ASTROBIOLOGY SCIENCE CONFERENCE 2006 Washington, DC March 25 – 31, 2006 Viral Evolution 03.29.06 HEPATITIS B VIRUS: COMMENTS ON VIRAL AND HUMAN EVOLUTION Baruch S. Blumberg Fox Chase Cancer Center Philadelphia, PA, 19111, USA
Jan 04, 2016
ASTROBIOLOGY SCIENCE CONFERENCE 2006
Washington, DC
March 25 – 31, 2006
Viral Evolution03.29.06
HEPATITIS B VIRUS: COMMENTS ON VIRAL AND HUMAN EVOLUTION
Baruch S. Blumberg
Fox Chase Cancer CenterPhiladelphia, PA, 19111, USA
1. Hepatitis B Virus is a very common virus.
2. Humans have been infected with virus for a very long time, possibly from the time of the origin of humans.
3. Viruses closely related to HBV (“Hepadna viruses”) are known in many species other than humans.
4. HBV is a major deadly infectious agent.
5. Males are more likely than females to become chronic carriers of HBV and to die as a consequence
of infection.
6. HBV related deaths are highest in older males; high
HBV prevalence decreases the male to female ratio in older age groups.
7. There are a series of polymorphisms that affect
susceptibility to chronic infection.
8. Parents who are carriers of HBV have a higher ratio of males to females in their newborn offspring than do parents who have antibody against the surface antigen of HBV; high HBV incidence increases the male to female ratio at birth.
9. There may be host advantages to the carrier state.
10. The worldwide vaccination program is decreasing the prevalence of HBV.
11. Virus sequences are very common in the human genome.
12. HBV as an “engine” of human evolution.
13. Were viruses an early form of life and, possibly, the earliest form?
Primary Cancer of the Liver– Worldwide:
• Third most common cause of death from cancer in males
• Seventh most common cause of death from cancer in females
• More than a million deaths per year• Hepatitis B virus (about 85%) and hepatitis C
virus account for most of these cancers• Many other factors involved in the pathogenesis
Human Hepatitis Viruses
Genome
Virus Genome Size (Kb) Envelope Classification
HAV RNA 7.5 - Picornavirus
(Hepatovirus)
HBV DNA 3.2 HBsAgHepadnavirus
HCV RNA 9.4 + Pestivirus- or
Flavivirus-like
HDV RNA 1.7 HBsAgUnclassified
HEV RNA 7.5 - Claicivirus-like
or Alpha-like
supergroup
HBV is one of the most common infections in the world.
About 600,000 to 1,000,000 deaths per year
are attributable to the diseases associated with HBV.
(H. Margolis, Center for Disease Control. Paper presented at ThirdInternational Conference on Therapies for Viral Hepatitis, Maui, 12/12/99)
VirusNumberInfected(Millions)
Low 15%
34
CaseFatality
Rate
TotalDeaths
(Millions)
High 25%
100%
371
HIV
HBV
34
92.8
55.7
PREDICTED DEATHS FROM PREVALENT CARRIERS OF HIV AND HBV
“Hepatitis B is a viral infection of the liver. More than
two thousand million (2 billion) people alive today have
been infected with the hepatitis B virus. Approximately
350 million are chronically infected and are at high risk
of serious illness and death from cirrhosis of the liver
and primary liver cancer.
Hepatitis B is preventable with a safe and effective
vaccine — the first vaccine against cancer.”
WHO website, 2004
0
500
1000
1500
2000
2500
25-34 35-44 45-54 55-64 65-74
Age group (years)
Mor
tali
ty p
er 1
00,0
00 p
y M HBV+ M HBV- F HBV+ F HBV-
MORTALITY BY AGE, GENDER AND HBV RESPONSE
HAIMEN CITY, CHINA
G. Chen, W. Lin, F. Shen, U. Iloeje, T. London and A. Evans
Inter. J. of epid. 2004, in print
HEPATITIS B VIRUS MORPHOLOGY
CharacteristicsNucleic acid: DNAClassification:hepadnavirus type 1Serotypes: multipleIn vivo replication:reverse transcription inliver and other tissuesIn vitro propagation:primary hepatocyteculture and transfectionby cloned HBV DNA
42 nm
22 nm
C
HBsAg
HBcAgHBV DNA
HEPATITIS B LIKE VIRUSES
Hepadnaviruses
Human Homo sapiens HBVGorilla Gorilla sp. HBVChimpanzee Pan troglodytes ChHBVGibbon Family Hylobatidae HBVOrangutan Pongo pygmaeus HBVWoolly monkey Lagothrix lagotricha WMHBVTree shrew Tupaia belangeri HBV(Kangaroo Family Macropodidae KHV)Woodchuck or Groundhog Marmota monax WHVBeechey ground squirrel Spermophilus beecheyi GSHVArctic squirrel S. parryi kennicotti ASHBVRichardson ground squirrel S. richardsonii RGSHV(Tree squirrel Sciurus carolinensis THBV)Pekin duck Anas domesticus DHBVGreat blue heron Ardea herodias HHBVGrey heron A. cinerea HHBV Snow goose Anser caerulescens SGHBVRoss’ goose A. rossii RGHBVWhite Stork Ciconia ciconia STHBVDemoiselle crane Anthropoides virgo CHBVGrey crowned crane Balearica regulorum CHBV (Stink snake Elaphe carinata SSHV)
(Items in parentheses have not been validated. Tree shrews were experimentally infected.)
CONTROL OF HEPATITIS B VIRUS IN CHINA
Z.Y. Xu, T.Q. Yan, S.J. Zhao, et al. Shanghai Medical University
“Infant HBV immunization has been implemented into public health service in China since 1986… the seropositivity for HBsAg was reduced from 16.3% (879/5397) of historical controls to 1.43% (70/4886) in cross-sectional study and 1.81% (210/11582) in a cohort study.”
In the United States, the number of new HBV infections per year has declined from an average of 260,000 in the 1980s to about 78,000 in 2001. The highest rate of disease occurs in the 20-49 age group. Greatest decline is the consequence of the routine HBV vaccination program among children and adolescents. There are an estimated 1.25 million chronically infected Americans, of whom 20-30% acquired their infection in childhood.
CDC Website, 2004
HBV VACCINATION IN THE UNITED STATES
A universal childhood vaccination program was undertaken between 1981 and 1983 in Native Americans in Alaska, USA (McMahon, et al., 1996).
Acute hepatitis B infection dropped from 215 cases/100,000 before the vaccination program, to 7 to 14 cases in 1993 after the program was in place.
In 1995, no cases were reported.
HBV VACCINATION IN ALASKA, USA
As of May 2003, 151 (79%) of 192 national members of the WHO had universal childhood vaccination programs. There are 89 member states that have been designated as having a high prevalence of HBV carriers. Sixty four (72%) have universal infant vaccination programs. It is the goal of the WHO to have vaccination programs in all countries by 2007.
Hepatitis B Virus Worldwide Vaccination Program
Distribution of Australia Antigen (HBsAg) by Gender
Marshall Islands, USTTPI Male Female TotalCebu, Philippines Male Female TotalManila, Philippines Male Female TotalCashinahua, Peru Male Female Total
Total Number
243226495
430334764
13859197
454489
NumberPositive
191433
271037
639
106
16
PercentPositive
7.86.26.7
6.33.04.8
4.35.14.6
22.213.618.0
Blumberg, et al, Amer. J. Human Genetics 18, 594, 1966
Parent’s response
To HBV
Either parent HBsAg + :
anti-HBs –
Both parents HBsAg - :
anti-HBs –
Both parents HBsAg - :
either parent anti-HBs +
Couples
(No.)
33
29
154
Live births
Male Females
60 (1.8 ± 0.2)
51 (1.8 ± 0.2)
24 (1.6 ± 0.1)
24 (0.7 ± 0.1)
35 (1.2 ± 0.2)
22 (1.4 ± 0.1)
Sex ratio
250 (161,429)*
146 (96,230)*
109 (91,131)*
PLATI, GREECE. NUMBER OF MALE AND FEMALE LIVE BIRTHS ACCORDING TO THE RESPONSES TO HBV OF PARENTS
*In parentheses, the 5 percent confidence limits.Blumberg, B.S. Sex differences in response to Hepatitis B Virus, Arthritis and Rheumatism,22, 1261, 1979
Hepatitis B and Sex Ratio: Individual Level Estimates
Notes: This table shows sex ratios among the children of carrier and non-carrier parents in four regions. Data were collected by testing married women and, in all cases except for Greenland, their husbands for HBV. Detailed reproductive histories were also collected. The table represents all births to women in those samples, with generally more than one birth to each women. The last two studies (Greece 2 and France) were designed specifically to test the hypothesis that HBV affects offspring sex ratio, and were run after the original theory was expressed.
LocationGreenlandGreenlandKar Kar IslandKar Kar IslandGreece 1Greece 1PhilippinesPhilippinesGreece 2Greece 2FranceFrance
HBV StatusPositiveNegativePositiveNegativePositiveNegativePositiveNegativePositiveNegativePositiveNegative
Sons64
17463
16385
28766
30452
100620
149
60
19454
20646
25541
30130
95512
122
Sex Ratio1.070.901.170.791.851.131.611.011.731.051.661.22
Daughters
From Oster, E. 2004
Notes: Sex ratio is number of boys for each girl. Only countries with more than 15,000 people used to caclulate HBV pravalence are included. Citations for each country are in Appendix B.
Se
x R
atio
at B
irth
SEX RATIO AND HEPATITIS, WORLD
Hepatitis Rate (%)
Brazil
Belarus
Bangladesh
Iran
Malaysia
Singapore
Israel
Pakistan
China
Mexico
Turkey
France
IrelandGreece
South Korea
Spain
AustraliaItaly
PolandJapan
1.14
1.12
1.1
1.08
1.06
1.04
1.02
10 2 4 6 8 10 12 14 16
Oster, E., Hepatitis B and the Case of the Missing Women, Presentation, October 12, 2004
N. Amer &W. Europe
EFFECTS OF VACCINATION PROGRAMALASKA
• High HBV prevalence among Alaskan Native Americans; low among non-Native American
• Universal vaccination program (including catch-up) instituted in early 1980s.
Oster, E., Hepatitis B and the Case of the Missing Women, Presentation, October 12, 2004
1996-20021991-19951986-19901980-1985
CHANGES IN SEX RATIO IN ALASKA BEFORE AND DURING VACCINATION PROGRAM
1.16
1.14
1.12
1.1
1.08
1.06
1.04
1.02
1
Native American High HBVNative American Low HBVNon-Native American
Oster, E., Hepatitis B and the Case of the Missing Women, Presentation, October 12, 2004
• HBV explains about 50% of the missing women overall: over 90% in China, 11% in India
• Vaccination programs appear to decrease sex ratio
Oster, E., Hepatitis B and the Case of the Missing Women, Presentation, October 12, 2004
Microorganism Gene Affinity Clusters
Locus Allele Agent/Disease Chrom Function
MHC Class II DRB1*1302 HBV chronicity (P) Chrom 6 Immune response
HBV response to interferonMalaria, cerebral (P)Pappiloma virus
VDR tt HBV chronicity (P) Chrom 12 Vitamin D ReceptorBinds Vit. D 1,25D3
tt TB Pulmonary (P)
TT Leprosy, tuberculoid (P)
Tt Leprosy, infection (P)tt Leprosy, lepromatous (P)tt Bone mineral density,
lower Osteoporosis,increase risk Prostaticcancer (P) Inflamatory boweldisease
Microorganism Gene Affinity Clusters (cont.)
Locus Allele Agent/Disease Chrom Function
TNF G-308 HBV chronicity Chrom 6 Tumor NecrosisFactor
Malaria, cerebralMicrocutaneous leish.Lepromatous leprosyMeningococcalMeningitisTrachomaAsthma
MBP Codon 52 HBV chromicity Chrom 10 Mannose BindingProtein
SLE, HIV (?)Infections in childhood
SM-1 5q31-33 Schistosomiasis Chrom 5 Schist. Susceptibility
? HBV chronicity
IL-10 Promoter Mutat. - 108 HBV chronicity Chrom 1 Immune response
Mutat. - 059 HBV chronicity
HBV and Iron in Down’s Syndrome Patients With and Without HBsAg
Increased Hemoglobin, Hematocrit, Serum Iron and decreased Total Iron Binding Capacity (TIBC) in 20 Down’s Syndrome patients with serum HBsAg
compared to 20 without. The differences are significant.
HBsAg(+)Mean
SD
HBsAg(+)Mean
SD
Hemoglobing/100ml
15.21.4
14.91.4
Hematocrit%
44.23.8
43.53.6
Serum Irong/100ml
163.7115.1
84.133.6
TIBCg/ml
250.4108.2
356.8144.8
Sutnick, Blumberg, Lustbader. Ann. Int. Med. 81, 855, 1974
Serum Iron Levels (mg/dl)
Serum Iron levels in 1) Patients with Down’s Syndrome 2) Patients on renal dialysis and 3) Residents of a rural community in Senegal, West Africa.
Blumberg in Szentivanyi and Friedman, Editors, Viruses, Immunity and Immunodeficiency, Plenum 1986
HBsAg(+)
HBsAg(-)
Number
Downs SyndromeMale Female
164 -
84 -
40 -
Total
164
84
40
Renal Dialysis Male Female
114 214
98 100
40 117
Total
145
100
220
Senegal Male Female
77 81
75 58
81 112
Total
79
65
193
Large numbers of retroviral sequences (includingthose of HBV) are found in the human genome. These are often the “fossil” record of viruses that were incorporated into the germ line in previous generations. It is estimated that 8% of the modern human genome is made of retroviral sequences, a larger number than the coding sequences, and they are often highly conserved.
Modified from Blumberg, B. S. 2005, Hepatitis B virus. Conjectures on human interactions and the origin of life, in, “Life As We Know It”, Volume 10 of the series “Cellular Origins, Life in Extreme Habitats and Astrobiology” edited by J. Seckbach, Springer, Dordrecht, NL.; and Kilbourne, E. D. (2004). Virus paleontology, disease, and evolution: an introduction. Proc. Amer. Philosophical Society 148: 261 and following articles.
• Hepatitis B vaccination is one of the largest worldwide disease prevention programs.
• It has decreased the spread of HBV, particularly in China and East Asia. It has significantly decreased morbidity from liver disease and prevented the death of millions.
• HBV vaccination appears to prevent primary cancer of the liver; it is the first widely used preventive cancer vaccine.
SUMMARY (1)
• There are important non-pathological interactions of HBV with Humans. Parents who are carriers of HBV have a higher ratio of males to females among their offspring than parents who developed antibody against the surface antigen. This may account for the high sex ratios seen in China and in other areas with a high prevalence of HBV infection. The apparent “loss” of females in these populations may be ascribed, at least in part, to HBV infection.
• In two studied populations the HBV vaccination has decreased the ratio of males to females among newborns. If confirmed, this may have important, biological, demographic and economic effects.
SUMMARY (2)
• The response of the host to HBV infection is related to a series of polymorphic locii that are, in turn, related to other disease causing agents.
• There may be advantages to the HBV carrier state at certain periods of the hosts life, i.e. there is increased iron retention in HBV carriers compared to those with anti-HBs and uninfected people.
• HBV is integrated into the genomes of tens of millions of humans.
SUMMARY (3)