXPRESS ITSELF WITH THE IKK
ALPHA -- YOU CAN SEE THAT IN THE
CELLS EXPRESSING THIS H WILD
TYPE ALPHA YOU CAN SEE
SIGNIFICANT INCREASE IN LIPID
DROPLET FORMATION.
WHEREAS WHEN YOU OVER EXPRESS
THE NEGATIVE DOMINANT MUTANTS,
YOU SEE ACTUALLY A DECREASE IN
THE LIPID DROPLET FORMATION IN
THE CELLS EXPRESSING THIS
NEGATIVE DOMINANT IKK ALPHA.
SO HOW DOES HCV INDUCE THE LIPID
DROPLET FORMATION?
THIS IS A GENOME VIRUS.
IT'S A TEN KILLER BASE AGENT
ENCODING A POLY PROTEIN HERE BUT
THERE ARE TWO -- TRAPS LATER
REGIONS THAT PLAY A CRITICAL
ROLE IN BIOTRANSLATION
REPLICATION FURTHERMORE THE --
ENCODES SO-CALLED
PATHOGEN-ASSOCIATED -- THAT CAN
BE RECOGNIZED BY -- OR LEAD TO
INDUCTION OF INTERFERON.
THIS IS DESCRIBED BY -- MANY
YEARS AGO.
TO MAKE A LONG STORY SHORT WAS
ABLE TO SHOW THAT THIS WAS
INDEED RESPONSIBLE FOR THE
INDUCTION OF LIPID DROPLETS,
SHOWING YOU HERE SUSTAINING IKK
ALPHA AND LIPID DROPLETS.
AND WHEN YOU TREAT THE CELL.
THESE ARE NOT INFECTED CELLS AS
IKK ALPHA.
YOU CAN SEE THE DECREASE OF
LIPID DROP FORMATION.
WHEN YOU TREAT THE CELLS WITH
HCV10, YOU CAN SEE THERE WAS A
SIGNIFICANT INDUCTION OF LIPID
DROPLETS AS SHOWN HERE.
AND THAT WHEN YOU TREAT THE
CELLS HCV10 TRARYT CELLS AS IKK
ALPHA SRNA HE WAS ABLE TO
AGGREGATE THE HIGH INDUCTION
OVER LIPID DROPLETS.
A TECHNIQUE OF QUANTIFYING LIPID
DROPLETS EIGHTY AGAIN HCV10 WAS
ABLE TO SIGNIFICANT INDUCE THE
GREEN COLOR THAT'S
REPRESENTATIVE OF THE LIPID
DROPLET.
SIMILARLY USING A VIRAL MIMETIC
BACK IN -- FUNCTION OF THE
MOLECULE WAS ABLE TO INDUCE THE
PRODUCTION OF LIPID DROPLETS.
SO THE IKK ALPHA IS INVOLVED IN
LIPID DROPLET BIOGENESIS -- THAT
IS MEDIATED BY IKK ALPHA.
AND THIS HCV10 IS RESPONSIBLE
FOR THIS EFFECT.
SO TO STUDY FURTHER AS I
MENTIONED TO YOU THAT IKK ALPHA
IS ACTIVATED AND SHOWED THAT IN
HCV INFECTOR CELLS -- THERE'S NO
CHANGE IN THE LEVEL OF IKK
ALPHA.
FURTHERMORE THE PHOSPHORYLATED
IKK ALPHA IS DISTRIBUTED INTO
THE TRANSLOCATOR INTO THE NUCLEI
WHEN YOU PERFORM VACCINATION OF
CYTOPLASMIC TO NUCLEAR
EXPERIMENT AND IT'S JUST A
QUANTIFICATION OF THE SIGNAL.
AND THAT'S WHY HE SAW THAT.
THE IKK ALPHA PHOSPHORYLATION
AND LOCALIZATIONS.
TO FURTHER EXPLORE THE LOCAL
CASE IKK ALPHA INFECTOR CELL
FRANK PERFORMED MY MICROSCOPY --
GREEN REPRESENTS ACD CORE SO HCV
INFECTOR CELLS.
AS YOU CAN SEE THAT IN THE HCV
INFECTOR CELLS THERE SEEMS TO BE
INCREASE RED COLOR IN THE
NUCLEI.
USING THE SOFTWARE OF THE -- HE
WAS INDEED ABLE TO SEE THESE
CELLS INFECTED HCV, THIS
INCREASE LOCALIZATION ACTUALLY
COULD QUANTIFY BY MEASURING MANY
OF THE NEW FLUORESCENT INTESSITY
OF THESE CELLS TO GIVE YOU
STATISTICAL AND SIGNIFICANT
INCREASE OF LOCALIZATION OF IKK
ALPHA IN HCV INFECTED CELLS.
SO I GUESS THE NEXT QUESTION, SO
WHAT IS IKK ALPHA DOING ONCE YOU
GO THROUGH THE NUCLEUS.
THE ANSWER TO THIS QUESTION
FRANK DESIGNED THE FOLLOWING
EXPERIMENT, YOU CAN HAVE FOUR
CONDITIONS WHERE ONE CONDITION
WOULD BE JUST YOU MAKE IT A
CONTROL.
AND THEN ANOTHER CONDITION JUST
TREAT THE CELL WITH -- IKK ALPHA
AND THE THIRD CONDITION WOULD BE
CONTROL THE SIRNA INFECTED HCV
VERSUS THE IKK ALPHA -- THE FULL
CONDITION INDEED QPCI WILL
DEMONSTRATE REDUCTION OF IKK
ALPHA SILENCING AND DECREASE
REPLICATION AND -- INFECTED
CELLS.
SO WHEN YOU DO THE EXPERIMENT
AND LOOK AT THE PATHWAY NOW LOW
AND BELOALD LACEY INFECTED GENES
UP REGULATED BELONG TO THE
METABOLISM GENES.
THIS INCREASE CAN BE REDUCED BY
EITHER SIRNA AGAINST IKK ALPHA
REPRESENTED BY THE BLUE COLOR.
EVEN IN CELLS THAT ARE NOT
INFECTED BY HCV, THERE WAS A
SIGNIFICANT REDUCTION OF -- IN
THE CELLS.
AND THEN TO LOOK SPECIFICALLY AT
THESE MICRO GENEIC GENES.
THESE ARE REGULATORS OF THE
LIPID METABOLISM ITSELF.
WHEN YOU QUANTIFY THE EXPRESSION
OF THESE TWO GENES YOU SAW AN
INCREASE IN THE HCV INFECTED
CELL HAT CAN BE BLOCKED
SPECIFICALLY BY TREATING THE
CELL WITH IKK ALPHA SIRNA.
SO HCV INFECTION INDUCES IKK
ALPHA MEDIATED EXPRESSION OF
LIPID METABOLITED GENE -- AND
JUST TO LOOK FURTHER I TOLD YOU
HCV10 IS A RESPONSIBLE ELEMENT
FOR HCV.
HE SAW THE SAME THING INDUCTION
SIVP APPLICATION OF THIS
INDUCTION FOR THE TREATMENT OF
IKK ALPHA.
AND FURTHERMORE WHEN YOU TREAT
THE CELL AGAINST SIEBP HE WAS
ABLE TO REPLICATE THE PHENOTYPE
THAT REPLICATIONS SIGNIFICANT
DECREASE WHEN YOU SILENCE THE
EXPRESSION IN CELLS AS SHOWN
HERE.
THE REASON THAT THE HCV10
REDUCES THE EXPRESSION OF --
METABOLISM GENES AND THE SI ONE
AND TWO FOR HCV PROPAGATION.
SO THIS IS JUST ALSO SHOW THAT
USING THE OVEREXPRESSION, YOU
CAN INCREASE EXPRESSION BUT WITH
DOMINANT AND NEGATIVE MUTATION
YOU CAN DECREASE THE SREBP
INDUCTION.
AGAIN GOING BACK TO PRIMARY
HUMAN PA AT -- HEPATOCYTES, THEY
WERE SIGNIFICANTLY ABLE TO RULES
THE IPP ONE AND TWO IN THE HUMAN
HEPATOCYTE ONLY WITH INHIBITORS
AGAINST ALL THE IKK BUT NOT IKK
DATA SPECIFICALLY INHIBITORS
HERE.
SO THEREFORE WE CONCLUDE THE IKK
ALPHA PLAYS A CRITICAL ROLE IN
THE TRANSCRIPTIONAL REGULATION
OF I -- ONE AND TWO.
TO SUMMARIZE THIS PART OF MY
TALK DO YOU KNOW WHY
GENOME-WIDE -- IN THE PATHWAY
THAT HAVE ANTI-VIRAL EFFECTS,
IKK ALPHA HAS A PREDOMINANTLY
PROVIRAL EFFECT.
IT KK ALPHA PLAYS AN IMPORTANT
ROLE IN THE STEP OF THE HCV LIVE
CYCLE.
HCV INFECTION ACTIVATES RULES
THE EXPRESSION OF SREBP1 AND 2.
THIS IS THE INDUCTIONS THAT LEAD
TO LIPID FORMATION AND TO SERVE
THE HCV ASSEMBLY.
FINALLY HCV EXPLOITS THE HOST
IMMUNE RESPONSE RESPONSE AND
HIGH JACKS HOST LIPID METABOLISM
TO ITS ADVANTAGE.
THE IDENTIFICATION OF NOVEL HOST
HAS MAJOR IMPLICATIONS.
I SHOWED YOU THE BLOCK IKK
ALPHA.
AND IF YOU SAW THAT ITS
PHENOTYPE INFECTION IS QUITE
DRAMATIC.
I'M NOT SUPPOSING TO USE
INHIBITOR THERAPY BUT I THINK
THIS GIVES YOU A LEAD ABOUT WHAT
YOU COULD DO IN THE FUTURE.
SO MOVING ON TO THE MICRO RNA
PERTURBGENS WITH THIS RISK
COMPLEX SPECIFIC TARGET AND
USING A SILENCING TRANSLATION
LEADING TO ITS DEGRADATION.
SO HOW ABOUT MICRO RNA
INFECTION.
THE THERE ARE PLENTY OF EXAMPLES
OF THAT.
FIRST OF ALL MANY HOST RNA VIRAL
BEGAN EXPRESS IN LIFE CYCLE.
CONVERSELY THAT SOME VIRUS
ESPECIALLY THE DNA VIRUS AND
CO-VIRAL MICRO RNA'S SO-CALLED
THAT WILL AFFECT THE HOST GENE
EXPRESSION.
IT'S A COMPLICATED INTERACTION
THERE WITH SCE -- PLAYS A
CRITICAL ROLE IN HCV REPLICATION
FROM THE WORK OF PETER -- GROUP
PUBLISHED IN SCIENCE MANY YEARS
AGO.
INHIBITORS OF THIS IS ACTUALLY
BEING DEVELOPED AS ANTI-HCV
THERAPY IN THE CLINIC.
SEVERAL PAPER ILLUSTRATED THE
CONCEPT OF THAT IN A RECENT
STUDY PUBLISHED IN THE NEW
ENGLAND JOURNAL DEMONSTRATED
EFFICACY OF THIS APPROACH.
OTHER MICRO RNA LIVE CYCLES
REGULAR LAG HOST FACTOR HAS BEEN
IDENTIFIED.
THESE ARE JUST SOME EXAMPLES.
SO THESE ARE MORE SYNTHETIC RNA
SO WE CAN TAKE ADVANTAGE OF THE
SO-CALLED MIMICS OR INHIBITORS
AS TOOLS TO EXPLORE BIOLOGY.
TRANSSECTOR CELL WILL MIMIC THAT
WILL LEAD TO DECREASED
EXPRESSION OF THE TARGET GENE
WHEREAS WHEN YOU TRANSECT A
CELL -- SO YOU CAN IMAGINE THIS
COULD BE ADAPTED -- GAIN
FUNCTION OR LOSS FUNCTION.
THAT'S EXACTLY WHAT FRANK DID A
LIBRARY ABOUT A THOUSAND MICRO
RNA GENOME WIDE SCREEN IN THE
SAME FORMAT.
HE WAS ABLE TO IDENTIFY MICRO
RNA THAT'S IMPORTANT TO HCV
REPLICATION.
THIS IS JUST DATA THAT PLOTTED
IN THIS CALLED VOLCANIC PLOT.
TO IMPLICATE THE CUT OFF VALUE.
ON THE X AXIS IT'S A CHANGE AS A
RESULT OF THE MICRO RNA
TREATMENT AND THE Y AXIS IS A T
VALUE.
AND THE COLOR DOTTED LINE WHICH
REPRESENTS THE CUT OFF AND THEN
THE BLOCKOUT REPRESENTS THE T
VALUE OF .0025.
WITH ANY POINT FOLLOWING THIS
AREA CONSIDERS HITS.
INTERESTINGLY ENOUGH IT CAME TO
A POSITIVE HIT RIGHT THERE.
THAT IS THE PLOTS OF PART ONE
AND PART TWO INHIBITORS ASSAY.
JUST POINT OUT THIS IS THE SAME
SLIDE I SHOWED PREVIOUSLY BUT IN
THE INHIBITOR ASSAY THE MICRO
RNA TURNS OUT TO BE THE OTHER
SIDE AS YOU EXPECT BEIT'S THE
INHIBITORS THAT WILL INHIBITOR
BIOREPLICATION.
THIS IS GENERATED BY HELEN WHEN
SHE PUT EVERYTHING TOGETHER HAD
THE MICRO RNA WITH MANY
DIFFERENT HOST FACTORS AND
NETWORK FORMAT THAT'S
PRELIMINARY AND MANY OF THESE
HOST FACTORS ACTUALLY OVERLAP
WITH SRNA GENOME SCREEN.
LET ME END MY TALK WITH THE
PROBE OF PERTURBAGENS.
THIS IS OF THE ROADMAP
INITIATIVE MANY YEARS AGO USING
COMMON FUNDS TO ENCOURAGE PEOPLE
TO EXPLORE BIOLOGICAL PHENOMENA
USING THE TECHNOLOGY BACK THEN
WAS NGTC AVAILABLE LOOKING AT
LARGE POOL OF SMALL MOLECULE
LIBRARIES.
SO THAT'S GREAT, WE HAVE AN
INTERESTING ASSAY.
I WENT TO OUR COLLEAGUE AT
NGC -- HE LOOKED AT MY ASSAY
FORMAT AND LAUGHED.
HE SAID NO YOUR ASSAY FORMAT
ALTHOUGH USING -- HAS AUTOMATED
IMAGE.
IT'S NOT THE TRUE FORMAT WHERE
YOU'RE TALKING ABOUT SCREENING
AGAINST OF COMPOUNDS.
YOU GOT TO REALLY BE ABLE TO
ADMINISTER IT EVEN FURTHER.
GEE THAT'S TOO BAD.
GOING BACK TO THE DRAWING BOARD
AND SPENT TIME TO TRY TO SET UP
OR OPTIMIZE SO WE CAN SCREEN THE
LARGE CHEMICAL LIBRARY THAT N
CAT HAS.
SO THE CHARACTERISTICS OF THIS
HIGH THROUGHPUT ASSAY IS SIMPLE.
YOU CAN DO STAINING AND THESE
OTHER THINGS YOU DO TO KNOCK
AROUND THE CELL.
YOU GOT TO -- MINIMAL
MANIPULATION I SAID.
AND THESE 1536 WELL PLATE
FORMAT.
THEY MAY CONTAIN FIVE MICROLITER
OF THE MEDIAN.
YOU HAVE A VERY HIGH SIGNAL OF
RATIO.
IT HAS A ROBUST REPRODUCIBILITY.
THESE ARE NARC FACTORS THAT WE
LOOK AT.
YOU HAVE A TRIATION BASE
APPROACH AND THEN OBVIOUSLY YOU
GOT TO ADDRESS THE WHOLE ISSUE
OF CYTOTOXICITY WHEN YOU DO A
CELL BASE ASSAY.
NOT TO BORE YOU WITH THE
DETAILS.
THE SET UP ASSAY SEEMED TO WORK
AND THEN IN COLLABORATION WITH
NCGC WE SCREEN ABOUT 500,000
COMPOUND LIBRARY.
USING -- ROBOTICS AND -- SUCH AS
LOOKING POTENCY PROFILING,
ACTIVITY CLASSING, STRUCTURE
CLUSTERING.
THIS IS -- THIS IS COMPOUND
PRECURSOR OF A PROTEASE
INHIBITOR THAT IS IN CLINICAL
USE FOR HEPATITIS C FOUND TO BE
GREAT SIMILAR WITH ONE CLASS OF
COMPOUNDS THAT IDENTIFIES -- SO
THIS IS GOOD TO KNOW WE'RE
PICKING OUT SOMETHING THAT'S
VERY SIMILAR TO SOMETHING THAT'S
IN THE CLINIC.
THEN WE GO IN THIS APPROACH WE
HAVE IDENTIFIED ABOUT 600
COMPOUNDS AND WE THOUGHT MAYBE
WE SHOULD GO THROUGH A SECONDARY
CONFIRMATORY SCREEN.
WE'LL USE MORE DOZENS AND THEN
SAME FORMAT BUT SIMILAR WE
INCLUDE THE CYTOTOXIC ASSAY
HERE.
SO USING THIS WE'LL CONFIRM
ACTIVITY IN MANY OF THEM AND
MANY OF THEM ALSO WERE
NON-CYTOTOXIC.
USING THIS APPROACH NARROWED
DOWN TO 200 COMPOUNDS.
IT'S NOT TOO MANY TO WORK WITH.
SO WHAT DO WE DO NEXT.
WE DECIDE TO USE A SECONDARY
SCREEN THAT'S SOLELY DIFFERENT
FROM OUR PRIMARY SCREEN.
WENT BACK TO THE SAME FORMAT
THAT WE USE FOR THE STAININGOR
THE -- BECAUSE THE NUMBER'S
MANAGEMENT 284 -- AND THEN USING
THIS WE'RE ABLE TO NARROW IT
DOWN COMPOUND THE HIGH EFFICACY
HIGH MOTE SEE LOW TOXICITY OF
158 COMPOUNDS FOR EACH LIFE
CYCLE ASSAY.
GOING THROUGH THE WHOLE LIFE
CYCLE ASSAY, WE'RE ABLE TO
SELECT THE COMPOUND BASED ON
HIGH POTENCY AND EFFICACY -- HCV
LIFE CYCLE.
AND BY PERFORMING STRUCTURED BIO
FOE MATICS.
SO WITH ALL THESE ASSAYS WE ARE
DOWN TO FIVE LEAD COMPOUNDS --
SELECTED FOR ASSAY CHEMISTRY AND
FURTHER DEVELOPMENT.
GOING BACK TO MY FIRST.
SO ARE WE AT ZERO DATE FOR
HEPATITIS C YET.
THE QUESTION IS NOT YET BUT WE
ARE CLOSE.
I NEVER HAPPENED THE TIME TO
SHARE WITH YOU ALL THE
DEVELOPMENT OR ADVANCES IN HCV
TREATMENT BUT YOU HEARD WE'LL
ACTUALLY BE ABLE TO CURE ABOUT
70% OF THE PEOPLE WITH THE
NEWEST COMBINATION OF THERAPY.
JUST THINK THIS WAS DISCOVERED
LESS THAN 25 YEARS AGO.
WE CAN RIGHT NOW, NOT YET BUT
PROBABLY IN FIVE YEARS WE CAN
ACTUALLY CURE EVERYBODY OF
HEPATITIS C.
I THINK THAT'S A REMARKABLE
JOURNEY AND IT'S REALLY, I MEAN
IT'S ONE OF THE THINGS THAT IT'S
VERY EXCITING TO BE PART OF THIS
HISTORY.
I'M SURE DR. ALTER HAS A LOT TO
SAY ABOUT THAT AS WELL.
AND IN LIGHT OF THIS ACTUALLY
HARVEY AND I WROTE AN EDITORIAL
IN ANNALS OF INTERNAL MEDICINE
LAST YEAR ON ADVANCING THERAPY
HEPATITIS C THE END OF THE
BEGINNING AND POSSIBLY THE
BEGINNING OF THE END AND REALLY
HIGHLIGHT WHAT'S BEEN HAPPENING.
BUT CERTAINLY TOWARD THE END
BOTH HE AND I LAMENT THE FACT
THAT WE'RE GOING TO BE SO
SUCCESSFUL, WE'RE GOING TO BE
OUT OF A JOB IN A COUPLE YEARS.
I THINK HARVEY IS FINE.
I NEED A SECOND CAREER SO I
BETTER START THINKING ABOUT
THAT.
FINALLY I WANTED TO RECOGNIZE
THE PEOPLE WHO HAVE CONTRIBUTED
TO THE WORK IN MY LAB.
THIS IS A PHOTO OF THE WHOLE
BRANCH.
I'M GLAD TO WORK WITH ALL OF
THESE WONDERFUL PEOPLE IN THE
GROUP.
I MENTIONED SOME OF THE NAMES
WHO HAVE BEEN INVOLVED IN THE
SRNA AND MICRO RNA SCREENING
PROJECTS -- AND HAVE BEEN
INVOLVED IN THE MOLECULAR
LIBRARY INITIATIVE.
I CERTAINLY WANT TO ACKNOWLEDGE
THE PEOPLE THAT COLLABORATED
WITH THE MEDICAL SCHOOL IN THE
EARLY PART OF THIS STUDY.
AND FINALLY TO THE N CAST PEOPLE
WHO HAVE BEEN EXTREMELY HELPFUL
IN MOVING THIS PROJECT ALONG AND
IS REALLY EXTREMELY VALUABLE
RESOURCE ON NIH CAMPUS.
AND ON THAT NOTE I'LL STOP.
I THINK THE PLAN IS THAT WE'RE
NOT GOING TO TAKE ANY QUESTIONS
AND HARVEY'S GOING TO GO AHEAD
AND GIVE HIS LECTURE AND WE WILL
ANSWER SOME QUESTIONS TOGETHER
AT THE END.
OKAY.
ALL RIGHT.
[APPLAUSE]
HEPATITIS E WAS FIRST DISCOVERED
IN 1981 AND IT WAS ANOTHER BAD
*** -- OUTCOME OF THE AFGHAN
WARS.
THIS WAS AT THE TIME WHEN IT WAS
RUSSIA FIGHTING IN AFGHANISTAN
EXPHB HUGE NUMBERS OF RUSSIAN
SOLDIERS WERE COMING DOWN WITH
ACUTE HEPATITIS.
IT WAS AN EPIDEMIC AND IT SEEMED
LIKE IT WAS EVENTITIS A VIRUS.
WHEN YOU ACTUALLY TESTED FOR IT,
IT WAS NOT HEPATITIS A AND A
RUSSIAN SCIENTIST WENT BACK AND
STUDIED THIS FURTHER.
AND UNCOVERED THE NEW VIRUS AND
AS PART OF HIS WORK HE ACTUALLY
ATE SOME FILTRATE WITH THIS
PROJECTED VIRUS, CAME DOWN WITH
A SEVERE CASE OF HEPATITIS
HIMSELF BUT WAS ABLE TO GET
SAMPLES OF SERUM AND STOOL AND
EVERYTHING.
AND HE DISCOVERED THE HEPATITIS
E VIRUS.
SO IF YOU WANT TO DISCOVER
SOMETHING, INFECT YOURSELF.
THEE THE LESSON TODAY.
ANYWAY, THIS WAS NOW THE
HEPATITIS E VIRUS.
AND IT WAS INDEED DIFFERENT FROM
HEPATITIS A VIRUS NOT
SEROLOGICALLY BUT IT HAD CERTAIN
CLINICAL FEATURES THAT DIFFERED.
IT HAD A MALE PREDOMINANCE,
QUITE STRIKING.
TENDED TO HAPPEN IN OLDER
PEOPLE.
COULD BE EQUALLY SEVERE.
BUT HEPATITIS A WAS ALWAYS A
SELF LUMEN INFECTION AND SOME
HINT THAT THIS MIGHT BECOME A
CHRONIC INFECTION.
THERE WAS A HIGHER MORTALITY
RATE.
IN THIS PARTICULAR STUDY IT WAS
IN HEPATITIS A AND 6% IN
HEPATITIS E AND GENOTYPES THREE
AND FOUR WHICH I'LL TALK ABOUT
IN A MOMENT.
THERE IS A MORTALITY RATE WITH
HEPATITIS A IN PATIENTS BUT THE
RATE IS HIGHER.
THESE WERE THREE STUDIES OF --
HEPATITIS, AND HEV WAS MUCH MORE
LIKELY TO BE ASYMPTOMATIC --
EVEN THOUGH IT'S TYPICALLY
PRESENTED, IT WAS FOUND BECAUSE
OF ACUTE OBSERVABLE HEPATITIS
WHEN YOU STARTED THE SAMPLE
LARGE NUMBERS OF PEOPLE YOU
FOUND MAJORITY OF CASES WERE
SUBLINCOLN LIKE HEPATITIS C
WHICH IS BASICALLY A SUBCLINICAL
DISEASE.
SO HEPATITIS A WAS BEING MASKED,
HEPATITIS E WAS BEING MASK
BECAUSE OF THE CLINICAL --
HEPATITIS A.
IT WASN'T UNTIL YOU COULD RULE
OUT A THAT YOU COULD FIND E.
SIMILARLY REMINDED ME OF THE
RECENT DISCOVERY OF THE GENE FOR
SHYNESS.
NOW, THIS GENE WOULD HAVE BEEN
DISCOVERED MUCH SOONER EXCEPT
THAT IT WAS HIDING BEHIND
ANOTHER GENE.
CAN'T WIN THEM ALL.
HEPATITIS E IS A SMALLER THAN
HEPATITIS C TO KILLER BASE
NON-ENVELOPED SINGLE STRANDED
RNA VIRUS.
IT NOW HAS ITS OWN
CLASSIFICATION THAT'S CALLED --
LIKE HEPATITIS C IT'S GOT ITS
OWN GENOUS.
THERE ARE FOUR GENOTYPE BUT ONLY
ONE SERO TYPE WHICH IS IMPORTANT
IN TESTING.
GENOTYPES ONE AND TWO ARE
ACTUALLY HUMAN VIRUSES.
THEY ARE ENDEMIC AND EPIDEMIC,
PARTICULARLY THE FAR EAST.
GENO TYPES THREE AND FOUR ARE
SWINE VIRUSES THAT CAN AFFECT
HUMANS.
THIS IS A ZOO NOSIS.
THIS IS THE MAIN GOON --
GENOTYPE IN THE U.S. AND SOUTH
AMERICA.
IN THE ENTITY HEPATITIS E, SO
YOU HAVE THE VIRUS AND YOU
ACTUALLY HAVE THE DISEASE
HEPATITIS E.
YOU CAN SEE THE FAR EAST
HEPATITIS E ACCOUNTS FOR A LARGE
NUMBER, NEAR 50% OF ACUTE
HEPATITIS CASES.
IN THE MIDDLE EAST, IT'S STILL
SIGNIFICANT DOWN ABOUT 7%, 17%.
IN EGYPT, ABOUT 22%.
BUT IN THE U.S. AT THE TIME OF
THESE MAPS WERE MADE, HEPATITIS
E DIDN'T MAKE UP ANY OF THE
SEGMENTS.
THE SMALL SEGMENT THERE IS
ACTUALLY NON-A TO E HEPATITIS,
AN UNKNOWN ENTITY AT PRESENT.
CDC HAS RECENTLY SUMMARIZED ALL
THE CASES THAT WERE SINCE THEN,
THEY HAD A HEPATITIS E TESTING
LABORATORY, AND PEOPLE AROUND
THE COUNTRY WHO HAD CASES OF
NON-A NON-B NON-C HEPATITIS,
SENT SAMPLES TO THE CDC TO SEE
IF IT MIGHT BE HEPATITIS E.
INDEED 26 OUT OF 154 CASES OR
17% WERE HEPATITIS E INFECTIONS.
AND THE CDC THEN STUDIED
EPIDEMIOLOGICALLY THESE CASES
AND FOUND 11 OUT OF 26 WERE
ACTUALLY TRAVELERS WHO WOULD
TRAVEL TO ENDEMIC AREAS WHO HAD
GENO TYPES ONE AND TWO PREVALENT
IN THOSE AREAS.
BUT 15 WERE NON-TRAVELERS WHO
HAD SO-CALLED -- INFECTIONS.
THE MEANS INFECTIONS DEVELOP
WHERE THEY RESIDED BUT THEY
WEREN'T IMPORTED FROM OUTSIDE.
YOU CAN SEE THE STRIKING
DIFFERENCE BETWEEN THOSE IN THE
TRAVELERS VERSUS THE
NON-TRAVELERS WHERE THE
NON-TRAVELERS WERE MUCH MORE
LIKELY TO BE SUBCLINICAL AND
CARRY INFECTIONS, OCCUR IN THE
HIGH PROPORTION OF CASES IN
PEOPLE WHO WERE
IMMUNOSUPPRESSED, VERY FEW HAD
ORGAN TRANSPLANTS.
THEY WERE ALL GENOTYPE THREE AND
THE OTHERS WERE GENO TYPES ONE
AND TWO.
SOME OF THEM THEY HAD HEPATIC
FAILURE.
SO THESE CASES WERE CLEARLY
DIFFERENT THAN THE IMPORTED
CASES.
AND THAT REALLY WAS REFLECTION
OF THE GENO TYPES.
SO GENOTYPE ONE, THE EPIDEMIC
FORM AND BASICALLY A WATERBORNE
INFECTION.
IT OCCURS IN A RELATIVELY EQUAL
MALE FEMALE RATIO WHOSE GENOTYPE
THREE IS PREDOMINANTLY IN MALES.
IT'S PREDOMINANTLY IN OLDER
PEOPLE.
NEITHER ONE IS BARELY SPREAD TO
ANY GREAT DEGREE.
THE SOURCE FOR GENOTYPE ONE
IS -- GENOTYPE THREE WE'LL GET
INTO IN FOOD.
AND AGENT OF GENOTYPE ONE AS
HUMAN AGENT OF GENOTYPE THREE IS
PREDOMINANTLY A SWINE AGENT.
AND THE FATALITY RATES
STRIKINGLY IN GENOTYPE ONE HAS
BEEN DESCRIBED FATALITY IN WOMEN
WHO ARE INFECTED IN THE THIRD
TRIMESTER OF PREGNANCY.
WE'RE UP TO 20% DIED FROM
HEPATITIS E.
WHEREAS GENOTYPE THREE THIS HAS
NOT BEEN OBSERVED AND THE DEATHS
ARE OCCURRING IN PEOPLE THAT
WE'LL TALK ABOUT.
THE EXTRA HEPATIC MANIFESTATIONS
OF BOTH GENOTYPE ONE, THE
PANCREAS IS ONE OF THE EXTRA
HEPATIC ORGANS THAT ARE INVOLVED
WITH GENOTYPE THREE, MOSTLY CNS,
DIFFERENT -- SYNDROME HAS BEEN
DESCRIBED WITH DIFFERENT
RADICULOPATHYS.
WE'LL GET BACK TO PEOPLE WHO ARE
IMMUNOSUPPRESSED.
SO THIS IS A TYPICAL COURSE THAT
I BORROWED FROM -- THIS IS
CHARACTERISTIC OF ALMOST ALL
VIRAL INFECTIONS.
THE FIRST THING YOU FIND IS A
VIRAL NUCLEIC ACID HERO
CURING -- IN THE FIRST LINE
GOING UP.
THEN THE DISEASE BEGINS ALT
ELEVATIONS SHOWN HERE IN YELLOW.
SYMPTOMS IF YOU'RE GOING TO HAVE
THEM.
AND THEN THE DISAPPEARANCE OF
IGM ANTI-BODY AND THE APPEARANCE
OF IGG AND ANTI-AGV.
THIS WOULD BE THE SAME IN
HEPATITIS C OR HEPATITIS B.
AND ALSO THE SAME IN HEPATITIS B
AND C IS THAT THE DISEASE IS
REALLY AN ICEBERG.
WHAT WE SEE IS SEVERE ACUTE
RENAL FAILURE OR EVEN ACUTE
ENTERIC HEPATITIS IS A SMALL
PROPORTION OF THIS ICEBERG IS
THE VISIBLE PART BUT YOU HAVE A
LOT OF -- HEPATITIS.
YOU HAVE PEOPLE WHO HAVE NO
HEPATITIS AT ALL.
THEY JUST HAVE ANTI-BODIES, ZERO
CONVERSIONS ARE VERY TRACK GENT.
MOST OF THE DISEASES IS
SUBSURFACE AND THAT'S TRUE WITH
HEPATITIS C AS WELL.
WHAT ARE THE CLINICAL FEATURES
OF ATV INFECTIONS.
THE INCUBATION PERIOD IS THREE
TO EIGHT WEEKS.
AS I SAID MOST CASES ARE SELF
LIMITED BUT NOW VERY IMPORTANTLY
CHRONICITY IS BEING SEEN IN THE
NEW COMPROMISED PATIENTS AND
THAT CHRONICITY CAN LEAD TO
CIRRHOSIS.
IN A CRUISESHIP IT WAS THE ONE
OF THESE -- IT WASN'T ONE OF
THOSE CRUISESHIPS, IT WAS A NICE
EPIDEMIOLOGY I STUDIED BECAUSE
YOU HAD A CLOSED POPULATION AND
THERE WAS HEPATITIS E THAT
OCCURRED ON BOARD.
IT WAS PROBABLY FOOD, FOOD BORNE
IN SHELLFISH BUT IT HASN'T BEEN
PROVEN.
BUT OF ALL THE PEOPLE ON THIS
SHIP WHO ATE THAT, WHATEVER IT
WAS, ONLY 21% BECAME
SYMPTOMATIC.
AND MOST OF THOSE WERE ELDERLY
MEN.
SO I'M NOT GOING ON ANY
CRUISESHIPS.
[LAUGHTER]
NOW IN THE TOXIN CASES THE
AVERAGE AGE IS GREATER THAN 60,
MALE GREATER THAN FEMALE AT
LEAST THREE TO ONE.
THE FATALITY OF COURSE ALL GENO
TYPES IS ABOUT 5%.
MENTIONED THE -- HEPATITIS IN
PREGNANCY.
AND NOW THE CONTRARY CASES OF
ACUTE -- LIVER FAILURE THAT HAVE
OCCURRED EVEN IN THE U.S.
AND MOST OF THESE REPRESENT
ACUTE CHRONIC LIVER DISEASE
WE'LL GET INTO.
DR. SOMALIA IS HERE AND SHE'S
ACTUALLY DOING A LARGE STUDY OF
THIS ACUTE ON CHRONIC LIVER
DISEASE.
MEANING AN ACUTE SOMETHING ADDED
ON TO A CHRONIC EXISTING LIVER
DISEASE.
AND IT CAN BECOME VERY SERIOUS.
I MENTIONED THE EXTRA HEPATIC
MANIFESTATIONS.
INTERESTINGLY, IN CHINA NOW
THERE IS AN EFFECTIVE ATV
VACCINE THAT'S GONE THROUGH
CLINICAL TRIAL INVOLVING A
MILLION PEOPLE.
ONLY IN CHINA COULD YOU DO THAT.
AND IT WAS HIGHLY EFFECTIVE.
I BELIEVE IT'S BEGINNING TO BE
USED IN CHINA.
IT'S NOT LICENSED IN THE U.S.
NOR TO WE ACTUALLY NEED IT IN
THE U.S. AT THIS TIME.
THIS JUST SHOWS THE MALE
PREDOMINANCE AGAIN AND THE
MORTALITY RATE ACROSS STUDIES.
U.S. MORTALITY BEING VERY LOW
AND RANGING FROM 4 TO 10%.
SO WHEN YOU ARE LOOKING FOR A
CAUSE OF THE LIVER DISEASE NOW,
YOU HAVE TO LOOK FOR -- SOME
TIME.
AND ATV HAS BECOME ONE OF THE
ZEBRAS, ONE OF THE THINGS YOU
WOULDN'T TYPICALLY LOOK FOR.
I SHOW THAT BECAUSE I TOOK THIS
PICTURE WHEN IN AFRICA AND I
LIKED IT.
[LAUGHTER]
I'M GIVING YOU A CASE EXAMPLE OF
LOOKING FOR THE ZEBRA.
HERE'S AN ELDERLY MAN, 79 YEAR
OLD WHO DEVELOPED FATIGUE AND
JAUNDICE.
HAD NO PREEXISTING HISTORY OF
LIVER DISEASE, NO ALCOHOL USE,
NO OTHER RISK FACTORS OF VIRAL
HELPTITIS.
A LOT OF MEDICAL PROBLEMS.
AND WHO WAS ON A LOT OF
MEDICATIONS MANY OF WHICH I HAVE
NEVER EVEN HEARD OF.
BUT IMPORTANTLY ALL THE
MEDICATION HAD BEEN TAKEN LONG
TERM.
THERE WASN'T ANY NEW DRUG
INTRODUCED JUST BEFORE HIS
HEPATITIS.
ON EXAM HE WAS JAUNDICED AND THE
LABORATORY SHOWED A BILIRUBIN
VERY HIGH ACROSS THE NORMAL
BEING 40.
ELEVATED PHOSPHATASE.
HE WAS TESTED FOR HEPATITIS A,
HEPATITIS B, HEPATITIS C.
THEY WERE ALL NEGATIVE.
TESTED FOR ANTI-NUCLEAR
ANTI-BODIES IN SMOOTH MUSCLE
ANTI-BODIES LOOKING FOR IMMUNE
HEPATITIS.
THEY WERE NEGATIVE.
HAD AN ULTRASOUND WHICH WAS
UNREVEALING.
SO THE FIRST THING YOU WANT TO
DO IN THIS SORT OF SITUATION IS
ASSUME IT MIGHT BE -- STOP ALL
THE MEDICATIONS.
AND LO AND BEHOLD THE PATIENT
GOT BETTER.
THE ALT LEVEL DROPPED TO NORMAL.
NOT TO NORMAL BUT IT DID
EVENTUALLY GET DOWN TO NORMAL.
AND BILIRUBIN CAME DOWN.
IT WAS A DRUG INDUCED HIPTITIS.
THEY WERE LOOKING FOR ZEBRA AT
THE SAME TIME AND THEY TESTED
FOR ANTI-*** AND SURE ENOUGH AT
THE SAME TIME THAT THE DRUGS
WERE BEING STOPPED THEY FOUND
THAT HE HAD IGM AND IGG ANTI-ATV
AND ATV/RNA GENOTYPE THREE.
AS YOU FOLLOW THIS PATIENT OVER
THE COURSE, THE IGM DISAPPEARED.
THE IGG REMAINED POSITIVE AND
THE RNA DISAPPEARED.
A CLASSIC CASE OF ACUTE
HEPATITIS E.
SO SINCE ALL THE DRUGS HAD BEEN
CONSTANT, THIS WAS PROBABLY THE
CAUSE OF THIS ACUTE HEPATITIS.
WHICH IT'S BEEN A PARADIGM SHIFT
NOW IN OUR THINKING ABOUT
HEPATITIS E AND NOW I'M
BEGINNING TO LEAD INTO BLOOD
TRANSFUSION ASPECTS OF WHAT THE
IMPLICATION OF HTV ARE FOR BLOOD
TRANSFUSION.
WE HAVEN'T WORRIED ABOUT IT.
BUT NOW IT'S BEEN THIS PARADIGM
SHIFT BECAUSE IT WAS ALWAYS
THOUGHT TO BE AN ACUTE SELF
LIMITED DISEASE SO THAT THE LACK
OF A DONOR COMING IN
ASYMPTOMATIC DONOR COMING IN
WHEN THERE WAS NO VIREMIA WAS
UNLIKELY.
I HAVEN'T MENTIONED THIS YET,
IT'S FOUND THE ANTI-BODY TO ATV
IS FOUND IN EXTRAORDINARILY HIGH
PREVALENCE.
IN THE U.S.
GET BACK TO THAT.
WE NOW KNOW THAT THIS CAN CAUSE
A CHRONIC INFECTION.
THAT TOTALLY CHANGES THE
PERCEPTION OF HOW SERIOUS THIS
DISEASE IS.
SO FAR ONLY AN IMMUNOSUPPRESSED
PATIENTS.
PARTICULARLY THE SOLID ORGAN
TRANSPLANT PATIENTS.
IT'S KNOWN THAT NOT ONLY CAN IT
EVOLVE TO CIRRHOSIS BUT IT CAN
EVOLVE QUITE RAPIDLY MUCH MORE
RAPIDLY THAN HEPATITIS C.
AND IN THESE IMMUNOSUPPRESSED
PATIENTS, IT CAN LEAD TO A
CHRONIC CARRIER STATE.
WHAT WE WORRY ABOUT IN
TRANSFUSION IS A SILENT CARRIER
STATE.
WE HAVE NOT YET SHOWN THAT THERE
IS A SILENT CARRIER STATE IN
ASYMPTOMATIC PEOPLE IN THE U.S.
EVIDENCE FOR THIS CHRONIC
INFECTION OR JUST A LITTLE BIT
MORE ABOUT IT IS THAT THERE HAS
BEEN MULTIPLE CASES.
IN LIVER AND KIDNEY TRANSPLANT
RECIPIENT IN CASES OF LYMPHOMA,
PARTICULARLY THOSE TREATED WITH
TUSKIMAB -- ALMOST ALL THESE
CASES OF CHRONIC HEPATITIS HAVE
BEEN REPRESENTED -- GENOTYPE
THREE INFECTIONS IN ENDEMIC
REGIONS, NON-ENDEMIC REGIONS.
VIREMIA LEVELS TEND TO FIVE OR
TEN TO THE SEVEN COPIES PER ML.
THIS IS A SCARY PART.
THIS EVOLUTION TO CIRRHOSIS AND
UP TO 50%.
AND LIVER FAILURE AND DEATH MAY
ENSUE FROM THAT.
SO FROM THE TRANSFUSION
STANDPOINT, IMMUNOSUPPRESSED
TRANSFUSION RECIPIENTS THEREFORE
COULD BE AT RISK.
AND MANY OF THE PATIENTS THAT WE
TRANSFUSE PARTICULARLY HERE AT
THE CLINICAL CENTER ARE
IMMUNOSUPPRESSED.
SO I WORRY ABOUT THIS.
NOW, THERE'S MORE EVIDENCE FOR
THIS CHRONIC HEPATITIS.
THIS WAS A STUDY, A NICE STUDY A
MULTICENTRAL REVIEW OF 85 ATV
INFECTED RECIPIENTS IN 17
DIFFERENT BLOOD CENTERS.
THESE ARE ORGAN TRANSPLANT
PATIENTS.
OUT OF THOSE 85 ORGAN TRANSPLANT
PATIENTS, 56 OR 66% HAD CHRONIC
ATV INFECTION.
18 OF THOSE CLEARED WHEN THEY
REDUCED THE DOSE OF
IMMUNOSUPPRESSION.
SO AGAIN SHOWING THE
RELATIONSHIP TO
IMMUNOSUPPRESSION.
20 OF THEM THEY TREATED MOSTLY
WITH INTERFERON.
AND 14 OF THEM WENT INTO A
SUSTAINED VIRAL LOGIC
RESPONSE -- TWO OF THEM DIED
THERE CIRRHOSIS.
SO OVERALL, EIGHT OUT OF THOSE
56 PATIENTS DEVELOPED CIRRHOSIS
OR 14%.
BACK TO THE ACUTE CHRONIC LIVER
DISEASE, THIS WAS DEFINED AS
ACUTE LIVER INJURY WITH JAUNDICE
AND COAGULATOPATHY.
THE PATIENT PREVIOUSLY DIAGNOSED
OR UNDIAGNOSED WITH LIVER
DISEASE.
SO YOU MIGHT HAVE A PATIENT WITH
HEPATITIS C CHRONIC ASYMPTOMATIC
HEPATITIS C.
THEY BECOME JAUNDICE AND MAY GO
INTO HEPATIC FAILURE AND
ENCEPHALOPATHY.
WHEN YOU SEE THIS PATTERN YOU
THINK ABOUT SUPER INFECTION WITH
ANOTHER VIRUS.
A C PATIENT GETTING B OR A C
PATIENT GETTING E OR B PATIENT
GETTING E OR IT COULD BE
HEPATITIS B ITSELF SOMETIME
REACTIVATES IN A VERY VIRULENT
FASHION.
IT COULD BE A PATIENT YOU'RE
FOLLOWING AND SUDDENLY IS
IMBIBING A LOT OF ALCOHOL.
SO THESE THINGS THAT ARE HEALTHY
CAN BE VERY BAD FOR YOUR LIVER
OR IT COULD BE A FLARE IN AN
AUTOIMMUNE HEPATITIS OR NEW
ONSET OF IMMUNE HEPATITIS.
IN THAT PICTURE YOU HAVE TO
THINK ABOUT HEPATITIS E NOW.
IN *** -- BANGLADESH THEY FOUND
22 PERCENT WERE DUE TO HEPATITIS
C VIRUS.
IT IS BECOMING MORE COMPLEX THAN
EVER IMAGINED AND A MORE
IMPORTANT DISEASE.
IT REMINDED ME OF THE RELATIVE
COMPLEXITY OF MEN AND WOMEN THAT
I'VE STUDIED INTENSELY.
AND IT WAS DEPICTED ON THIS
SLIDE WHERE WE'RE JUST A SIMPLE
ON OFF SWITCH BECAUSE WOMEN ARE
VERY VERY VERY COMPLEXED.
SO I WANT TO TALK NOW ABOUT THE
EPIDEMIOLOGY OF HEPATITIS E AND
THE ZOONOSIS.
ZOONOSIS IS AN ANIMAL AGENT THAT
HAS ADAPTED TO HUMANS.
A LOT OF THAT IS IN THE FOOD
CHAIN AND AN IMPORTANT EXAMPLE
PERHAPS IS THIS WHERE A SIMIAN
IMMUNE DEFICIENCY VIRUS IN
PRIMATES, IN AFRICA GOT TO BE
EATEN BY HUNTERS AND TRIBAL
PEOPLE AND OVER TIME MUTATED AND
BECAME *** CAPABLE OF INFECTING
MAN AND THEN SPREADING FROM MAN
TO MAN.
THE SAME HAPPENED WITH SIMIAN T
LYMPHOTROPIC VIRUS WHERE MONKEYS
KILLED MUTANT ADAPTIVE MUTATED
BECAME HUMAN T LYMPHOTROPIC
VIRUS INFECTION.
AND IN THE SAME WITH SIMIAN --
VIRUS INFECTION BUT *** WAS
CLEARLY THE MOST IMPORTANT OF
THESE TRANSMISSIONS.
BUT THE OTHER REALLY INTERESTING
ONE IS THIS.
SHEEP WERE INFECTED WITH A
DISEASE CALLED SCRAPIE.
BECAUSE THEY GOT ITCHY.
THEY WOULD SCRAPE AGAINST
FENCES.
THAT WAS SHOWN TO BE A PRE-ON
DISEASE.
THE SHEEP WERE THEN SLAUGHTERED
AND FOR FOOD BUT ALSO PART OF
THE REMAINS WERE PUT INTO OFAL.
OFAL IS A FOOD GIVEN TO COWS.
THIS CAUSED A NEUROLOGIC DISEASE
IN COWS FOR BOVINE --
ENCEPHALOPATHY, ANOTHER PRE-ON
DISEASE.
BUT THE COWS WOULD GROUND OFTEN
INCLUDING THEIR NEUROLOGIC
TISSUES AND PUT INTO MEAT PIES
AND HAMBURGERS, PARTICULARLY IN
ENGLAND AND CAUSE VARIANT CHOICE
OF -- DISEASE THE HUMAN VERSION
OF MAD COW DISEASE.
THIS WAS A CLEAR FOOD CHAIN
THROUGH MULTIPLE SPECIES.
AND THERE WAS OF THE DISEASE NOW
IN ELK AND DEAR CALLED CHRONIC
WASTING DISEASE WHICH IS ANOTHER
PRE-ON DISEASE WHICH HASN'T YET
BEEN PROVEN TO TRANSMIT DEMAND
BUT COULD THROUGH HUNTERS EATING
FRESH ELK AND DEER MEAT.
LASTLY THE TSARS VIRUS, THE
RESPIRATORY VIRUS IN CHINA
CAUSES EPIDEMIC AND FEAR
ACTUALLY TRACED TO A CIVIC CAT.
THESE CIVIC CATS WERE OFTEN
EATEN.
I DON'T KNOW IF THAT'S EXACTLY
HOW THE VIRUS GOT INTO HUMAN.
IT BECAME A RESPIRATORY
TRANSMITTED DISEASE.
THE THINGS WE WORRY ABOUT NOW
THAT OF COURSE ARE ALL TROUBLE
NOW IN THE BLOOD WORLD ARE THESE
VECTOR BORNE DIAGNOSIS.
SO YOU HAVE WEST NILE VIRUS
WHICH IS REALLY AN INFECTION OF
BIRDS AND SOMETIMES HORSES.
AND MOSQUITOES BITE THE BIRDS
AND THEN BY -- BITES MAN AND GETS
INFECTED.
MAN IS THE END STAGE OF THIS
DISEASE BUT THE HOST IS REALLY
THE BIRD.
AND THE SAME IS TRUE NOW FOR
DEER, DEER AND MICE.
THEY CARRY TICKS.
THEY ARE A TAXI SERVICE FOR
TICKS.
TICKS BY THE MAN.
THIS IS AN EARLY DISEASE -- AND
ALL THESE ARE BLOOD
TRANSMISSIBLE.
IT'S BEEN A LOT OF TALK ABOUT
USING PIG ORGANS FOR
TRANSPLANTS, PIG HEARTS OR PIG
LIVERS.
ALTHOUGH I DON'T KNOW ANY CASES
THIS WOULD CERTAINLY SCARE ME
THAT SOME PIG VIRUS WOULD GET
INTO HUMANS.
AND I COULD REALLY SHOULD NOT
PUT THE PIG UP HERE AS A FOOD
BORNE SOURCE THAT I'M SHOW YOU
IN A MOMENT.
SO THAT'S THE PICTURE OF THE
ZOONOSIS.
WHY PIGS?
WELL THE PIGS ARE THE HOST FOR
HEV, THE PRIMARY HOSTS FOR HEV.
YOU CAN SHOW THAT THE RATES OF
ANTIBODY TO HEV ARE HIGH IN
BLOOD DONORS AND GO OFTEN UP WITH AGE.
ANYBODY WHO WORKS AROUND PIG
FARM ARE MUCH MORE INFECTED.
AND SO HOW, HOW IS THIS
HAPPENING.
HOW IS HEV AND WE'RE NOT
GENERALLY EATING RAW PIG MEAT
BUT THERE ARE SOME THINGS THAT
MAY FRIGHTEN YOU.
AND I CAUTION YOU, THIS IS NOT
FOR THE QUEASY.
BUT THERE IS THIS GASTRO ELITISM
MOVEMENT RIGHT NOW WHERE PEOPLE
EAT WILD BOAR PAP DELI.
THERE'S A WHOLE VARIETY OF
EXOTIC FOODS USING PIGS THAT ARE
NOT ALWAYS COOKED TO THE
ULTIMATE.
IN FRANCE AND OTHER PARTS OF
FRANCE WHERE THERE'S -- WHICH IS
A TREMENDOUS FAVORITE OF PEOPLE
WHERE 80% OF THE PEOPLE ARE
INFECTED HEV.
THIS IS BASICALLY UNCOOKED PIG
LIVER AND OTHER PARTS.
APPARENTLY VERY TASTILY.
THEY WILL ESSENTIALLY EAT
ANYTHING, ANYTHING EXCEPT
AMERICAN FOOD.
[LAUGHTER]
SO I FOUND OUT THAT PET TREATS
CONTAIN PORK LIVER.
SO HAVE YOU EVER MUNCHED ON A
MILK BONE.
THERE'S LIVER SLIME THAT COMES
OUT OF PIG POOP AND IT'S USED TO
IRRIGATE VEGETABLES IN PLANTS.
SO HAVE YOU EATEN ANY VEGGIES
TODAY.
THIS IS CONCEIVABLY A WAY THAT
NON-MEAT COULD BE CONTAMINATED
WITH PIG.
ALSO WATER FROM PIG FARM, THE
IRRIGATION OF VEGETABLES.
SO WASH YOUR VEGETABLES.
DUNKIN' DONUTS I FOUND SELLS
PORK DOUGHNUTS IN CHINA.
SCRAPPLE.
SCRAPPLE, A VERY POPULAR
SOUTHERN DISH IS MADE FROM PIG
HEADS AND PIG LIVER AND NOT IN
NECESSARILY COOKED TO THE
ULTIMATE.
WENT AROUND, CVC WENT AROUND AND
TESTED RAW PIG LIVER IN THE PAR
MARKETS.
YOUR AVERAGE DAILY SUPERMARKET
AND 11% OF THESE TESTED HEV/RNA
POSITIVE.
SO EVERY ONE OF THESE COOKED
PROPERLY WHEN YOU GET THEM HOME.
USD SAYS YOU HAVE TO COOK PORK
MEAT TO 145 DEGREES BUT ORGANS
ARE COOKED TO 160 DEGREES.
I THINK PEOPLE WHO LOVE ORGANS
MIGHT NOT LIKE THEM OVERCOOKED.
SO THAT'S A POTENTIAL SOURCE.
BASICALLY THESE ARE SOME OF THE
WAYS BUT WE REALLY DON'T KNOW
HOW ALL THIS HEV IS GETTING
AROUND.
BUT FOOD IS THOUGHT TO BE THE
MAIN CULPRIT.
SO LET'S GET TO TRANSFUSION NOW.
THIS WAS THE FIRST CASE OF
TRANSFUSION TRANSMITTED
HEPATITIS, IN JAPAN.
VERY NICELY STUDIED CASE WHERE
THE ALT LEVELS ARE SHOWN IN RED
AND THE BILIRUBIN LEVELS IN
YELLOW.
AND YOU CAN SEE THAT ABOUT 18
DAYS AFTER TRANSFUSION, THE ALT
WENT UP TO 1800.
THE BILIRUBIN WENT UP TO 18 AS
QUITE A SEVERE CASE OF JAUNDICE.
AND THEY WENT BACK AND TRACED
THE DONORS TO THIS PATIENT AND
THEY FOUND ONE DONOR WHO HAD
BEEN A REPEAT DONOR.
ON PREDONATIONS THEY TESTED
NEGATIVE FOR HEV DONATION GIVEN
HERE IT WAS POSITIVE FOR HEV/RNA
OR NEGATIVE IGM OR IGG ANTIBODY.
BUT FIVE MONTHS LATER SAMPLE ON
THE SAME DONOR SHOWED THE DONOR
NOW TO BE HEV/RNA NEGATIVE BUT
POSITIVE FOR IGM AND IGG.
SO THIS WAS A NICE TASTE OF
EVOLVING HEPATITIS E IN THE
DONOR.
THEN TRANSMITTED TO THE
RECIPIENT AND THE TWO HAD
COMPLETE SEQUENCE IDENTITY.
THEY WERE BOTH GENOTYPE FOUR.
SO THIS IS A NICE CASE.
IN THAT SAME STUDY, THEY LOOKED
AT DONORS WHO HAD ELEVATED
TRANSAMASE LEVELS.
THEY FOUND IN SIX OF THE 16 WHO
HAD ELEVATED TRANSAMASE WERE RNA
POSITIVE AND FIVE OR SIX OF
THOSE WERE IGM POSITIVE.
IN JAPAN THEY SCREENED, SUSAN DO
THEY SCREEN FOR ALT?
I DON'T KNOW WHETHER THESE
DONORS WOULD HAVE BEEN ABLE TO
DONATE OR NOT BUT CERTAINLY IT
SHOWS THAT HEV/RNA WAS IN THE
DONOR POPULATION.
HERE'S THE FIRST CASE IN
ENGLAND, EXCEPT A MUCH DELAYED
ONSET.
THIS WAS A PATIENT WHO HAD
LYMPHOMA, WAS A CHEMO THERAPY
ABOUT 33 TO 40 DAYS AFTER THE
TRAPS FUSION, ALT LEVELS WENT
UP
TO 800.
I BELIEVE WENT UP QUITE HIGH AS
WELL.
AND DURING THE COURSE OF THAT
ACUTE HEPATITIS ATV/RNA WAS
PRESENT.
LATER ON IGM WAS DETECTABLE UP
TO THIS POINT IGG WAS NOT
DETECTED IN THIS CASE.
THEY WENT BACK TO THE DONORS
HERE FOUND THAT THERE WAS A
DONOR WHO DEVELOPED FLU-LIKE
SYMPTOMS, 14 DAYS AFTER THAT
DONATION.
THE DONOR AT THAT TIME HAD AN
ALT OF OVER 2000.
AND THE DONOR WAS THEN IGM
ANTI-HGV POSITIVE GENOTYPE THREE
AND THE PATIENT WAS SEQUENCE
IDENTICAL WITH THE DONOR.
THESE ARE UNEQUIVOCAL CASES.
THEY ARE ABOUT SIX TO EIGHT OF
THESE CASES NOW.
SO ITV CLEARLY CAN BE A
TRANSFUSION TRANSMITTED DISEASE.
THIS IS A NICE STUDY IN AN
ENDEMIC AREA.
IT'S HARD TO PICK UP TRANSFUSION
TRANSMISSION IN ENDEMIC AREA
BECAUSE YOU DON'T KNOW IF IT'S
COMING FROM THE FOODOR THE
WATER.
IN A RECOLLECT SPECULATIVE STUDY
THEY LOOKED AT PEOPLE WHO HAS
BEEN MULTIPLY TRANSFUSED VERSUS
THOSE NOT TRANSFUSED FOUND THAT
9% OF THOSE MULTIPLY
TRANSFUSE -- PRECEDING THREE
MONTHS, THEY FOUND THAT THEY
FOUND THAT 43% HAD ATV/RNA
COMPARED TO 2% WHO HAD NOT BEEN
TRANSFUSED.
THEY DID A PROSPECTIVE STUDY OF
25 PEOPLE.
SMALL STUDY BUT THEY FOUND THAT
THOSE OF THOSE 25 WERE
SUSCEPTIBLE ANTI-HEV NEGATIVE
PRIOR TO TRANSFUSION.
13.6% CONTAIN HEV INFECTED FROM
THE SAWDUST STUDY TO THE FOLLOW
UP COMPARED TO NON-IN THE
NON-TRANSFUSED GROUP.
SO THIS IS INDIRECT EVIDENCE
THAT WOULD SUGGEST TRANSMISSION.
THEY DID TRACE THESE CASES,
THESE SERO CONVERSIONS IN A
RECIPIENT, THEY TRACE IT TO FOUR
DONORS WHO ARE HEV POSITIVE AND
IGM POSITIVE.
HERE AT NIH BOB PERSELL TOOK
SOME OF OUR HARD STUDY CASES.
THESE ARE CASES OF POST
TRANSFUSION HEPATITIS BACK IN
THE LATE 60'S WHERE MOST OF THE
CASES WERE IN RETROSPECT
HEPATITIS B OR C.
AND ONLY ONE CASE APPEARED TO BE
HEPATITIS E.
I'M GOING TO SKIP THIS SLIDE FOR
TIME.
WE JUST LOOKED AT ALMOST 2000
DONORS HERE AT NIH.
AND WE FOUND THAT IGG ANTI-HEV
AMOUNT BODY WAS PRESENT IN 18.8%
OF OUR DONORS.
THESE ARE HEALTHY VOLUNTEER
DONORS.
AND .4% OF THEM WERE IGM
POSITIVE.
NONE OF THEM HAD HEV/RNA.
YOU SEE THE CONFIDENCE INTERVALS
WERE PRETTY SMALL BECAUSE IT WAS
A LARGE NUMBER OF DONORS.
SO BETWEEN 17 AND 20% ARE BLOOD
DONORS IN AMERICA ARE ATV
EXPOSED.
THAT'S BEEN SHOWN NOW IN OTHER
PLACES AS WELL.
YOU CAN SEE IN THE DONORS
THERE'S THIS NICE STEP WISE AGE
DISTRIBUTION.
IT'S AS IF THIS INFECTION KEEPS
ACCUMULATING AS YOU KEEP GETTING
EXPOSED OVER TIME.
AND THE CUMULATIVE RATE IS QUITE
HIGH.
THE KEY IN OUR STUDY WAS A
PERSPECTIVE EVALUATION OF 362
TRANSFUSED PATIENTS.
SO IN THIS DONOR POPULATION
WHERE 20% HAVE IGG ANTIBODY,
WHAT'S HAPPENING TO THE
RECIPIENTS
WELL WE FOUND THAT ONLY TWO OF
THESE RECIPIENTS WERE .5% HAD
APPARENT ATV/AGG SERO CONVERSUS.
THEY WERE NEGATIVE
PRETRANSFUSION AND POSITIVE POST
TRANSFUSION.
AS YOU GET SERO SAMPLES --
RETROSPECTIVE NO ATV/RNA AND NO
IGM.
AND WE CONCLUDED THERE WERE
ACTUALLY NO NEW INFECTIONS
BECAUSE ONE OF THEM HAD RECEIVED
A HIGH TITER ANT BY.
THE OTHER ONE IN RETROSPECT
PROBABLY HAD AN INFECTION
BEGINNING IN THAT FIRST SAMPLE.
IT WAS NEGATIVE BUT IT WAS HIGH
NEGATIVE.
AND PROBABLY INFECTION WAS
STARTED.
SO THAT'S THAT.
AND SO WE DIDN'T OBSERVE ANY
INFECTIONS.
IN THE UPPER BOUND OF THAT ZERO
OBSERVATIONS IS ABOUT .8%.
SO VERY LOW THAT WE'VE
DEMONSTRATED SO FAR.
THIS IS THAT PARTICULAR PATIENT
WHO YOU CAN SEE HAD NO ANTIBODY.
THESE ARE OPTICAL DENSITIES ON
THE LEFT.
THERE'S NO ANTI-BODY
PRETRANSFUSION.
36 THE LAST OF OUR PROSPECTIVE
STUDY SAMPLES HAS A HIGH LEVEL
OF ANTI-ATV.
SO YOU SAY OKAY, THIS IS AN ATV
INFECTION FROM THE TRANSFUSION.
BUT NO, IF YOU HAVE THE INTERIM
SAMPLES AND IF YOU HAVE THE
DONOR SAMPLES, YOU CAN LOOK AT
IT FURTHER.
WHAT WE FOUND IS THAT THERE WAS
NO IGM OR RNA IN THE PATIENT,
THAT THE PATIENT ACTUALLY WAS
CONTINUOUSLY TRANSFUSED,
RECEIVED 17 RED CELLS AND
PLATELETS.
WHAT WE FOUND WAS FOUR DAYS
BEFORE WE GOT THIS SAMPLE, HE
RECEIVED RECELLS FROM A DONOR
WITH HIGH TITER IGG ANTI-BODY.
SO THE ANT BODY WE PICKED UP WAS
COMING FROM A DONOR.
AT THAT TIME HE ALSO RECEIVED AN
ATV/RNA POSITIVE DONOR AND HE
MIGHT HAVE GOTTEN INFECTED BUT
HE DIED SEVERAL DAYS LATER SO WE
COULDN'T SEE THE OUTCOME OF THAT
RNA POSITIVE.
IT'S VERY IMPORTANT TO, AND YOU
CAN ONLY DO THIS IN A PROSPECTUS
STUDY FOR ZERO CONVERSION.
SHOULD DONORS BE SCREENED.
THAT'S THE QUESTION WE'RE FACING
NOW.
IT'S NOT A MAJOR ISSUE AT
PRESENT BUT IT'S SOMETHING THAT
THE FDA IS CONSIDERING.
SUSAN IS HERE FROM THE FDA.
AND WHAT I CALL THIS THE
TRIANGLE OF TRANSFUSION
TESTABILITY.
WHAT ARE THE THING THAT MAKE YOU
WANT TO TEST FOR A VIRUS.
WELL ONE, CAN YOU DEMONSTRATE AN
ASYMPTOMATIC VIREMIA.
WOULD A DONOR LIKE YOU TO COME
WITH AN INFECTION AND YOU DON'T
KNOW.
THAT'S WHAT HAPPENED WITH
HEPATITIS C ALL THE TIME.
IS THERE A CLINICAL DISEASE.
I'VE SHOWN YOU THERE IS IF
YOU'RE AN IMMUNOSUPPRESSED
RECIPIENT.
IS IT A TRANFUSED -- YES, I'VE
SHOWN YOU THERE IS.
WITH THAT INFORMATION THE PIECE
WE DON'T KNOW IS HERE.
WE DON'T KNOW IF THAT
ASYMPTOMATIC VIREMIA EXISTS.
SO WOULD YOU TEST OR NOT BASED
ON THIS.
WE ALSO HAVE GUIDED NOW WHAT'S
CALLED THE PRECAUTIONARY
PRINCIPLE.
THIS CAME OUT OF THE *** CALL
THE CASES OF TRANSFUSION
TRANSMISSION FROM ***.
SO MAMEDZ CAME UP WITH THIS
PRECAUTIONARY PRINCIPLE SAID FOR
SITUATIONS OF SCIENTIFIC
UNCERTAINTY THE POSSIBILITY OF
RISK SHOULD BE TAKEN INTO
ACCOUNT EVEN IN THE ABSENCE OF
PROOF TO THE CONTRARY.
OUR TYPICAL WAY IS TO WAIT FOR
EVIDENCE-BASED MEDICINE TO SAY
YES WE SHOULD BE DOING.
BUT THE EVIDENCE BASE OFTEN
DOESN'T APPEAR FOR YEARS AND
YEARS AND MEANWHILE PEOPLE CAN
BE INFECTED.
SO THE COROLLARY WITH THE
PRECAUTIONLY PRINCIPLE IS THAT
MEASURES NEED TO BE TAKEN TO
FACE POTENTIAL SERIOUS RISKS
EVEN WITHOUT ABSOLUTE PROOF.
UNLESS YOU HAVE PROOF TO THE
CONTRARY.
SO THAT'S IN THE BACKGROUND IN
MAKING OUR DECISION ALSO.
SO WHY AREN'T WE DOING HEV
TESTING RIGHT NOW?
WELL ONE, WE HAVE NO STANDARDS.
WE HAVE NO PEDIGREE PANELS BY
WHICH TO COMPARE ASSAY
SENSITIVITY AND SPECIFICITY.
IF YOU COME UP WITH A TEST THAT
HAS HIGH NON-SPECIFICITY, YOU
START TO ELIMINATE MILLIONS OF
BLOOD DONORS.
IT'S A VERY DANGEROUS THING
BEFORE YOU HAVE GOOD ASSAYS.
WE'RE NOT AT THAT STAGE YET.
WE'RE PROBABLY GOING TO HAVE TO
SCREEN FOR HEV RNA RATHER THAN
ANTI-BODIES SINCE ANTI-BODIES
ARE SO COMMON.
WE DON'T HAVE ANY HEV ASSAYS
THAT ARE CURRENTLY LICENSED.
I DON'T KNOW IF ANY ARE IN THE
PIPELINE.
THIS IS THE KEY HERE.
WE DON'T KNOW THE FREQUENCY AND
THE DURATION OF ASYMPTOMATIC
VIREMIA IN AMINO-COMPETENT BLOOD
DONORS.
THIS IS WHAT'S GOING TO DRIVE
THE RISKY RISK -- RISK EQUATION --
FREQUENCY OF THE DOSE THAT MIGHT
BE EXCEEDED IN HEALTHY BLOOD
DONORS.
AND WE DON'T KNOW THE FREQUENCY
OF THE SIGNIFICANT OPEN FECTIONS
OF THE AMINO COMPETENT AND
SUPPRESSED PATIENTS.
WE HAVE A GOOD IDEA THAT IT IS
SIGNIFICANT IN SUPPRESSED
PATIENTS.
HOW MUCH IS THIS AND HOW OFTEN
DOES IT OCCUR AND WHAT'S THE
COST BENEFIT RATIO OF
IMPLEMENTING A TEST LIKE THIS.
SO THOSE ARE THE THINGS THAT
BLOOD BANKS ARE DEALING WITH
RIGHT NOW.
SO I'LL SKIP.
JUST TO SAY THAT THIS IS NOT
UNIQUE TO BLOOD BANKING.
THIS IS NOT UNIQUE TO HEV,
RATHER.
THERE ARE MANY AGENTS THAT WE
DON'T CURRENTLY TEST FOR.
BECAUSE THEY ARE TOO PREVALENT
OR NOT PREVALENT ENOUGH OR
WHATEVER.
BUT BASICALLY ANY AGENT THAT HAS
AN ASYMPTOMATIC VIREMIA HAS A
THREAT TO THE TRANSFUSION
TRANSMITTED.
IT'S LIKELY THAT TRANSMISSION IS
HIGHLY DEPENDENT ON THE DURATION
OF THE VIREMIA AND THE CONCERN
IS DEPENDENT ON SEVERITY OF THE
DISEASE.
SO IN THIS CASE WE HAVE VARYING
HEV WITH A HAVE MALARIA, WE HAVE
DENGHY AND ENENCEPHALITIS THAT
WE CAN'T TEST FOR EVERYTHING.
WE'RE ON THE VIGILANCE.
THIS IS ANOTHER ONE OF MY
AFRICAN SLIDES.
BUT IT'S NOT A UNIQUE DILEMMA
FOR HEV.
WE'VE CONQUERED ALL THE
PROBLEMS, WE'VE HANDLED MAD COW
DISEASE.
WE DON'T WORRY ABOUT THESE MAD
COWS SO MUCH ANYMORE.
WE HAVE MEASURES TO PREVENT
THAT.
WE'VE GOTTEN PAST BIRD FLU WHERE
IT CAUSED DEVASTATING DISEASE IN
THE FLAMINGO POPULATION.
THESE ARE NOT REAL FLAMINGOS.
SO I SEE NO REASON WHY WE'RE NOT
GOING TO BE ABLE TO HANDLE THE
SWEET LITTLE PIG THINGS.
I THINK WE'LL GET TO THIS
PROBLEM AND WE WILL OR WON'T
TEST BUT WE'LL KNOW IN A COUPLE
YEARS.
SO IN CONCLUSION, I AGREE WITH
EVERYTHING I'VE SAID.
[LAUGHTER]
AND WE CAN HAVE QUESTIONS NOW
FOR BOTH OF US.
THANK YOU.
[APPLAUSE]
>> THE HEPATITIS VIRUS TARGET
LIVER.
>> THAT'S A GOOD QUESTION.
BECAUSE THEY DO GO PERHAPS TO
OTHER ORGANS BUT THEY'RE VERY
SPECIFIC TO THE LIVER.
IT'S A MATTER OF RECEPTORS.
THE SPECIFIC GROUP OF RECEPTORS
THAT THE VIRUS NEEDS TO CONVEY
THE ORGAN ARE PRESENT IN THE
LIVER.
>> IN ADDITION TO THE RECEPTOR
OR THE ENTRY FACTOR RESPONSE FOR
THE VIRUS GETTING IN, ALSO
FACTORS THAT LIVER SPECIFIC
VIRAL -- ETCETERA.
SO THERE ARE OTHER FACTORS
[INDISCERNIBLE] SPECIFIC FOCUS.
HAVE A QUESON.
WHERE YOU SHOAFTD THAT THE --
CAUSED ZERO CONVERSION IN THAT
PATIENT.
YOU SAID HE DIED BUT DO WE KNOW
IF LIVER FAILURE WAS --
>> NO, HE DIED, HE WAS A VERY
SICK PATIENT.
HE HAD RECEIVED 72 UNITS OF
BLOOD.
HE WAS IN BAD SHAPE.
IT WASN'T ACUTE AND CHRONIC.
>> SO IS THERE A MOVE TO TEST,
GIVEN THE DIFFICULTIES, IF AN
IMMUNOCOMPROMISED PATIENT IS
GOING TO BE RECEIVING BLOOD
TRANSFUSIONS, IS THERE AN EFFORT
TO SELECT OUT THAT GROUP TO TEST
THE BLOOD THAT THEY WOULD BE
GETTING?
>> THAT'S HARD TO DO.
IT'S HARD TO HAVE TWO
INVENTORIES IN THE BLOOD BANK.
IT WAS DONE IN THE PAST WHERE
CMV SCREEN BLOOD ONLY WENT TO
IMMUNOCOMPROMISE PATIENTS.
BUT I THINK IF THE TESTS WERE
IMPLEMENTED, IT WOULD BE DONE
FOR EVERYBODY.
BUT YOUR QUESTION RAISES, IF WE
WANT TO STUDY THIS FURTHER,
MAYBE WHAT WE SHOULD DO IS STUDY
IMMUNE DEFICIENT PATIENTS.
WE'RE DOING THAT TO SOME EXTENT
SPECIFICALLY TARGETING
IMMUNOSUFFICIENT PATIENTS TO SEE
IF THEY ARE CONVERTING.
>> WHAT ABOUT IN THE MIDDLE EAST
AND OTHER PARTS OF THE WORLD
WHERE YOU SHOWED THE DATA OF THE
RYHIGH PREVALENCE OF THIS.
WHAT ARE THEY DOING?
>> I DON'T THINK ANYBODY IS
SCREENING FOR ATV FOR THE BLOOD
SUPPLY.
AND THE HIGHER THE PREVALENCE,
THE MORE DIFFICULT IT IS TO
SCREEN ACTUALLY S BUT IF YOU
SCREEN FOR ANTIBODY, IF YOU
SCREEN FOR HEV/RNA, THAT COULD
BE DONE BUT IN THOSE AREAS MOST
OF THE TRANSMISSION IS COMING
FROM WATER SUPPLIES.
UNDEVELOPED NATIONS AND THE
DEVELOPED NATIONS AND THE RATE
OF NEW INFECTIONS ARE LOW.
IT'S A LOT OF EFFORT FOR MAYBE A
SMALL PAYOFF.
FIRST TO GET THE STANDARDIZED
PANELS AND STANDARDIZED TESTS
BECAUSE WE COULDN'T DO THIS EVEN
IF WE WANTED TO RIGHT NOW.
AND SECONDLY, TO REALLY STUDY
THE ASYMPTOMATIC VIREMIA BETTER.
BY THE WAY RED CROSS IS TESTING
10,000 DONORS TO SEE HOW MANY
HAVE HEV/RNA.
>> YOU MENTIONED THERE'S A
VACCINE AVAILABLE IN CHINA.
CAN YOU TELL US IF IT'S -- AND
THERE IS AN INTENT TO BRING IT
OVER TO PEOPLE WHO ARE DIAGNOSED
TO HEV HERE?
>> WELL, THE EFFICACY IS VERY
GOOD, ABOUT 95% EFFICACY.
AND I THINK IN PLACES WHERE HEV
IS VERY PREVALENT, THIS COULD BE
INTRODUCED BY CHINA, COULD BE
INTRODUCED AS A NATIONAL POLICY.
BUT IT'S NOT A THERAPEUTIC
VACCINE SO YOU DON'T WANT TO
GIVE IT TO PEOPLE ALREADY
INFECTED.
SO THE NEED IN THE DEVELOPED
WORLD IS NOT SUFFICIENT RIGHT
NOW, I DON'T THINK, TO INTRODUCE
THAT VACCINE.
>> WHAT ABOUT INJECTION DRUG
USERS FOR HEV, SHOULD THEY BE
VACCINATED FOR HEV?
>> NO, I THINK WE SHOULD
VACCINATE THE OVER EATERS.
[LAUGHTER]
>> JUST ONE OTHER QUESTION.
IF SOMEONE IS *** POSITIVE BUT
THEIR DISEASE IS UNDER CONTROL
TH ART, ARE THEY STILL MORE
SUSCEPTIBLE FOR HEV INFECTION.
>> I DOUBT IT.
I THINK IT'S ALL THE MATTER OF
DEGREE OF IMMUNOSUFFICIENCY.
>> WHILE I'M WALKING UP HERE,
WHAT DO THE MITOCHONDRIA LOOK
LIKE IN HEV WHERE YOU HAVE LIPID
DROPLET ACCUMULATION.
>> YES.
I MEAN WE HAVEN'T REALLY LOOKED
AT IT CLOSELY.
IT'S POSSIBLE THAT MAYBE IT'S
INFECTED.
THERE IS SOME DATA SUGGESTS THE
MITOCHONDRIA -- NOT CLEAR HOW
THAT'S INVOLVED MAYBE IT HAS TO
DO WITH THE OX -- OXYGEN
SPECIES -- TRANS.
>> IN BLOOD TRANSFUSIONS, WHAT
IS, LET'S SEE, WHAT IS KNOWN
ABOUT OPTIMAL MATCHING OF THE
DONOR AND THE RECIPIENT.
AND THE SECOND PART TO THE
QUESTION IS WHAT ARE THE
MEASURES OF SUCCESS IN BLOOD
TRANSFUSION?
>> WELL, I MEAN THE MATCHING
ISSUES IS A DIFFERENT ISSUE THAN
TRANSMISSION.
I MEAN WE ARE MATCH DONORS FOR
MANY DIFFERENT BLOOD GROUPS.
NOT ALL AND WE LOOK FOR ANTIBODY
TO BLOOD GROUPS FROM THE
RECIPIENTS.
BUT AS FAR AS THE TRANSMISSION
OF THE MAJOR DISEASES, ***,
HTLV, HBV AND HCV, THOSE ARE NOW
EXTREMELY RARE PHENOMENA.
***, HCV ONE IN TWO MILLION
BEING AT RISK FOR TRANSFUSION.
THE BLOOD SUPPLY IS REALLY SAFE
FOR THE AGENTS WE CAN TEST FOR.
SO THE RISKS OF BLOOD
TRANSFUSION NOW ARE EITHER GOING
TO BE AROUND THE AGES WE DON'T
YET TEST FOR OR NEW AGENTS THAT
MIGHT EVOLVE OR THING THAT HAVE
NOTHING TO DO WITH INFECTION.
NOW THERE'S BACTERIAL
CONTAMINATION OF BLOOD PRODUCTS,
THERE ARE ALL KIND OF OTHER
ISSUES IN BLOOD UNRELATED TO
INFECTIOUS DISEASE.
BUT AS FAR AS INFECTION, WE'VE
COME A LONG WAY AND THE BLOOD IS
INCREDIBLY SAFE.
>> WHAT'S THE MAIN -- RNA
POSITIVE -- IGE POSITIVE, WHAT'S
THAT MEAN TO PROTECT, THE PEOPLE
GOT PROTECTION.
>> IF YOU HAVE HEV/RNA, YOU ARE
INFECTED AT THAT POINT.
IGM IS ALSO A SIGN OF RECENT
INFECTION.
IF YOU HAVE ONLY IGG, IT MAY BE
A LEVEL OF PROTECTION BUT I
DON'T KNOW THAT.
BUT TYPICALLY IGG ALONE IS
PROTECTED.
NOT IN HEPATITIS C IT ISN'T
THOUGH.
>> HARVEY WHAT'S THE STATUS OF
TREATING BLOOD IN ADVANCE
WITHOUT KNOWING WHAT AGENT MAY
BE PRESENT.
PURIFYING THE BLOOD OR WHATEVER.
>> THIS IS THE HOLY GRAIL OF
BLOOD TRABLES -- TRANSFUSION.
ONE IS TREATMENT WITH UV LIGHT
AND THE OTHER IS RIBOFLAVIN WITH
UV LHTS.
THEY CAN GET YOU DOWN TO ZERO
COPIES OF THAT AGENT.
IN EUROPE, MUCH OF EUROPE NOW
THEY ARE TESTING PLATELETS.
AND USING ONE OF THESE TWO
METHODS TO QUOTE PURIFY
PLATELETS.
SEEMS TO BE EFFECTIVE AND SEEMS
TO HAVE NO DELETERIOUS EFFECTS.
THE US FDA HAS NOT YET APPROVED
THAT PROCESS IN AMERICA.
BUT THAT'S WHERE WE HAD LIKE TO
HEAD.
IT JUST HASN'T HAPPENED YET.
THE BIGGEST IMPEDESTRIANMENT IS
RED CELLS BECAUSE IF YOU ADD
AGENTS TO RED CELLS YOU KILL THE
RED CELLS.
YOU MIGHT KILL THE RED CELLS.
RIBOFLAVINS SEEM TO BE SAFE FOR
RED CELLS.
>> IS THERE AN INCREASED RISK OR
SEVERITY IN PREGNANT WOMEN FOR
HEPATITIS E?
>> I DON'T THINK SO.
I THINK IT'S ONLY IN ASIA AND
IT'S IF YOU ARE IN THE LAST
TRIMESTER AND YOU ACTUALLY GET
THE HEPATITIS AT THAT POINT.
REUSCEPTIBLE, MORE
SUSCEPTIBLE TO BAD OUTCOMES BUT
NOT TO THE INFECTION ITSELF.
>> I DON'T UNDERSTAND THAT.
>> IF YOU'RE A PREGNANT WOMAN
YOU'RE NOT MORE LIKELY TO GET
THE INFECTION.
BUT IF YOU GET THE INFECTION
YOU'RE MORE LIKELY TO HAVE A BAD
OUTCOME.
>> OH, I SEE.
WELL LISTEN, DO YOU WANT TO HAVE
A LAST WORD, ANYONE.
I WANT TO THANK YOU.
>>