Cancer and virsues

General Features of Viral
Carcinogenesis
 Most are DNA viruses (exceptions: some retroviruses and
flaviviruses)
 Influence the cell cycle by
 Encoding proteins that direct cell cycle progression
 Integrating near cellular genes that control cell cycle
progression
 The Central Tenets of Viral Carcinogenesis
 Viruses can cause cancers in humans and animals
 Tumor viruses frequently establish persistent infections
 Host susceptibility factors are important determinants
 Viruses are seldom carcinogenic on their own
 Virus infections are far more common than viral cancers
 Prolonged periods (years) are usually required for viral carcinogenesis
 Viral strains may be different in their capacity to cause cancers
 Cancer viruses modulate cell cycle progression
 Animal models can reveal mechanisms of viral carcinogenesis
 Viral markers are usually present in cancerous cells
 One virus species can be associated with multiple tumor types

Interactions of Tumor Viruses With Their Hosts
 Persistent infections
 All known human tumor viruses establish persistent infections
 Genetic differences in individuals results in differential
susceptibilities
 Host immune response
 Persistent viruses must evade the host immune response
 Different viruses have evolved different evasion mechanisms
 Mechanisms of action by human cancer viruses
 Viral gene is able to subvert cell cycle control
 Viruses alter the expression of normal cell cycle progression
genes
 Either results in cellular transformation into an oncogenic state
 Cell susceptibility to virus
 Tumor viruses possess cell specificity and do not infect other
cells
 EBV infects B cells
 HTLV infects T cells

General characteristics of human cancer viruses are:
1. the viruses that have been implicated in human
carcinogenesis are frequently ubiquitous (e.g., EBV,
HPV, hepatitis viruses);
2. cancer is a rare outcome of a virus infection and only
a small percentage of infected individuals develops
cancer;
3. the time intervals between the initial infection and
cancer development is long (usually decades);
4. the cancers are usually clonal; and
5. chemical or physical agents are often implicated as
playing cofactor roles.

DNA virsues
History :-
 Avian leukemia in Denmark in 1908 and avian
sarcoma in chickens in 1911.
 Peyton Rous, shown that cell free extracts from a
sarcoma in chickens could induce tumors in injected
chickens within a few weeks, even when passed
through filters that retained bacteria, was recognized
with a Nobel Prize in 1968.
 In the 1930s Richard Shope demonstrated cell free
transmission of tumors in rabbits.
 Ludwig Gross - murine leukemia viruses.
 Gross, Stewart, and Eddy - mouse polyoma virus

History
 In 1964 Epstein et al. demonstrated herpes virus–like
particles in human lymphoblasts derived from Burkitt's
lymphoma: Epstein-Barr virus (EBV).
 During the 1970s, role for hepatitis B virus (HBV) in
primary hepatocellular carcinoma (HCC) in humans.
 Orth et al. - human papillomaviruses (1970)
associated with skin cancers in patients with a rare
skin disease called epidermodysplasia verruciformis.
 In 1980, human T-lymphotropic virus 1 (HTLV-1) was
isolated by the Gallo group and subsequently linked
to adult T-cell leukemia.

History
 In the mid-1980s specific human papillomaviruses
(HPV) were identified in human cervical cancers by
Boshart et al. and Durst et al.
 In the 1990s, a new herpes virus, Kaposi's sarcoma-
associated herpesvirus (KSHV; also known as HHV-
8) was identified by Yang Chang and Patrick Moore
and linked to Kaposi's sarcoma (KS).
 In 2008 using deep sequencing Chang and Moore
also identified a new candidate human tumor virus, a
polyomavirus, from Merkel cell carcinomas (MCC), a
rare tumor that is seen more frequently in
immunosuppressed individuals.

Human Viruses with Oncogenic
Properties
Virus Family Type Associated Human Tumors Cofactors
Adenovirus Types 2, 5, 12 Not associated with human
cancer
Flaviviruses Hepatitis C (HCV) Hepatocellular carcinoma —
Hepadnavirus Hepatitis B (HBV) Hepatocellular carcinoma Aflatoxin, alcohol, smoking
Herpesviruses EBV Burkitt's lymphoma Malaria
Immunoblastic lymphoma Immunodeficiency
Nasopharyngeal carcinoma Nitrosamines
Hodgkin's lymphoma —
Leiomyosarcomas —
Gastric cancers —

KSHV (HSV8) Kaposi's sarcoma HIV infection
Pulmonary effusion lymphoma HIV infection
Castleman's disease HIV infection
Papillomaviruses HPV-16, -18, -33, -39, Others Anogenital cancers and some
upper airway cancers
Smoking, other factors
HPV-5, -8, -17, others ? nonmelanoma skin cancer EV, sunlight, immune
suppression

Polyomavirus Merkel cell virus Merkel cell carcinomas Immunosuppression
SV40 (monkey virus) ? Brain tumors —
? Non-Hodgkin's lymphomas —
? Mesotheliomas —
JC virus ? Brain tumors —
BK virus ? Prostate cancer —
Retroviruses HTLV-1 Adult T-cell
leukemia/lymphoma
Uncertain

DNA Tumor Viruses
Virus Viral Oncoproteins Cellular Targets
Polyomavirus
SV40
Large T antigen
Small t antigen
p53 and pRb tumor suppressor
genes
PP2A
Human
papillomavirus
E6
E7
p53, DLG, MAGI-1, MUPP1
pRb
Bovine
papillomavirus
E5 PDGFβ receptor
Adenovirus
E1A
E1B-55k
pRb
p53
Adenovirus 9 E4ORF1 DLG, MAGI-1, MUPP1
Epstein-Barr virus
LMP1
vIL10
BCL2 homolog
TRAFs
IL-10 receptor (soluble viral cytokine)
Rescues cell from apoptosis

Hepatocellular Carcinoma
 HCC is one of the world's most common
malignancies.
 chronic HBV infection is associated with a 100-fold
increase in HCC risk .
 HBV is a small ds DNA virus classified as a member
of the hepadnavirus family.
 HBV is the only human virus in this family.
 5% of patients go on to have persistent (usually
lifelong) hepatic infection and viremia, and most of the
demonstrated HCC risk falls within this subgroup of
infections.
 Another factor that adds to risk is the severity of
chronic liver injury.

 HBV serves indirectly as an agent of oncogenesis,
chiefly by provoking cellular proliferation in response
to immune-mediated injury.
 mammalian viruses harbor an additional coding
region, termed ORF X . This gene encodes a small
regulatory protein (HBx) implicated possibly in a
variety of signal transduction and transcriptional
activation pathways. This open reading frame is
absent in the avian viruses, which fail to induce HCC
in their native hosts despite the regular induction of
persistent infection.
 HBx expression is important in carcinogenesis in vivo,
it must be involved at early stages and be
dispensable during later tumor progression.

HBV integration
The insertion of HBV genome
in cellular genes frequently
targets genes that regulate
key cellular pathways. The
figure illustrates that HBV
targets a variety of genes
controlling various steps of
cellular signalling, cell
proliferation and viability

 Activation or inactivation of cellular genes by the
integrated copies of viral DNA in the tumor cells.
 Unlike retroviruses, hepadnaviruses do not specify
genetic functions that direct genomic integration, and
such integration is not essential for HBV replication.

Papillomaviruses
 The papillomaviruses are nonenveloped DNA viruses
that induce squamous epithelial and fibroepithelial
tumors in their natural hosts.
 These viruses have a specific tropism for
keratinocytes and express their full productive cycle
only in squamous epithelial cells.
 The control of papillomavirus late gene expression is
tightly linked to the differentiation state of the
squamous epithelial cells.
 Vegetative viral DNA synthesis and expression of the
capsid proteins occur only in the most terminally
differentiated epithelial cells.

 The HPV genome can be divided into two distinct
regions: an early region, which encodes the viral
proteins involved in viral DNA replication,
transcriptional regulation, and cellular transformation,
and a late region, which encodes the viral capsid
proteins.
 The genes located in the early region of the genes are
designated as E1, E2, and so forth, and the two
genes located in the late region that encode the
capsid proteins are designated L1 and L2.

ORF FUNCTION
 L1 - L1 protein, major capsid protein (basis of current
preventive VLP vaccines)
 L2 - L2 protein, minor capsid protein
 E1 - Initiation of viral DNA replication, helicase, ATPase
 E2 - Transcriptional regulatory protein, auxiliary role in
viral DNA replication, genome maintenance
 E4 - Late protein; disrupts cytokeratins
 E5 - Membrane transforming protein; interacts with
specific growth factor receptors
 E6 - Transformation; targets degradation of p53;
activates telomerase
 E7 - Transformation; inactivates pRB and RB-related
proteins, affects centrosome duplication

(von Knebel Doberitz/European Journal of Cancer 2002; 38: 2229-2242).
Genomic Map of HPV

Human Papillomaviruses and Anogenital
Cancer
 Cervical cancer is the most common cancer of
women in most developing countries. It occurs less
frequently in developed countries because of effective
screening programs.
 In the mid-1970s, zur Hausen suggested an
association between papillomaviruses and genital
cancers.
 For discovery of HPV-16 and HPV-18 and their
association with cervical cancer led to zur Hausen
receiving the Nobel Prize in Physiology or Medicine in
2008.
 HPV-31, HPV-33, HPV-39, HPV-42, among others
that are each associated with a small percentage of
cervical carcinomas.

 Specific HPVs are also found in a lower percentage of
other human genital tract carcinomas, including penile
carcinomas, vulvar carcinomas, and perianal
carcinomas.
 In HPV-positive cancers there appears to be a
selection for the integrity of the E6-E7 coding region
and the upstream regulatory region in that E6 and E7
genes are regularly expressed in HPV-positive
cervical cancers.

Papillomaviruses and Head and Neck
Cancer
 Since HPVs infect squamous epithelial cells, cancers
that arise from any squamous epithelium or an
epithelium that has the potential to undergo
squamous metaplasia would be potential candidates
for an HPV association.
 Most of these HPV-associated cancers are located in
the oral pharynx, which includes the tonsils, tonsillar
fossa, base of the tongue, and soft palate.
 HPV-positive tumors tend to have a characteristic
basaloid morphology, are less likely to harbor
mutations of p53 or pRb, and more likely to express
p16. HPV positive head and neck cancers may also
have improved disease-specific survival.

Papillomaviruses and Nonmelanoma Skin
Cancer
 skin cancers in patients with epidermodysplasia
verruciformis (EV), a rare lifelong disease in humans
that usually begins in infancy or childhood.
 disseminated polymorphic cutaneous lesions that
resemble flat warts and also as reddish macules
sometimes referred to as pityriasis-like lesions.
 Molecular studies reveal a likely role for HPV infection
in skin carcinogenesis as a cofactor in NMSC. The
genus beta-HPV types are present in more than 90%
of NMSCs in EV patients and are also detected at a
high frequency in NMSC of immunosuppressed
patients and of the general population.

 Role of the beta-HPVs in NMSC may be at the
initiation stage of the tumor, and that it might not be
required for maintenance.
 Several of the beta-HPV types have been shown to
prevent apoptosis after ultraviolet radiation exposure,
an activity that may be mediated by E6 targeting the
degradation of the pro-apoptotic protein Bak.

Papillomavirus Prevention and Therapy
 Gardasil, the U.S. Food and Drug Administration
(FDA)–approved Merck vaccine is a quadrivalent
vaccine containing VLPs from HPV-16, HPV-18, HPV-
6, and HPV-11; and Cervarix, the FDA-approved
GlaxoSmithKline commercial vaccine, is bivalent,
composed of HPV-16 and HPV-18 VLPs in a
proprietary adjuvant.
 Gardasil has been shown to prevent genital warts in
males, and its use in men and boys was approved by
the FDA in 2009.
 VLP vaccine is expensive and is not heat stable, two
characteristics that might impede its use in developing
countries where the cervical cancer disease burden is
the greatest.

 Papillomaviruses
 Features
 Nonenveloped icosahedral (55 nm)
 Circular ds-DNA (8 kb)
 Nuclear replication
 Stimulate cellular DNA synthesis
 Highly restricted host range and tissue range
 Many human types
 Only a few are known to cause cancers
 Cervical cancer is the most important
 Vaccine is now available (Gardasil; types 6, 11, 16, 18)
 Cause warts (abnormal cellular proliferation)
 Replicate in basal stem cells and keratinocytes of the skin and
mucosa
 HeLa cells are cervical cancer cells from Helen Lang (fatal)

Epstein Barr Virus
 Epstein-Barr virus (EBV), also called Human
herpesvirus 4 (HHV-4), is a virus of the herpes family
(which includes Herpes simplex virus and
Cytomegalovirus),
 one of the most common viruses in humans.
 Most people become infected with EBV,
 often asymptomatic
 but commonly causes infectious mononucleosis.
 It is named after Michael Epstein and Yvonne Barr,
who together with Bert Achong discovered the virus in
1964.

 On infecting the B-lymphocyte, the linear virus
genome circularises and the virus subsequently
persists within the cell as an episome.
 The virus can execute several distinct programmes of
virally-encoded gene expression
 broadly categorised as being lytic cycle or latent cycle.
 The lytic cycle or productive infection results in staged
expression of a host of viral proteins with the ultimate objective
of producing infectious virions. Formally, this phase of infection
does not inevitably lead to lysis of the host cell as EBV virions
are produced by budding from the infected cell.
 The latent cycle programmes are those that do not result in
production of virions.

EBV-associated malignancies
 The strongest evidence linking EBV and cancer
formation is found in Burkitt's lymphoma and
Nasopharyngeal carcinoma

Burkitts Lymphoma
 a type of Non-Hodgkin's lymphoma
 most common in equatorial Africa
 co-existent with the presence of malaria.
 Malaria infection causes reduced immune surveillance of EBV
immortalised B cells, so allowing their proliferation. This proliferation
increases the chance of a mutation to occur. Repeated mutations can
lead to the B cells escaping the body's cell-cycle control, allowing the
cells to proliferate unchecked, resulting in the formation of Burkitt's
lymphoma. Burkitt's lymphoma commonly affects the jaw bone,
forming a huge tumour mass. It responds quickly to chemotherapy
treatment, namely cyclophosphamide, but recurrence is common.
 Other B cell lymphomas arise in immunocompromised patients
such as those with AIDS or who have undergone organ
transplantation with associated immunosuppression.
 Smooth muscle tumours are also associated with the virus.

Nasopharyngeal carcinoma
 found in the upper respiratory tract, most
commonly in the nasopharynx, and is linked to
the EBV virus.
 It is found predominantly in Southern China
and Africa, due to both genetic and
environmental factors. It is much more
common in people of Chinese ancestry
(genetic), but is also linked to the Chinese diet
of a high amount of smoked fish, which
contain nitrosamines, well known carcinogens
(environmental).

 When EBV infects B-lymphocytes in vitro,
lymphoblastoid cell lines eventually emerge
that are capable of indefinite growth.
 The growth transformation of these cell lines
is the consequence of viral protein
expression.
 EBNA-2, EBNA-3C and LMP-1 are essential
for transformation while EBNA-LP and the
EBERs are not.
 The EBNA-1 protein is essential for
maintenance of the virus genome

 EBNA-2 is the main viral transactivator, switching
transcription from the Wp promoters used during
initial infection to the Cp promoter.
 Together with EBNA-3C, it also activates the LMP-1
promoter. It is known to bind the host RBP-Jκ protein
that is a key player in the Notch pathway. EBNA-2 is
essential for EBV-mediated growth transformation.
 EBNA-3A/EBNA-3B/EBNA-3C also bind the host
RBP-Jκ protein.
 EBNA-3C is also a ubiquitin-ligase and has been
shown to target cell cycle regulators like pRb.

Kaposi's sarcoma
 form of skin cancer that can involve internal
organs. It most often is found in patients with
acquired immunodeficiency syndrome (AIDS),
and can be fatal.

K.S.
 Kaposi's sarcoma (KS) was once a very rare form of
cancer, primarily affecting elderly men of
Mediterranean and eastern European background
(tumours on lower legs), until the 1980s, when it
began to appear among AIDS patients.
 AIDS-related KS, emerged as one of the first illnesses
observed among those with AIDS. Unlike classic KS,
AIDS-related KS tumours generally appear on the
upper body, including the head, neck, and back. The
tumours also can appear on the soft palate and gum
areas of the mouth, and in more advanced cases,
they can be found in the stomach and intestines, the
lymph nodes, and the lungs.

 KS is a composite of three processes: a proliferative
component (made up of spindle-shaped endothelial
cells), an inflammatory component (T and B cells and
monocytes), and an angiogenic component
(comprising highly aberrant, slit-like neovascular
spaces).
 In advanced KS, the spindle cell proliferation
dominates, resulting in nodule formation; but even in
such cases, the disease is often oligo- or polyclonal.

Kaposi Sarcoma and HHV8
 Studies in 2000 showed that HHV-8 was the culprit
behind KS.
 It does not work alone.
 In combination with a patient's altered response to
cytokines (regulatory proteins produced by the
immune system) and the HIV-1 transactivating protein
Tat which promotes the growth of endothelial cells,
HHV-8 can then encode interleukin 6 viral proteins,
specific cytokines that stimulate cell growth in the
skin.
 This becomes KS.

HHV-8
 HHV-8 destroys the immune system further by
directing a cell to remove the major
histocompatibility complex (MHC-1) proteins
that protect it from invasion.
 These proteins are then transferred to the
interior of the cell and are destroyed.
 This leaves the cell unguarded and vulnerable
to invaders which would normally be targeted
for attack by the immune system.

How does KSHV infection predispose to KS?
 KS requires expression of both the KSHV latency
genes and the lytic genes.
 There are seven latency genes known to be
expressed in KS.
 One latency cluster expresses a set of three genes
from a common promoter. Their products include
LANA, an antigen that appears to function in KSHV
genomic maintenance in latency, but also can impair
p53 and Rb function as well as up-regulate the β-
catenin pathway; expression of LANA in primary
endothelial cells extends their survival, though it does
not immortalize or transform them.

 A second latent viral promoter directs production of
transcripts encoding the kaposin family. These are
transmembrane and soluble proteins that appear to
be active in signal transduction.
 A third latent promoter directs production of the K1
glycoprotein, a membrane protein that, when
expressed in B cells, activates a signaling pathway
similar to that of the B-cell antigen receptor.
 KS tumors also harbor smaller numbers of lytically
infected cells that appear to be significant for the
tumor phenotype.

Merkel Cell Polyomavirus and Merkel Cell
Carcinoma
 Merkel cell carcinoma (MCC) is a highly lethal skin
cancer that typically occurs in sun-exposed areas of
elderly patients and in patients with HIV or chronic
lymphocytic lymphoma.
 Merkel cell polyomavirus (MCV) encodes a large T
antigen (LT) and small T antigen (ST) highly similar to
these oncoproteins encoded by the DNA tumor virus
SV40.
 Mutations in the viral DNA that would retain
expression of MCV ST and the N-terminal half of LT
but delete the C-terminal half of MCV LT.
 The N-terminus of MCV LT, similar to other
polyomavirus LT proteins, binds to Rb and Rb-related
proteins to inactivate the Rb tumor suppressor
pathway.

RNA viruses
 Retroviridae - human T-lymphotropic virus (HTLV)
and human immunodeficiency virus (HIV), and
 Flaviviridae - hepatitis C virus (HCV)
 HTLV-1 appears to contribute directly to the
development of adult T-cell leukemia (ATL); HIV and
HCV are associated with human malignancy, but
likely contribute to its development in an indirect
manner.
 Thus, these viruses may play key initiating or
contributing roles to carcinogenesis, additional events
are needed for infection to yield the full malignant
phenotype.

Retroviruses: Background, Replication
Cycle, and Molecular Genetics
Seven genera based on molecular genetic analysis:-
 Alpha-, Beta-, Gamma-, Delta-, and Epsilon-
retroviruses, Lentiviruses, and Spumaviruses
 known human retroviruses:- Deltaretroviruses HTLV-1
and HTLV-2 (additional Deltavirus isolates, termed
HTLV-3 and HTLV-4 also have been reported), and
the Lentiviruses HIV-1 and HIV-2.
 RNA genome that replicates through a DNA
intermediate.
 Retroviral virions contain two identical plus-sense
RNA molecules. The RNA genome contains a 5′
untranslated region, the three genes common to all
retroviruses—gag, pol, and env—and a 3′
untranslated region and polyadenylated tail.

 In general, the gag gene encodes viral structural proteins,
pol encodes viral enzymatic proteins, and env encodes
viral envelope glycoproteins.
 Following entry into a cell, the single-stranded viral
genome is converted to a double-stranded DNA copy by
reverse transcriptase, an RNA-dependent DNA
polymerase.
 Then, the retroviral integrase protein inserts the double-
stranded DNA viral genome into a host cell chromosome
where it permanently resides as a provirus.
 An integrated retroviral provirus resembles cellular genes
in that it is duplicated along with the cell's genome, passed
on to daughter cells during mitosis, and subsequently
transcribed and processed into mRNA.

Mechanisms by which oncogenic retroviruses may
participate in the malignant transformation process are :-
 Slowly transforming viruses (e.g., avian leukosis virus, an
Alpharetrovirus) alter cellular gene expression by random
integration of a provirus within or adjacent to cellular
protooncogenes (insertional mutagenesis). Direct physical
disruption of a gene or effects of viral promoters and
enhancers on cellular gene expression can lead to a
malignant phenotype in infected cells.
 Acutely transforming retroviruses (e.g., Rous sarcoma
virus [RSV], an Alpharetrovirus) have incorporated into
their genomes viral oncogenes derived from cellular
protooncogenes (protooncogene capture) and
subsequently transfer these altered or deregulated
oncogenes into newly infected cells, thus leading to
development of a malignant phenotype.

 Trans-acting retroviruses (e.g., HTLV-1, a
Deltaretrovirus) alter cellular gene expression and
function and, consequently, the control of cell growth
via viral protein(s) that act in trans.

HTLV-1
 naturally infects CD4+ T lymphocytes and can be
transmitted between close contacts through blood
transfer or from mother to infant through cells in
breast milk.
 In most cases the infection is harmless. However, as many as
1 in 20 infected individuals eventually develop a type of adult T
cell leukaemia in which every tumour cell carries a clonally
integrated HTLV1 provirus.
 HTLV1 differs from the standard 'chronically
oncogenic' and 'acutely oncogenic' retroviruses in its
mechanism of action;
 it appears to drive cell growth through expression of a
particular viral protein, Tax, in latently-infected cells.

Human T-Lymphotropic Virus Type
1
 ATL is an aggressive malignancy of CD4+ T cells
caused by HTLV-1.
 In addition to gag, pol, and env, the virus genome
contains additional open reading frames (encoding
Tax, Rex, p12I, p13II, p30II) located in a region at the
3′ end of the genome termed pX. HTLV-1 basic
leucine zipper (HBZ) protein is transcribed from the
complementary strand of the genome and may play a
role in leukemogenesis.
 the trans-regulating proteins - Tax and Rex.
 Both proteins are expressed early in the viral
replication cycle and are important for expression of
viral genes.

HTLV retrovirus and adult T-cell
leukaemia

 Rex promotes the cytoplasmic accumulation of singly-
spliced (env) and unspliced (genomic) mRNAs.
 Tax activates transcription from the HTLV-1 LTR by
associating with a number of cellular transcription
factors.
 p12I, p13II, p30II - required for in vivo infectivity of the
virus.
 HTLV-1 infection is not associated with marked
cellular immunodeficiency unless ATL develops.
 Significant viremia is not detected.
 Viral spread to uninfected cells by cell-to-cell
transmission of the virus. This cell-to-cell spread of
HTLV-1 appears to involve polarization of the
cytoskeleton of infected cells to a cell-cell junction,
promoting spread of virus to new cells.

 In addition to cell-to-cell virus transmission, the
number of HTLV-1–infected cells within an individual
increases by simple mitosis of provirus-containing T
cells, thereby amplifying the number of infected T
cells.
 HTLV-1 infection in an individual patient can persist
even in the presence of a strong immune response.

 Tax can transactivate expression of a number of
key cellular genes that enhance cell growth.
 The best examples are the genes encoding
 interleukin 2 (a T cell growth factor) and
 the interleukin 2 receptor (a molecule that allows cells to
respond to the growth factor).
 As a consequence, the infected cells not only make
their own growth signals, but also respond to them

 HTLV1 induces a weak growth transformation of T cells in the
laboratory but, in the body, is probably never sufficiently strong to
induce T cell leukaemia on its own.
 BUT, a virally infected cell in which growth controls have even
partly broken down, is more susceptible to further genetic
accidents.
 During persistent infection a gradual build-up of HTLV1-positive
T cells which have accumulated additional genetic changes may
occur.
 Eventually this can lead to selection and outgrowth of a fully
malignant, HTLV1-positive clone.
 At this stage malignant cell growth can occur in the absence of
tax gene expression.

Human Immunodeficiency
Virus
 HIV-1 and HIV-2 are members of the Lentivirus genus
of retroviruses.
 Both viruses became human pathogens after zoonotic
transmission to humans from primate reservoirs.
 Although HIV-2 can also cause AIDS in humans and
monkeys, the majority of AIDS cases worldwide are
the result of HIV-1 infection.
 HIV replicates actively following initial infection, which
results in high levels of viremia. In addition, HIV,
unlike HTLV-1, is highly cytopathic for CD4-positive T
cells.
 HIV encodes two trans-acting proteins, Tat and Rev,
analogous in function to the HTLV-1 proteins Tax and
Rex.

 Tat interacts directly with a 5′ LTR region of HIV RNA
known as the trans-activating region, and promotes
processive transcription through further interactions
with cellular factors that modify RNA polymerase II
function.
 HTLV Rex and HIV Rev use similar mechanisms to
promote expression of viral structural and enzymatic
proteins by binding to their respective RNA response
elements, rxre and rre, to mediate the export of full-
length and singly spliced viral transcripts from the
nucleus to the cytoplasm.
 In HIV-infected persons, non-Hodgkin lymphoma
(Burkitt, immunoblastic, and primary CNS), Kaposi
sarcoma, and cervical cancer, anal squamous cell
carcinoma are all AIDS-defining illnesses.

Hepatitis C Virus
 HCV belongs to the Hepacivirus genus of the Flaviviridae
family of viruses.
 a single-stranded plus sense RNA molecule surrounded by
a nucleocapsid and envelope.
 The HCV genome consists of 5′ and 3′ untranslated
regions and a single open reading frame encoding a
protein precursor that is proteolytically processed into
individual viral structural and enzymatic proteins.
 Structural proteins include the nucleocapsid (C) and
envelope proteins (E1, E2). The NS2/3 metalloprotease
and serine protease (NS3) perform most of the proteolytic
processing of the polyprotein precursor. NS3 also
possesses helicase activity. NS4A is a cofactor of the NS3
protease. NS4B is involved in membrane association of
the replication complex. NS5B encodes the RNA-
dependent RNA polymerase.

 HCV is transmitted percutaneously in the majority of
cases.
 The virus also can be transmitted perinatally and via
sexual routes; in about 10% of cases, known risk factors
for transmission are not identified.
 HCV infection is strongly associated with the development
of hepatic cirrhosis and HCC.
 Following initial infection by HCV, about 25% of people
develop acute clinical hepatitis while others are
asymptomatic.
 HCV infection is chronic in 50% to 80% of cases. Of these
cases, 60% to 70% will develop chronic hepatitis, with
about 20% of this group progressing to cirrhosis.
 Individuals chronically infected with HCV who develop
HCC is estimated to be 1% to 5%. The rate of HCC
development in those with cirrhosis is estimated to be 1%
to 4% per year.

 After initial HCV infection, there is an approximately
10- to 20-year period prior to development of cirrhosis
and a 20- to 30-year period prior to development of
HCC.
 It appears likely that HCC largely develops indirectly
as a result of the cellular turnover occurring during the
inflammatory responses that lead to hepatocyte
destruction, regeneration, and fibrosis characteristic
of cirrhosis.
 HCV core protein may contribute to tumor
development.
 The core protein also has been suggested to affect
expression of genes that are ultimately involved in
regulation of the cell cycle via the cyclin-dependent

 For those infected with HCV, combined therapy with
peg-interferon-α2a or -2b and ribavirin, a synthetic
guanosine analogue, has been the standard of care.
 The regimen is only effective in about 50% of patients
infected with genotype 1 virus.
 Serious side effects are flulike symptoms, fever,
fatigue, hemolytic anemia, and depression, resulting
in low enrollment rates and patient compliance.
 Telaprevir, an HCV 3/4A serine protease inhibitor, in
conjunction with peg-interferon, can be effective in
reducing viral load, with sustained response rates
varying from around 50% to 80%.

 A cyclosporine derivative (DEBIO-025) that inhibits
HCV protein binding to cyclophilin, a cellular protein
required for HCV replication, has recently garnered
encouraging clinical results in early clinical trials.
 small-molecule antagonist of the scavenger receptor
B1 (SR-B1), an obligate cellular coreceptor for all
HCV genotypes. This molecule, ITX5061, inhibits
infection of HCV of diverse genotypes at nanomolar
potency.

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