MOLECULAR EPIDEMIOLOGY OF HUMAN

CANCER VIRUSESBY

IBEMGBO, SYLVESTER AGHAB.Sc. Hons. (Ife)

MAY,2013

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ABSTRACT

Both DNA and RNA viruses have been shown to be capable of causing

cancer in humans. This review deals with the molecular

epidemiology of viruses that are strongly associated with human

cancers, and these viruses include; Epstein-Barr virus(EBV),

human papilloma virus(HPV), hepatitis B virus(HBV), human herpes

virus-8(HHV-8), Human T lymphotrophic virus type 1(HTLV-1) and

hepatitis C viruses(HCV).

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1.0 INTRODUCTION

Cancer results from alterations in critical regulatory genes that

control cell proliferation, differentiation, and survival.

Studies of tumor viruses revealed that specific genes (called

oncogenes) are capable of inducing cell transformation, thereby

providing the first insights into the molecular basis of cancer

(Rao, 2012).Cancer is a major public health challenge all over

the world and lots of current medical research works are aimed at

finding a solution to this problem. With 10.9 million new cases

and 6.7 million deaths per year, cancer is a distressing disease,

presenting amassive disease burden to those affected and their

families as well as health care systems (Parkin et al.,2005). It

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is estimated that 15-20% of all human cancers are etiologically

linked to viruses (Hausen,2001 and Parkin,2002), these viruses

are called oncoviruses. As obligate intracellular parasites,

oncoviruses encode proteins that reprogram host cellular

signaling pathways that control proliferation, differentiation,

cell death, genomic integrity and recognition by the immune

system (Margaret and Karl,2008).

Both DNA and RNA viruses have been shown to be capable of causing

cancer in humans. Epstein-Barr virus, human papilloma virus,

hepatitis B virus, and human herpes virus-8 are four DNA viruses

that are strongly associated with the development of human

cancers. Human T lymphotrophic virus type 1 and hepatitis C

viruses are two RNA viruses that contribute to human cancers

(Liao, 2006)

Viral carcinogenesis provided the breakthroughs that crystallized

current concepts of cancer development and revealed mechanisms

responsible for the orchestration of normal cell growth control.

Both the RNA tumor viruses and the DNA tumor viruses played

pivotal roles in the establishment of paradigms that extend far

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beyond virology to form the foundation of contemporary cancer

biology (Butel, 2000).

2.0 OVERVIEW OFHUMAN CANCER VIRUSES

Human tumor viruses belong to a number of virus families,

including the RNA virus families Retroviridae and Flaviviridae

and the DNA virus families Hepadnaviridae, Herpesviridae, and

Papillomaviridae. Presently, the viruses that are strongly

associated with human malignancies include; HTLV-1, etiologically

linked to adult T-cell leukemia/lymphoma (ATLL) (Poiesz et al.,

1980; Boshart et al., 1984); HPV, etiologically linked to cervical

cancer, skin cancer in patients with epidermodysplasia

verruciformis (EV), head and neck cancers, and other anogenital

cancers(Durst et at., 1983,); HHV-8 etiologically linked to

Kaposi's sarcoma (KS), primary effusion lymphoma, and Castleman's

disease (Chang et al., 1994); EBV, etiologically linked to

Burkitt's Lymphoma (BL), nasopharyngeal carcinoma (NPC), post-

transplant lymphomas, and Hodgkin's disease (Epstein et al.,

1964); and, HBV andHCV which are both linked to hepatocellular

carcinoma (HCC) (Dane et al., 1970 and Choo et al., 1979).

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Other viruses which may play a role in human cancers

include;simian vacuolating virus 40 (SV40) (brain cancer, bone

cancer, and mesothelioma) (Sweet and Hilleman, 1960); BK virus

(BKV) (prostate cancer) (Gardner et al., 1971); JC virus (JCV)

(brain cancer) (Padgett et al., 1971); human endogenous

retroviruses (HERVs) (germ cell tumors, breast cancer, ovarian

cancer, and melanoma) (Bannert and Kurth., 2004; Gifford and

Tristem., 2003); human mammary tumor virus (HMTV) (breast cancer)

(Holland and Pogo, 2004); and Torque teno virus (TTV)

(gastrointestinal cancer, lung cancer, breast cancer, and

myeloma) (Nishizawa et al., 1997). Studies of the RNA and DNA

tumor viruses have led to the discovery of oncogenes and tumor

suppressors and have greatly added to our understanding of the

etiology of carcinogenesis, both virally and non-virally induced

(McLaughlin-Drubin and Munger, 2007)

Table 1 shows the route of transmission and the kind of human

malignancy caused by some human cancer viruses.

Table 1

Virus Family Cells Human Transmission

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infected malignancy routeEBV Herpesvirida

eB cells, oropharyngeal epithelialcells, lymphoid

Burkitt’s lymphoma, nasopharyngeal carcinoma

Saliva

HTLV-1 Retroviridae T-cells Non-Hodgkin’s lymphoma

Parenteral, venereal

HHV-8 Herpesviridae

Endothelial cells

Kaposi’s sarcoma, body cavity lymphoma

Venereal

HBV Hepadnaviridae

Hepatocytes Hepatocellular carcinoma

Parenteral, venereal

HCV Flaviviridae Hepatocytes Hepatocellular carcinoma

Parenteral

HPV Papovaviridae

Cervical epithelial

Cervical carcinoma

venereal

Source: J Butel (2000) carcinogenesis.

3.0 ONCOGENES, PROTO-ONCOGENES AND TUMOR SUPPRESSORS

Virus-mediated malignant transformations in cells are the

first step in the complex Oncogenesis process (Cupicet al.,

2005). The genes in the viral genome that changehost cell

proliferation control, lead to the synthesis ofnew proteins,

and are responsible for transformation characteristics are

called viral oncogenes (v-oncgenes) (Judsonet al., 1994).

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Protooncogenes (c-onc genes) are the cellular counterparts of

v-onc genes. Their functions arecellular growth and

development. The activationof c-onc genes with mutation leads

to uncontrolledcell growth (Vats and Emami, 1993). C-onc genes

are transformed intooncogenic form by amplification, point

mutation,deletion, or chromosomal translocation (Bell, 1988).

C-onc genes can beclassified into different groups in termsof

their protein products, such as protein kinases,growth

factors, growth factor receptors, and DNAbinding proteins.

Tumor suppressor genes are genes that prevent malignant

transformation. They are called anti-oncogenes(tumor

suppressor genes). When these genes losetheir suppressive

effects, unpreventable growthoccurs (Vats and Emami,

1993).Their normal functions are to prevent and regulate cell

growth. Among tumor suppressorgenes, the retinoblastoma gene

(Rb) and p53 are themost studied (Stass andMixson, 1997)

4.0 MECHANISM OF ONCOGENESIS IN VIRUSES

Oncogenesis is a cytological, genetic, and cellular

transformation process that results in malignant tumors.The

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activation of oncogenes requires genetic changes in cellular

proto-oncogenes. Oncogenes are activated by 3 genetic mechanisms:

Mutation, Gene amplification, and Chromosome rearrangements.These

mechanisms result in either an increase inprotooncogene

expression or a change in protooncogene structure. Neoplasia is a

multistep process; therefore, more than one of these mechanisms

contribute to the formation of tumors. Expression of the

neoplastic phenotype includes the capacity for metastasis and

usually requires a combination of protooncogene activation and

tumor suppressor gene loss or inactivation (Pierottiet al., 2010).

4.1 MECHANISM OF ONCOGENESIS IN DNA TUMOR VIRUSES

DNA tumor viruses have 2 life forms. In permissive cells, viral

replication causes cell lysis and cell death. In non-permissive

cells, viral DNA is mostly integrated into the different sites of

cell chromosomes. It encodes binding proteins and inactivates

cell growth, regulating proteins like p53 and retinoblastoma. The

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cell is transformed as a result of the expression of proteins

that control viral and cellular DNA synthesis (Cupicet al., 2005).

4.2 MECHANISM OF ONCOGENESIS INRNA TUMOR VIRUSES

All oncogenic RNA viruses are retroviruses (Klein,

2002).Retroviruses have 3 basic genes (gag, pol, andenv), which

are used for the synthesis of structuralproteins, virion-

associated enzymes, and envelope glycoproteins (Cullen, 1992).

Although retroviruses have been associated with many animal

tumors, to date, only one human retrovirus, HTLV-1, has been

associated with human cancers. Complex retroviruses such as

lentiviruses have an extra non-structural gene (v-onc) that

allows them to transform the cell (Weiss, 1996).

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Figure 1.Common oncoproteins and cellular targets

Source: Patrick and Moore(2010) perspectives

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TABLE 2: Human cancer viruses and their transforming agents

Virus Genome Size(KB) No of

Genes

Transformi

ng agents

HTLV ssRNA 9.0 6 Tax

HBV dsDNA 3.2 4 HBx

HPV dsDNA 8.0 8-10 E6, E7

EBV dsDNA 172.0 ~90 LMP-1

HCV dsDNA 9.4 9 NS3

HHV-8 dsDNA 165 ~90 vGPCR,LANA

Adapted fromMcLaughlin-Drubin and Karl, 2008

5.0 PREVALENCE OF SPECIFIC ONCOVIRUSES IN NIGERIA AND AFRICA

Cancer is an under-emphasized issue in Nigeria, and generally in

Africa, partly because of the overwhelming burden of communicable

diseases. However cancer is a common disease in Africa with

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650,000 people, of a population of 965 million, diagnosed

annually (Parkin et al., 2008). In females, the lifetime risk of

dying from cancer in Africa is almost double the risk in

developed countries. The cancers with the highest incidence are

cervical, breast, and now HIV-associated Kaposi's sarcoma. Some

of the most common cancers in males; Kaposi's sarcoma

(constituting 12.9% of all cancers in males) and cancer of the

liver (14.8%), and in females;cancer of the cervix (constituting

23.3% of all cancers in females) and Kaposi's sarcoma (5.1%),

cancer of the liver (5.0%) (Parkin et al.,2008), are strongly

associated with viruses. Some of the important oncoviruses and

their activities in Nigeria and Africa are discussed below.

5.1 HUMAN PAPILLOMAVIRUS IN NIGERIA AND AFRICA

Papillomaviruses (PVs) are double-stranded DNA viruses that

constitute the Papillomaviridae family.Approximately 200 human

papillomavirus (HPV) types have been described (de Villiers et

al., 2004). HPVs cause a range of epithelial hyperplastic lesions

and can be classified into two groups: mucosal and cutaneous.

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These groups can be further divided into low- and high-risk,

depending on the associated lesion's propensity for malignant

progression. The concept of low-risk and high-risk HPVs has been

most clearly established with the mucosal HPVs (McLaughlin-Drubin

and Munger, 2008).

HPV is also associated with oral and other anogenital

malignancies, however, it is most commonly associated with

cervical cancer; over 99% of all cervical cancers are associated

with high-risk HPV infections (Lowy and Howley, 2001). Figure 2

shows the mechanism of transformation by HPV

The incidence of cervical cancer in sub-Saharan Africa is among

the highest worldwide, with age-standardized rates of 35.7 per

100,000 in Bamako, Mali, and 41.7 per 100,000 in Kyadondo, Uganda

(Parkin et al, 2002). In a population based study, Thomas et al.,

(2004) stated that the prevalence of HPV of any type was 26.3,

24.8 and 40.9%, respectively, among women with normal and

abnormal cervical findings in Ibadan, Nigeria. According to

Elimaet al., (2012), the age standardized incidence rate (ASR) of

cervical cancer in Nigeria from the Ibadan population based

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cancer registry(IBCR) was 36.0 per 100 000 and 30.3 per 100 000

at the Abuja population based cancer registry (ABCR).

Figure 2 Mechanism of transformation by HPV. Source;

(McLaughlin-Drubin and Karl, 2008)

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5.2 EBV AND BURKITT’S LYMPHOMA IN NIGERIA

EBV is a ubiquitous double-stranded DNA virus of the γ-

herpesviruses subfamily of the Lymphocryptovirus (LCV) genus

(McLaughlin-Drubin and Munger, 2008). The EBV genome is a linear,

double-stranded, 184 kbp DNA composed of 60 mole percent guanine

and cytosine (Baer et al., 1984; Kieff and Levine, 1974 ;

Pritchett et al., 1975). As with other herpesviruses, EBV has a

toroid shaped DNA core in a nucleocapsid with 162 capsomeres, an

outer envelope with external glycoprotein spikes, and a protein

tegument between the nucleocapsid and envelope (Dolyniuk et al.,

1976; Dolyniuk et al.,1976; Epstein et al., 1965; Johannsen et

al., 2004)

Burkitt's lymphoma (BL) is an unusual type of non-Hodgkin's

lymphoma occurring endemically in the narrow zone across central

Africa, where malaria is endemic. (Ferry, 2006; Cheneet al.,

2009).). In a study that analyzed the profile of cancers recorded

in the first decade (1995-2004) of establishment of the Kano

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cancer registry (KCR), a histology/cytology-based registry in

Kano, Nigeria, BL (31.4%), other lymphoreticular cancers (23.8%)

and retinoblastoma (20%) predominated in children of a total of

1990 cancer cases. (Mohammed et al., 2008).Another study published

in 2009, comprising 5-year retrospective review of pediatric

solid tumors as seen at the Jos University Teaching Hospital,

Nigeria, non-hodgkin's lymphoma and BL accounted for 17 (19.5%)

and 12 (13.8%), respectively, of a total of 181 solid tumors of

children. (Tankoet al., 2009)

5.3 KAPOSI'S SARCOMA-ASSOCIATED HERPESVIRUS (KSHV)/HUMAN HERPES

VIRUS 8 (HHV-8) IN NIGERIA

HHV-8, also known as KSHV is a double-stranded DNA virus,

initially discovered on the basis of its association with

Kaposi's sarcoma, an endothelial neoplasm, it is now known to be

a member of the lymphotropic γ-herpesvirus subfamily (Knipe and

Howley, 2006). The KSHV genome is a double-stranded linear DNA of

165 to 170 kb (Renneetal., 1996). The genome contains a central

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unique region of 145 kb, which has all of the viral open reading

frames (ORF) (Russo et al.,1996), flanked by a series of highly

GC-rich direct terminal repeats (TR). Each TR unit is 801 base

pair (bp) long, with a base composition of 85% G+C, and is devoid

of substantial ORFs. In general, isolates have 20 to 25 kb of

total TR DNA per genome, but the number of repeats present at

each terminus can vary substantially (Lagunoff and Ganem, 1997).

The neoplastic potential of KSHV, especially in immunocompromised

individuals, is well-established: epidemiological studies link

KSHV to human malignancies (Parkin, 2006) KSHV transforms

endothelial cells (Flore et al., 1998)

A South African study showed rates of KSHV infection to vary from

35% to 49% across different municipalities within one province

(Maskew et al., 2011)

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5.4 HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 (HTLV-1)

HTLV-1 is a deltaretrovirus first isolated from the blood of an

African-American patient with cutaneous T-cell lymphoma in the

late 1970s (Poiesz et al., 1980); Human T-cell leukemia virus type

1(HTLV-1) is a slow transforming, single stranded RNA retrovirus

and is associated with adult T-cell leukemia (Gallo et al.,1983).

It possesses a diploid genome. The genome contains gag, pro, pol,

and env genes; the gag, pro, and pol genes are present in three

different reading frames, and expression of the Gag-Pro-Pol

protein requires two successive frameshifts (Lairmoreand

Franchini, 2007).

While the exact cellular events remain unclear, a variety of

steps, including virus, host cell, and immune factors, are

implicated in the leukemogenesis of ATLL (Matsuoka, 2003). A

number of studies indicate that the multifunctional viral

accessory protein Tax is the major transforming protein of HTLV-1

(Nerenberg et al., 1987; Grassmann et al., 1992; Pozzatti et al.,

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1990; Tanaka et al., 1990; Smith and Greene, 1991). Figure 3 shows

the mechanism of transformation by HTLV.

It has been shown that both HTLV-I and HTLV-II are endemic in

Nigeria (Olaleyeet al., 1998).Several studies haveshown that the

prevalence of HTLV-I is high in Africa. Seropositivity for HTLV-I

in the region range from 0.6% in Morocco, to 3.5% in South Africa

and 16.9% in Tanzania (Olaleye et al., 1998)

Figure shows the mechanism of cell transformation y HTLV-1

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Figure 2 Mechanism of transformation by HPV. Source:

(McLaughlin-Drubin and Karl, 2008)

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5.5 HEPATITIS B VIRUS (HBV) IN NIGERIA

HBV is a member of the Hepadnaviridae family. It is the only DNA

virus among the agents which commonly cause viral hepatitis. The

viral particle (called the Dane particle) is 42 nm in diameter

(Haaheimet al., 2002). HBV has a circular, partially double-

stranded, DNA genome with four overlapping open reading frames

(ORFs) that encode for the envelope (preS/S), core (preC/C),

polymerase, and X proteins (Seeger and Mason, 2000). Like

retroviruses, the replication of HBV is dependent on reverse

transcription; unlike retroviruses, integration of the viral

genome into the host chromosome is not necessary for viral

replication but does allow for persistence of the viral genome

(Feitelson and Lee, 2007).This virus is responsible for 80% of

all cases of primary liver cancer, which is one of leading causes

of death in Asia and Africa (Clement et al., 1990).

Hepatitis B Virus, a major public health problem worldwide is

more prevalent in the developing countries (Johnson et al.,

1986).In Nigeria, 11.6% prevalence rate has been reported from

Maiduguri (Harry et al., 1994), 13.8% from Lagos (Nasidiet al.,

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1993), 4.3% from Port Harcourt (Akaniet al., 2005), 5.7% from

Ilorin (Agbedeet al., 2007), 8.3% from Zaria (Luka et al., 2008),

17.1% from female sex workers, 14.9% (Forbi et al., 2008) from

healthy blood donors (Ejeleet al., 2004) and 25.7% among surgeons

(Belo, 2000). Although HBV prevalence varies widely across the

African continent, hepatitis B surface antigen (HBsAg) positivity

is estimated at 8-20% (Apurva and Jordan, 2007).

5.6 HEPATITIS C VIRUS (HCV) IN NIGERIA

HCV is a single-stranded RNA virus of the Hepacivirus genus in

the Flaviviridae family and is the only positive-stranded RNA

virus among the human oncogenic viruses. Its approximately 9.6 kb

genome contains an open reading frame (ORF) that codes for a 3000

amino acid residue polyprotein precursor (Choo et al., 1989) that

is cleaved by cellular and viral proteases into three structural

proteins (core, E1, E2) and seven nonstructural proteins (p7,

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NS2, NS3, NS4a, NS4B, NS5A, and NS5B) (Lindenbach and Rice,

2005).

HCV proteins have been reported to activate cellular oncoproteins

and inactivate tumor suppressors, such as p53, CREB2/LZIP, and

the retinoblastoma protein (pRB). HCV causes genome instability,

signifying that certain HCV proteins may have a mutator function

(McLaughlin-Drubin and Munger, 2008).

In 2005, Inyamaet al., (2005) put the prevalence of HCV among

Nigerian patients with HIV in Jos infection at 5.7%.So far the

prevalence of HCV infection is increasing in Nigeria, ranging

from 4.7-5% in Ilorin, to 5.3-6.6% in Enugu, to 11% in Ibadan and

20% in Benin (Ejioforet al., 2010)

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2.1.1 MOLECULAR EPIDEMIOLOGY OF HTLV-1

HTLV-1 has a worldwide distribution, with an estimated 12 to 25

million people infected. However, disease is only observed in

less than 5 percent of infected individuals. It is endemic to

Japan, South America, Africa, and the Caribbean (Gessian et al.,

1991; Wong-Staal and Gallo, 1985). The seroprevalence of HTLV-1

varies between 0.1% and 30% within endemic populations (Gessain

and Mahieux, 2000). Sporadic HTLV-1 infection occurs among at-

risk groups from non-endemic regions, including metropolitan

areas in the United States and western European countries

(Matsuoka and Jeang, 2005).The incidence rate is 2 to 4 per

100,000 person-years and males have higher risk than females

(Cleghornet al.,1995; Kondo et al., 1989).

2.1.2 TRANSMISSION AND PATHOGENESIS OF HTLV-1

HTLV-1 is transmitted through blood transfusions, sexual

contact, and during parturition. Typically, 1% to 5% of

individuals infected with HTLV-1 develop ATLL after a latent

period of 20 to 30 years (Cleghornet al.,1995; Yamaguchi and

Takatsuki, 1993).

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ATLL is an aggressive malignancy of T lymphocytes,

immunophenotypically characterized by multiple distinct cell

surface markers, including CD3+/CD4+/CD8-/CD25+/HLA-DR+ T-cells

(Uchiyama et al., 1977). The typical clinical symptoms and

presentations of patients with ATLL include malaise, fever,

lymphoadenopathy, hepatosplenomegaly, jaundice, weight loss, and

various opportunistic infections, such as Pneumocystis carinii (White

et al., 1995). Based on the clinical course of the disease, four

classifications are applied for ATLL, including (a) asymptomatic,

(b) preleukemic, (c) chronic smoldering, and (d) acute stages

(Kawano et al., 1985,Shimoyama, 1991, Yamaguchi et al., 1983). The

latter two forms represent the typical clinical presentation

mentioned above. Clinicopathologically, the chronic stage ATLL is

characterized by leukocytosis, whereas the acute stage is

characterized by lymphocytes with atypical cell morphology,

including multilobulated nucleus, lymphoadenopathy, and

hepatosplenomegaly (Yamaguchi and Takatsuki, 1993, Yamaguchi,

1994). Other clinicopathologic abnormalities seen in patients

with ATLL include hypercalcemia of malignancy, in association

with lytic bone lesions, elevated lactate dehydrogenase (LDH),

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and the presence of soluble form of interleukin-2 (IL-2) receptor

in serum samples. Infiltration of the skin by neoplastic

lymphocytes frequently occurs in patients with ATLL. Diagnostic

criteria of ATLL include HTLV-1 seropositivity, leukocytosis,

increased serum levels of IL-2 receptor and LDH, demonstration of

neoplastic T cells with polylobulated nuclear morphology (flower

cells), and the presence of clonally integrated HTLV-1 genomes

within the chromosomes of neoplastic lymphocytes (Shimoyama,

1991).The long clinical latency, together with the relatively low

cumulative lifetime risk of a carrier developing Adult T-cell

Leukemia (ATL), indicates that HTLV-1 infection alone is not

sufficient to elicit T-cell transformation.

2.1.3 T-CELL IMMORTALIZATION AND TRANSFORMATION BY HTLV-1

The terms immortalization and transformation of T cells by HTLV-1

refer to ligand (IL-2)-dependent or -independent indefinite

growth of infected T cells, respectively. Biochemically, this

distinction has been associated in most, but not all, HTLV-

1infected T cells with constitutive activation of the Jak/STAT

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signaling pathways (Migoneet al.,1995; Mulloyet al., 1998; Xuet al.,

1997), as well as with a reduction of the level of Src homology 2

(SH2)-containing tyrosine phosphatase-1 (SHP-1) (which could

result in decreased phosphorylation of STAT) (Migoneet al.,1998).

However, an inhibitor of Jak3, AG-490, does not affect the growth

of the HTLV-1infected T-cell line MT-2 (Kirkenet al., 2000),

suggesting that other pathways may be involved in the

proliferation of these cells.

Immortalization of primary human T cells in the presence of IL-2

can be induced by infection with various HTLV-1 isolates or by

Tax-1 expression alone (Grassmann et al., 1989; Iwanagaet al., 1999;

Tanaka et al., 1991). In some cases, however, continuous

stimulation of the TCR and Tax-1 expression is required (Tanaka

et al., 1991). The oncogenic properties of Tax-1 may be related to

its effect on cell cycle checkpoint inhibitors, cyclins,

telomerase activity, and transcriptional modulation of a wide

range of cellular genes involved in cellular growth and survival

(Kelly et al., 1992). Exploiting the NF-kB pathway, Tax activates a

large number of cellular genes that promote lymphocyte growth,

activation, and survival. These genes fall into several28

categories, including cytokines and growth factors such as IL-1,

IL-2, IL-6, IL-8, IL-15, and TGFb, growth factor receptors such

as IL-2Ra and OX40, and antiapoptotic factors such as BCL-xl

(Lemoine et al., 2001). Special importance is attributed to Tax

activation of the cellular proto-oncogene, c-MYC, which can

independently mediate cellular transformation via NF-kB

regulation (Keath et al., 1984; Adams et al., 1985).

Schematic depiction of the major biological activities that

contribute to the transforming activities of HTLV-1 (McLaughlin-

Drubin and Karl, 2008)

The ability of Tax to disable an important protective mechanism

that protects against chromosomal missegregation during mitosis

provides a potential mechanism for the high incidence of

aneuploidy in ATL cells (McLaughlin-Drubin and Karl, 2008)

2.1.4 TREATMENT, PREVENTION AND CONTROL OF HTLV-1

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Depending on the stage of disease progression, ATLL is highly

refractory to most forms of conventional therapy and, thus, has a

poor prognosis, especially for the acute form of the malignancy

(Taylor and Matsuoka, 2005). The median time of survival of

patients with ATLL is typically less than 1 year despite

aggressive chemotherapy. Complicating the treatment of ATLL are

paraneoplastic syndromes (e.g., hypercalcemia), which contribute

significantly to overall mortality of these patients (Blayneyet

al., 1983; Jaffe et al., 1984; Prageret al., 1997). Standard

cytotoxic or cytostatic chemotherapeutic agents (e.g.,

cyclophosphamide, adriamycin, vincristine, and prednisolone so

called CHOP therapy) remain an initial approach to treating

patients with ATLL despite variable success in median survival

times in most cohorts (Mufti et al., 1998; Ohshima et al.,1999;

Pawsonet al., 1998; Yamaguchi et al., 1983). Improved outcomes have

been reported for standard chemotherapy supplemented with the

cytokine, G-CSF (Bohliuset al., 2004). The relative insensitivity

of ATLL to chemotherapy has been speculated to be caused by the

enhanced expression of the multidrug resistance gene (Chuang

etal., 1997; Lau et al., 1998).

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Targeting NF-kB in ATLL is based on experimental evidence of its

importance in Tax-induced transformation. Bortezomib (PS-341) has

been used in an effort to block proteasome processing and thereby

interrupt NF-kB signaling in ATLL cells (Sato et al., 1991).

Sodium valproate, an inhibitor of deacetylases, has been reported

to reduce lymphoma growth in a sheep model of BLV, a member of

the deltaretroviruses, offering a new direction for ATLL therapy

(Achachiet al., 2005).

Monoclonal antibodies directed at cell surface markers have been

employed to target and kill ATLL cells. This therapy has the

potential to allow more selective targeting of molecules on the

surface of ATLL cells, such as the IL-2 receptor (CD25) (Green et

al.,1995;Waldmannet al., 1988).

The prevention of transmission of HTLV-1 and HTLV-2 has been

accomplished based on elimination of breastfeeding from HTLV-

1infected mothers in endemic regions (Hino et al., 1994), but

this intervention is problematic on a worldwide scale.

The viral envelope glycoproteins appear to be good candidates for

a subunit vaccine. The surface glycoprotein (SU) component of

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envelope mediates viral infection of cells by binding to the

cellular entry factors heparan sulfate proteoglycans (Pinonet

al.,2003; Jones et al., 2005). Subsequently, through a cascade of

conformational changes in envelope that includes isomerization of

a SU-transmembrane glycoprotein (TM) intersubunit disulfide

(Wallinet al., 2004; Li et al., 2008),envelope catalyzes the fusion

of the viral and cell membranes allowing entry of the virus into

the cell. Neutralizing Abs and synthetic inhibitory peptides

block envelope-mediated entry (Sagaraet al., 1996; Piñónet al.,

2003; Brighty and Jassal, 2001; Lamb et al.,2009), suggesting that

interfering with envelope function can prevent dissemination of

viral infection

3.0 HUMAN PAPILLOMAVIRUS (HPV)

The papillomaviruses (PVs) comprise a group of nonenveloped,

epitheliotropic DNA viruses that induce benign lesions of the

skin (warts) and mucous membranes (condylomas) (Knipe and Howley,

2006). Papillomaviruses (PVs) are adouble-stranded DNA viruses

that constitute the Papillomaviridae family.Approximately 200

human papillomavirus (HPV) types have been described (de Villiers

32

et al., 2004). HPVs cause a range of epithelial hyperplastic

lesions and can be classified into two groups: mucosal and

cutaneous. These groups can be further divided into low- and

high-risk, depending on the associated lesion's propensity for

malignant progression. The concept of low-risk and high-risk HPVs

has been most clearly established with the mucosal HPVs

(McLaughlin-Drubin and Munger, 2008).

3.1.0 MOLECULAR EPIDEMIOLOGY OF HPV

Both epidemiological and molecular evidence strongly supports the

link between infection with high-risk HPVs and the development of

cervical cancer. Nonetheless, the incidence of malignant

progression of high-risk HPV associated lesions is relatively

low; malignant progression usually occurs with other risk

factors, such as, decreased immune function, and/or a long

latency period after other genomic alterations in the host cell

DNAhave occurred. Smoking and prolonged use of birth control

pills have also been implicated as risk factors for progression.

The low-risk mucosal HPVs, such as HPV6 and 11, cause genital

warts, whereas the high-risk mucosal HPVs, such as HPV16 and 18,

33

cause squamous intraepithelial lesions that can progress to

invasive squamous cell carcinoma. HPV is also associated with

oral and other anogenital malignancies, however, it is most

commonly associated with cervical cancer; over 99% of all

cervical cancers are associated with high-risk HPV infections

(Lowy and Howley, 2001).

3.1.1 PREVALENCE OF HPV

Over a ten-year period (1991-2000), 815 women had Pap smears at

the Medical Women Centre in Enugu of whom only 4 (0.5%) ever had

a previous smear. The prevalence of abnormal smears was 12.2%,

the proportion rising with increasing age and doubling after the

age of 54 years. All the women with positive smears were or had

been coitally active; 97% were parous and 81% grand multiparous

(Chukwuali et al., 2003)

In a demonstration project, ‘prevention of cervical cancer

through screening using visual inspection with acetic acid(VIA)

and treatment with cryotherapy’, WHO reported that 5.7percent of

the Nigerians screened were positive.

34

According to CDC in 2012, Overall, about 26,000 (18,000 among

females and 8,000 among males) of 33,369 cancers at HPV-

associated sites were attributed to HPV infection. For the

individual cancers, the number and percentages attributable to

HPV were:

Cervix, 11,500 (96%)

Vulva, 1,600 (51%)

Vagina, 500 (64%)

Penis, 400 (36%)

Anus(women), 2,900 (93%)

Anus(men), 1,600 (93%)

Oropharynx(women) 1,500 (63%)

Oropharynx (men), 5,900(63%).

Infections with cutaneous HPVs appear extremely frequently in the

general population and some of these viruses, even the presumed

high-risk HPV, may be part of the normal “flora” of the skin as

they can be detected in follicles of plucked hair (Boxmanet al.,

1997; Boxmanet al., 1999).

35

A 2007 study in United States found approximately 26.8% of all

women examined (aged 14-59) were infected with the human

papillomavirus. It is important to note that most HPV infections

are cleared within two years (i.e. most infections are not

lifelong) (Dunne et al., 2007)

• 14-19 ~ 24.5%

• 20-24 ~ 44.8%

• 25-29 ~ 27.4%

• 30-39 ~ 27.5%

• 40-49 ~ 25.2%

• 50-59 ~ 19.6%

The true incidence of cervical cancer in most African countries

is unknown and there is gross under reporting. Only a few

countries have functional cancer registers and record keeping is

minimal or non-existent. Some of the figures quoted in the

literature are hospital-based which represents a small fraction

of women dying of cancer of the cervix as most women cannot

assess hospital care and die at home. (Anorlu, 2008)

36

3.1.2 TRANSMISSION OF HPV

The human papillomavirus is transmitted via skin-skin contact.

Sexual intercourse is not necessary for transmission, but is the

most common route. The virus can infect the genital, anal, and

oral regions of the body. Infection occurs when viruses enter

into small breaks in the skin or mucous membranes. The

probability of acquiring HPV from a single sexual encounter is

not known, but is probably high (Burchellet al., 2006)

Other than the appearance of genital warts, infection with the

human papillomavirus is asymptomatic. In most cases HPV doesn't

cause any problems and is cleared by the immune system (Hausen,

2001)

3.1.3 HPV IMMORTALIZATION AND TRANSFORMATION

The molecular mechanisms by which high-risk HPV causes cervical

cancer have been studied extensively, and numerous viral and host

37

interactions that may contribute to transformation and malignancy

have been described (Munger et al., 2004).HPV5 and 8 as well as

related cutaneous HPVs may contribute to the development of

nonmelanoma skin cancers (NMSC), particularly in

immunocompromised patients (Shamaninet al., 1994; Shamaninet al.,

1996).

It has been shown that E6 proteins of cutaneous HPVs can target

the proapoptotic Bcl-2 family member, Bak, for degradation. Bak

plays an important role in signaling apoptosis in response the UV

irradiation and hence it has been postulated that cutaneous

HPVexpressing cells may be less prone to undergo apoptosis after

UV induced DNA damage (Jackson et al., 2000).

Cellular targets of the papillomavirus E6 oncoproteins

Associated Cellular ProteinsFunctional Consequences

E6-associated protein (E6AP)Ubiquitylation and

proteolysis of associated

proteins

  Ubiquitylation of E6

p53 E6AP-dependent ubiquitylation

38

and proteolysis

E6BP (Erc55) Unknown

Paxillin Disruption of the actin

cytoskeleton

HDlg MUPP1 and hScrib E6AP dependent ubiquitination

and proteolysis

IRF-3 Inhibition of β-interferon

induction

Clatherin adaptor complex

AP-1

Unknown

Bak Inhibition of Bak-induced

apoptosis

CBP/p300 Inhibition of p53

transcriptional activity

Myc Activation of cellular

telomerase

NFX1 Activation of cellular

telomerase

E6TP1 E6-induced degradation

hADA3 Transcriptional regulation

39

Source: Fields Virology, 5th Edition Copyright ©2007 Lippincott

Williams & Wilkins

During carcinogenic progression the HPV genome frequently

integrates into a host cell chromosome and, as a result, the

viral oncoproteins, E6 and E7, are the only viral proteins that

are consistently expressed inHPV positive cervical carcinomas.HPV

genome integration is often associated with higher dysregulated

E6/E7 expression (Jeonet al., 1995). Persistent expression of E6

and E7 is necessary for maintenance of the transformed phenotype

of cervical carcinoma cells (Goodwin and DiMaio, 2000; Wells et

al., 2000).

The transforming activities of the high-risk E6 and E7

oncoproteins is related to their ability to associate with and

dysregulate cellular regulatory protein complexes, most notably

p53 and pRB (Munger and Howley, 2002). As p53 and pRB normally

control cellular proliferation, differentiation, and apoptosis,

the abrogation of their normal biological activities places such

a cell at a risk of malignant progression. In addition, high-risk

HPV E6 and E7 expressing cells have a decreased ability to

40

maintain genomic integrity (White et al., 1994). The high-risk HPV

E7 oncoprotein acts as a mitotic mutator and induces multiple

forms of mitotic abnormalities, including anaphase bridges,

unaligned or lagging chromosomes, and most notably multipolar

mitoses (Duensing and Munger, 2002). Multipolar mitoses are

histopathological hallmarks of high-risk HPV associated cervical

lesions and cancer (Crum et al., 1984) and are caused by the

ability of high-risk HPV to uncouple centrosome duplication from

the cell division cycle (Duensing et al., 2000; Duensing et al.,

2001).

41

Schematic depiction of the major biological activities that

contribute to the transforming activities of high-risk mucosal

HPVs. (McLaughlin-Drubin and Karl, 2008)

42

3.1.3 TREATMENT, PREVENTION AND CONTROL OF HPV/ CERVICAL

CANCER

High-grade dysplasias represent precancerous lesions that are

unlikely to resolve spontaneously, and their treatment is

recommended to prevent cervical cancer. HPV testing can be done

in case, because most successfully treated cases become negative

for HPV DNA, whereas incompletely treated cases may remain

positive (Zielinski et al., 2004). Cervical cancer is treated by

surgery, radiotherapy, and chemotherapy, with early stage tumors

having a better prognosis than more advanced tumors (McCreathet

al., 2005; Serkies and Jassem, 2005).

Public health programs aimed at controlling other sexually

transmitted infections should also be effective in preventing

genital HPV infection. Control of sexual promiscuity on the part

of both sexual partners should reduce the likelihood of exposure

to genital HPV.

43

Given the high rate of HPV infection that follows initiation of

sexual activity, the VLP vaccines would be most cost-effective

when given to young adolescents who are not yet sexually active

(Knipe and Howley, 2007). Gardasil® is FDA approved for the

prevention of HPV types 6, 11, 16 and 18 infection in young women

aged 9-26. On October 16, 2009, the FDA also approved Gardasil®

to prevent genital warts caused by HPV types 6 and 11 in young

men aged 9-26 (Markowitz et al., 2007; FDA, 2009).Cervarix® also

prevents infection by HPV 16 and 18. Cervarix® was approved for

use in the United States in October 2009 (FDA, 2009). Both the

quadrivalent HPV 16/18/6/11 vaccine (Gardasil®, Merck & Co.,

Inc.) and the bivalent HPV 16/18 vaccine (Cervarix™,

GlaxoSmithKline Biologicals) have shown high safety, efficacy,

and immunogenicity. HPV types 16 and 18 are responsible for 70%

of the cases of cervical cancer worldwide. The three dose

regimen required for vaccination with these vaccines costs $360,

the most expensive vaccine in history. When 80% of the cases of

cervical cancer occur in developing countries, the expense of the

vaccines becomes a difficult barrier (Goldie,2008)

4.0 MOLECULAR EPIDEMIOLOGY OF KSHV44

Several genomic regions display remarkable sequence variability,

making them useful as markers of strain diversity and potential

epidemiologic markers of spread. These include regions

surrounding internal sequence repeats and, especially, the coding

regions directly adjacent to the left- and right-hand terminal

repeats: ORFs K1 and K15, respectively (Knipe and Howley, 2006).

When many isolates are examined from across the globe, it is

clear that the K1 sequence allows separation into four major

subtypes: A, B, C, and D. These subgroup identifications are also

supported by sequence variations in other genomic loci (Zong et

al., 1999; Zong et al., 2002). The A and C subgroups have been

isolated from KSHV-infected subjects in Europe, the United

States, Asia, and the Middle East, whereas subgroup B strains are

found predominantly in sub-Saharan Africa; type D strains are

found primarily in south Asia, Australia, and the Pacific

islands. These findings suggest that KSHV is an ancient human

infection, having entered the human population at or around the

time that modern humans arose in Africa in the early Pleistocene

Age (Hayward, 1999).

45

and KSHV-encoded transforming genes have been identified. The

current model of KSHV-induced malignancy involves a combination

of proliferation, survival, and transformation mediated by

latently expressed viral proteins together with a paracrine

mechanism that is exerted directly or indirectly by the lytically

expressed v-cytokines and viral G-protein coupled receptor

(vGPCR). HIV-1 infected individuals are at the highest risk for

developing KS. Interestingly, KS lesions and tumors appear to

regress in patients who receive Highly Active Antiretroviral

Therapy (HAART), suggesting that KSHV gene expression may be

insufficient to initiate or maintain transformation (Lebbeet al.,

1998; Gill et al.,2002).

Patterns of KSHV Infection and non-HIV KS

KS incidence Regions

Population KSHVprevalence

Transmission Risk groups

Low North America,North Europe,

<5% Sexual Homosexual men, STDclinic attendees,

46

Asia transplantrecipients

Intermediate

Mediterranean,Middle Easterncountries,Caribbean

5-20% Sexual,nonsexual

Homosexual men, STDclinic attendees,transplantrecipients, olderadults

High Africa, parts ofAmazon basin

>50% Nonsexual,sexual

Older adults, lowersocioeconomicstatus

AIDS-KS rates are highly dependent on local HIVinfection rates and risk groups.Source: Fields Virology, 5th Edition Copyright ©2007 LippincottWilliams & Wilkins

4.1 TRANSMISSION OF KSHV

The relatively close conformity of the subtypes with ethnic and

geographic clusters also implies that (at least before the

context of the AIDS epidemic) the virus is primarily transmitted

in a familial pattern (e.g., vertically from parent to child and

horizontally among siblings within the family unit), with wider

horizontal transmission being less efficient. This inference is47

consistent with much of what is known from direct study ofKSHV

epidemiology (Knipe and Howley, 2006)

4.2 TREATMENT, PREVENTION AND CONTROL

Kaposi's sarcoma can be treated either surgically or through

local irradiation. Chemotherapy with drugs such as liposomal

anthracyclines or paclitaxel may be used, particularly for

invasive disease. Antiviral drugs, such as ganciclovir, that

target the replication of KSHV have been used to successfully

prevent development of Kaposi's sarcoma(Martin et al., 1999). For

patients with AIDS-KS, as mentioned earlier, the most effective

therapy is highly active antiretroviral therapy to reduce HIV

infection.

48

5.0 EPSTEIN-BARR VIRUS

Epstein-Barr virus (EBV) was discovered through the seminal

observations of Denis Burkitt, a British colonial surgeon in

Uganda, and Anthony Epstein, a pathologist in the United Kingdom.

In 1957, in Kampala, Burkitt encountered two young children with

multifocal jaw tumors, a disease for which he had no knowledge or

previous experience. He established that the tumors were

lymphomas and undertook a journey through sub-Saharan Africa to

study the prevalence of the lymphoma among the various tribes

living in different areas. Surprisingly, the lymphomas were

prevalent in children in climates supportive of holoendemic

malaria (Knipe and Howley, 2006).

Other diseases associated with EBV include; infectious

mononucleosis, Hodgkin’s lymphoma, and nasopharyngeal carcinoma.

In addition, EBV is linked with oral hairy leukoplakia, which may

be an earliest oral manifestation of HIV infection (Jain et al.,

2011)

49

EBV is a ubiquitous double-stranded DNA virus of the γ

herpesviruses subfamily of the Lymphocryptovirus (LCV) genus

(McLaughlin-Drubin and Munger, 2008). The EBV genome is a linear,

double-stranded, 184 kbp DNA composed of 60 mole percent guanine

and cytosine (Baer et al., 1984; Kieff and Levine, 1974 ;

Pritchett et al., 1975). As with other herpesviruses, EBV has a

toroid shaped DNA core in a nucleocapsid with 162 capsomeres, an

outer envelope with external glycoprotein spikes, and a protein

tegument between the nucleocapsid and envelope (Dolyniuk et al.,

1976; Dolyniuk et al.,1976; Epstein et al., 1965; Johannsen et

al., 2004)

5.1 MOLECULAR EPIDEMIOLOGY OF EBV

The Epstein-Barr virus is a human herpes virus (human herpes

virus 4) that infects over 90% of adults worldwide, irrespective

of race, ethnicity or geography (Rickinson and Kieff, 1996).

Worldwide, more than 95% of the population is infected with EBV

(Evans and Niederman, 1989); the majority of EBV infections occur

50

during childhood without causing overt symptoms. Post adolescent

infection with EBV frequently results in mononucleosis, a self-

limiting lymphoproliferative disease. EBV infects and replicates

in the oral epithelium, and resting B lymphocytes trafficking

through the oral pharynx become latently infected. Infected B

lymphocytes resemble antigen activated B cells, and EBV gene

expression in these cells is limited to a B cell growth program,

termed Latency III, that includes LMP1, LMP2a/b, EBNAs -1, -2, -

3a-3b, -3c, and -LP, miRNAs, BARTs, and EBERs. These cells are

eliminated by a robust immune response to EBNA3 proteins,

resulting in Latency I, a reservoir of latently infected resting

memory B cells expressing only EBNA1 and LMP2. The

differentiation of memory cells to plasma cells results in

reactivation of the replication phase of the viral life cycle

that includes expression of latency III gene products. In

addition, there is likely another amplification step by

reinfection of the epithelial cells followed by shedding virus in

the saliva to the next host.

51

5.2 TRANSMISSION OF EBV

Epstein-Barr virus is spread by the oral route. Most children in

the developing world become infected within the first 3 years of

life (IARC, 1997; Evans et al., 1989). In crowded, poor socio-

economic environments, primary infection occurs early (de Thé et

al., 1975) and over 80% of children in Uganda are thought to be

sero-positive by the age of one (Kafuko et al., 1972). Early

infection is generally clinically silent. Under more affluent,

less crowded conditions, primary infection may not occur until

adolescence or young adulthood, when a round 50% of cases present

as infectious mononucleosis or ‘kissing disease’. Those infected

remain life-long carriers (Baumforth et al., 1999). In apparent

contradiction to its ubiquity, EBV has oncogenic potential and is

able to transform B-cells in culture into a state of continuous

proliferation or ‘immortalization’(Khannaet al., 1995).

5.3 EBV AND BURKITT’S LYMPHOMA IN NIGERIA

Burkitt's lymphoma (BL) is an unusual type of non-Hodgkin's

lymphoma occurring endemically in the narrow zone across central

Africa, where malaria is endemic. (Ferry, 2006; Cheneet al., 2009)

52

As of a study published in 2009, comprising 5-year retrospective

review of pediatric solid tumors as seen at the Jos University

Teaching Hospital, Nigeria, non-hodgkin's lymphoma and BL

accounted for 17 (19.5%) and 12 (13.8%), respectively, of a total

of 181 solid tumors of children. (Tankoet al., 2009)

In an another study that analyzed the profile of cancers recorded

in the first decade (1995-2004) of establishment of the Kano

cancer registry (KCR), a histology/cytology-based registry in

Kano, Nigeria, BL (31.4%), other lymphoreticular cancers (23.8%)

and retinoblastoma (20%) predominated in children of a total of

1990 cancer cases. (Mohammed et al., 2008)

6.0 MOLECULAR EPIDEMIOLOGY OF HBV

Hepatitis B Virus, a major public health problem world wide is

more prevalent in the developing countries. (Johnson et al., 1986)

More than 2 billion people are infected with HBV world-wide while

53

some 280 million are chronic carriers, harboring the virus in

their liver (Clement et al., 1990). About 2 million of these

carriers die each year as a result of cirrhosis or primary liver

cell cancer induced by the virus. This virus is responsible for

80% of all cases of primary liver cancer, which is one of leading

causes of death in Asia and Africa (Clement et al., 1990).

In Nigeria, 11.6% prevalence rate has been reported from

Maiduguri (Harry et al., 1994), 13.8% from Lagos (Nasidi et al.,

1993), 4.3% from Port Harcourt (Akani et al., 2005), 5.7% from

Ilorin (Agbede et al., 2007), 8.3% from Zaria (Luka et al.,

2008), 17.1% from female sex workers, 14.9% (Forbi et al., 2008)

from healthy blood donors (Ejele et al., 2004) and 25.7% among

surgeons (Belo, 2000). Although HBV prevalence varies widely

across the African continent, hepatitis B surface antigen (HBsAg)

positivity is estimated at 8-20% (Apurva and Jordan, 2007).

Zonal distribution of subjects assayed for Hepatitis B viral load in Nigeria

Geographical

Zones

HBV viral load

tests

54

N (%)

NE 1 (0.2%)

NW 3 (0.5%)

NC 61 (10.3%)

SS 52 (8.8%)

SE 72 (12.2%)

SW 305 (51.3%)

Unknown 100 (16.9%)

Total 594 (100%)

Source; Okwuraiweet al., 2009

6.2 TRANSMISSION OF HBV

Transmission of HBV occurs through contact with an infected body

fluid. Various studies in Nigeria showed that blood transfusion

is an important source HBV transmission. (Obiaya and Ebohom,

1982; Multimeret al., 1994; Sear, 2000), but found no link between

traditional practices like, scarification, circumcision, ear

55

piercing and HBV infection (Chukwukaet al., 2003; Angyo and

Yakubu, 2001). Higher HBsAg prevalence noted among prisoners and

rural dwellers were attributed overcrowding and clustering.

(Amazigo and Chime, 1990). Studies from north-central Nigeria

indicates that unprotected sex is implicated in the transmission

of HBV (Ivlustapha and Jibrin, 2004; Sirisenaet al., 2002 )

The greatest sources of new infections worldwide have been from

infected mothers to the newborn, or among very young children.

The risk of vertical transmission varies, depending on geographic

regions. In North America, western Europe, and Africa, the risk

of vertical transmission from mothers who are chronically

infected is approximately 10% (Knipe and Howley, 2006)

6.3 HEPATOCARCINOGENESIS OF HBV

HBV-associated liver carcinogenesis is viewed a multifactorial

process. The integration of the HBV genome into the host

chromosome at early stages of clonal tumor expansion has been

demonstrated to both affect a variety of cellular genes as well

as exert insertional mutagenesis, while chronic liver

56

inflammation confers the accumulation of mutations in the host

genome.

HBV encodes HBx, a 154 amino acid multifunctional regulatory

protein that is highly conserved among all of the mammalian

hepadnaviruses(Diaoet al., 2001). HBx stimulates signal

transduction pathways such as MAPK/ERK and can also up-regulate

the expression of genes such as c-Myc, c-Jun, NF-κB, AP 1, Ap-2,

RPB5 subunit of RNA polymerase II, TATA binding protein, and CREB

(Pang etal., 2006).PreS2 activators, and HBSP may exert oncogenic

functions. However, exactly how these viral factors contribute to

higher risks of HCC development remains unclear.

6.4 CONTROL AND PREVENTION OF HBV INFECTION AND HCC

According to J Trop Paed (2003), there are broadly three

strategies for dealing with HBV infection in the developed

countries; immunization for at risk population, antiviral drugs

(lamivudine, adeforvir and dipivoxil) and immunostimulatory

therapy with alpha-interferon for those affected.

57

7.0 HEPATITIS C VIRUS (HCV)

HCV is a single-stranded RNA virus of the Hepacivirus genus in

the Flaviviridae family and is the only positive-stranded RNA

virus among the human oncogenic viruses. Its approximately 9.6 kb

genome contains an open reading frame (ORF) that codes for a 3000

amino acid residue polyprotein precursor (Choo et al., 1989) that

is cleaved by cellular and viral proteases into three structural

proteins (core, E1, E2) and seven nonstructural proteins (p7,

NS2, NS3, NS4a, NS4B, NS5A, and NS5B) (Lindenbach and Rice,

2005).

7.1 MOLECULAR EPIDEMIOLOGY OF HCV

HCV is the etiologic agent of posttransfusion and sporadic non-A,

non-B hepatitis (Choo et al., 1989) and infects approximately 2%

of the population worldwide, although the prevalence of HCV

infection varies by geographical location (Shepard et al., 2001)

HCV proteins have been reported to activate cellular oncoproteins

and inactivate tumor suppressors, such as p53, CREB2/LZIP, and

the retinoblastoma protein (pRB). HCV causes genome instability,

58

signifying that certain HCV proteins may have a mutator function

(McLaughlin-Drubin and Munger, 2008).

So far the prevalence of hepatitis C. virus infection is

increasing in Nigeria, ranging from 4.7-5% in Ilorin, to 5.3-6.6%

in Enugu, to 11% in Ibadan and 20% in Benin (Ejioforet al., 2010)

7.2 CONTROL AND PREVENTION OF HCV INFECTION

Available options for the management of HCV include; the use of

interferons, which are immune response modifiers; Ribavirin,

which is an antiviral drug; a combination of interferon and

ribavirin; or liver transplantation in the case of failed

chemotherapy (Ejioforet al., 2010)

CONCLUSION

Identification of viruses strongly associated with human cancers

provides an opportunity to advance preventive measures to inhibit

virus infections, hence reducing the risk of cancer.Development

of vaccines against cancer viruses is capable of reducing the

global incidence of cancer.

59

In sub-Saharan African countries, including Nigeria, where the

incidence of cervical cancer and other cancers of viral etiology

are on the increase, there is need to sensitize the citizenry on

the importance of early diagnosisand make vaccines available for

all those who are at risk.

60

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