the Intricate Relationship Between Tumor Viruses and Oncogenesis: A Complete Evaluation of Viral-Induced Tumorigenesis Mechanisms and Therapeutic Implications

the Intricate Relationship Between Tumor Viruses and Oncogenesis: A Complete Evaluation of Viral-Induced Tumorigenesis Mechanisms and Therapeutic Implications

 

INTRODUCTION

Viruses may cause benign or malignant tumors in lots of species

of animals (e.g., frogs, fishes, birds, and mammals). Regardless of the

frequent prevalence of tumor viruses in animals, only some

viruses are related to human tumors, and proof that

they’re really the causative brokers exists for only a few.

Tumor viruses don’t have any attribute measurement, form, or chemi-

cal composition. Some are giant, and a few are small; some are

enveloped, and others are bare (i.e., nonenveloped); some

have DNA as their genetic materials, and others have RNA.

The issue that unites all of them is their frequent means to

trigger tumors.

Tumor viruses are on the forefront of most cancers analysis for 2

foremost causes:

(1) They’re extra fast, dependable, and environment friendly tumor pro-

ducers than both chemical compounds or radiation. For instance, lots of

these viruses may cause tumors in all prone animals in 1 or

2 weeks and may produce malignant transformation in cultured

cells in only a few days.

(2) They’ve a small variety of genes in contrast with a

human cell (solely three, 4, or 5 for a lot of retroviruses), and

therefore their position within the manufacturing of most cancers could be readily

analyzed and understood. To this point, the genomes of many tumor

viruses have been sequenced and the variety of genes and their

capabilities have been decided; all of this has supplied impor-

tant info.

MALIGNANT TRANSFORMATION

OF CELLS

The time period malignant transformation refers to modifications within the

progress properties, form, and different options of the tumor cell

(Desk 43–1). Malignant transformation could be induced by

tumor viruses not solely in animals but additionally in cultured cells. In

tradition, the next modifications happen when cells turn into malig-

nantly reworked.

Altered Morphology

Malignant cells lose their attribute differentiated form

and seem rounded and extra refractile when seen in a micro-

scope. The rounding is because of the disaggregation of actin fila-

ments, and the diminished adherence of the cell to the floor of

the tradition dish is the results of modifications within the floor cost

of the cell.

Altered Progress Management

(1) Malignant cells develop in a disorganized, piled-up pat-

tern in distinction to regular cells, which have an organized, flat

look. The time period utilized to this variation in progress sample

in malignant cells is lack of contact inhibition. Contact inhibi-

tion is a property of regular cells that refers to their means to

cease their progress and motion upon contact with one other

cell. Malignant cells have misplaced this means and consequently transfer

on high of each other, proceed to develop to giant numbers, and

type a random array of cells.

(2) Malignant cells are in a position to develop in vitro at a a lot decrease

focus of serum than are regular cells.

(3) Malignant cells develop nicely in suspension, whereas regular

cells develop nicely solely when they’re hooked up to a floor (e.g., a

tradition dish).

(4) Malignant cells are simply cloned (i.e., they will develop into

a colony of cells beginning with a single cell), whereas regular cells

can’t do that successfully.

(5) An infection of a cell by a tumor virus “immortalizes” that

cell by enabling it to proceed rising long gone the time when

its regular counterpart would have died. Regular cells in tradition

have a lifetime of about 50 generations, however malignantly trans-

fashioned cells develop indefinitely.

Altered Mobile Properties

(1) DNA synthesis is induced. If cells resting within the G1 section

are contaminated with a tumor virus, they are going to promptly enter the S

section (i.e., synthesize DNA and go on to divide).

(2) The karyotype turns into altered (i.e., there are modifications in

the quantity and form of the chromosomes because of dele-

tions, duplications, and translocations).

(3) Antigens totally different from these in regular cells seem.

These new antigens could be both virus-encoded proteins, pre-

current mobile proteins which were modified, or beforehand

repressed mobile proteins that are actually being synthesized. Some

new antigens are on the cell floor and elicit both circulating

antibodies or a cell-mediated response that may kill the tumor

cell. These new antigens are the popularity websites for immune

surveillance in opposition to tumor cells.

(4) Agglutination by lectins is enhanced. Lectins are plant

glycoproteins that bind particularly to sure sugars on the cell

membrane floor (e.g., wheat germ agglutinin). The elevated

agglutination of malignant cells could also be because of the clustering

of current receptor websites fairly than to the synthesis of

new ones.

Altered Biochemical Properties

(1) Ranges of cyclic adenosine monophosphate (AMP) are

diminished in malignant cells. Addition of cyclic AMP will trigger

malignant cells to revert to the looks and progress proper-

ties of regular cells.

(2) Malignant cells secrete extra plasminogen activator than

do regular cells. This activator is a protease that converts plas-

minogen to plasmin, the enzyme that dissolves the fibrin clot.

(3) Elevated anaerobic glycolysis results in elevated lactic

acid manufacturing (Warburg impact). The mechanism for this

change is unknown.

(4) There’s a lack of high-molecular-weight glycoprotein

referred to as fibronectin. The impact of this loss is unknown.

(5) There are modifications within the sugar elements of glycopro-

teins and glycolipids within the membranes of malignant cells.

ROLE OF TUMOR VIRUSES IN

MALIGNANT TRANSFORMATION

Malignant transformation is a everlasting change within the behav-

ior of the cell. Should the viral genetic materials be current and

functioning always, or can it alter some cell part and

not be required subsequently? The reply to this query was

obtained by utilizing a temperature-sensitive mutant of Rous sar-

coma virus. This mutant has an altered reworking gene that

is purposeful on the low, permissive temperature (35°C) however not

on the excessive, restrictive temperature (39°C). When rooster cells

have been contaminated at 35°C they reworked as anticipated, however when

incubated at 39°C, they regained their regular morphology and

conduct inside just a few hours. Days or perhaps weeks later, when these

cells have been returned to 35°C, they recovered their reworked

phenotype. Thus continued manufacturing of some purposeful

virus-encoded protein is required for the upkeep of the

reworked state.

Though malignant transformation is a everlasting change,

revertants to normality do seem, albeit hardly ever. Within the revertants

studied, the viral genetic materials stays built-in in mobile

DNA, however modifications within the high quality and amount of the virus-

particular RNA happen.

 

PROVIRUSES & ONCOGENES

The 2 main ideas of the best way viral tumorigenesis happens

are expressed within the phrases provirus and oncogene. These con-

trasting concepts deal with the basic query of the supply of

the genes for malignancy.

(1) Within the provirus mannequin, the genes enter the cell on the time

of an infection carried by the tumor virus.

(2) Within the oncogene mannequin, the genes for malignancy are

already current in all cells of the physique by advantage of being current

within the preliminary sperm and egg. These oncogenes encode proteins

that encourage cell progress (e.g., fibroblast progress issue). In

the oncogene mannequin, carcinogens reminiscent of chemical compounds, radiation,

and tumor viruses activate mobile oncogenes to overproduce

these progress components. This initiates inappropriate cell progress

and malignant transformation (Determine 43–1).

Each proviruses and oncogenes might play a job in malig-

nant transformation. Proof for the provirus mode consists

of discovering copies of viral DNA built-in into cell DNA solely

in cells which were contaminated with the tumor virus. The cor-

responding uninfected cells don’t have any copies of the viral DNA.

1. Position of Mobile Oncogenes in

Tumorigenesis

The primary direct proof that oncogenes exist in regular cells

was primarily based on outcomes of experiments wherein a DNA copy

of the onc gene of the rooster retrovirus Rous sarcoma virus

was used as a probe. DNA in regular rooster embryonic cells

hybridized to the probe, indicating that the cells include a gene

homologous to the viral gene. It’s hypothesized that the mobile

oncogenes stands out as the precursors of viral oncogenes. Proto-

oncogenes are the conventional precursors of the mobile oncogenes.

Proto-oncogenes encode regular mobile proteins and are underneath

regulatory management. Mobile oncogenes have acquired mutations

that trigger them to flee regulatory management and overproduce

altered proteins. Determine 43–2 exhibits the capabilities of necessary

oncoproteins encoded by the mobile oncogenes.

Though mobile oncogenes and viral oncogenes are related,

they aren’t similar. They differ in base sequence at varied

factors; and mobile oncogenes have exons and introns, whereas

viral oncogenes don’t. It appears possible that viral oncogenes

have been acquired by incorporation of mobile oncogenes into

retroviruses missing these genes. Retroviruses could be thought

of as transducing brokers, carrying oncogenes from one cell to

one other. (See Chapter 4 for a dialogue of transduction.)

Since this preliminary commentary, greater than 20 mobile onco-

genes have been recognized by utilizing both the Rous sarcoma

virus DNA probe or probes comprised of different viral oncogenes.

Desk 43–2 describes the operate of a number of necessary cellula

oncogenes and their relationship to numerous human cancers.

Many cells include a number of totally different mobile oncogenes. In addi-

tion, the identical mobile oncogenes have been present in species as

numerous as fruit flies, rodents, and people. Such conservation

by means of evolution suggests a standard physiologic operate for

these genes. Some are identified to be expressed throughout regular

embryonic improvement.

A marked variety of viral oncogene operate has been

discovered. Some oncogenes, such because the src gene, encode a protein

kinase that particularly phosphorylates the amino acid tyrosine,

in distinction to the generally discovered protein kinase of cells,

which preferentially phosphorylates serine. There’s proof

that the kinase phosphorylates sign transduction components that

activate synthesis of cyclins. This drives the cell into S section and

subsequent mitosis.

Different oncogenes have a base sequence virtually similar to

that of the gene for sure mobile progress components (e.g., epider-

mal progress issue). A number of proteins encoded by oncogenes have

their impact on the cell membrane (e.g., the ras oncogene encodes

a G protein), whereas some act within the nucleus by binding to

DNA (e.g., the myc oncogene encodes a transcription issue).

These observations point out that progress management is a multistep

course of and that carcinogenesis could be induced by affecting one

or extra of a number of steps.

On the idea of the identified classes of oncogenes, the

following mannequin of progress management could be constructed. After

a progress issue binds to its receptor on the cell membrane,

membrane-associated G proteins and tyrosine kinases are

activated. These, in flip, work together with cytoplasmic proteins

or produce second messengers, that are transported to the

nucleus and work together with nuclear components. DNA synthesis is acti-

vated, and cell division happens. Overproduction or inappropri-

ate expression of any of the previous components in boldface sort

can lead to malignant transformation.

Word that not all tumor viruses of the retrovirus household

include onc genes. How do these viruses trigger malignant trans-

formation? It seems that the DNA copy of the viral RNA inte-

grates close to a mobile oncogene, inflicting a marked enhance in

its expression. This course of is named insertional mutagenesis.

Overexpression of the mobile oncogene might play a key position in

malignant transformation by these viruses.

Though it has been demonstrated that viral oncogenes can

trigger malignant transformation, it has not been instantly proven

that mobile oncogenes can achieve this. Nonetheless, as described in

Desk 43–3, the next proof means that they do:

(1) DNA-containing mobile oncogenes remoted from cer-

tain tumor cells can remodel regular cells in tradition. When

the bottom sequence of those “reworking” mobile oncogenes

was analyzed, it was discovered to have a single base change

from the conventional mobile oncogene (i.e., it had mutated). In

a number of tumor cell isolates, the altered websites within the gene are

the identical.

(2) In sure tumors, attribute translocations of chro-

mosomal segments could be seen. In Burkitt’s lymphoma cells, a

translocation happens that strikes a mobile oncogene (c-myc)

from its regular website on chromosome 8 to a brand new website adjoining to

an immunoglobulin heavy chain gene on chromosome 14. This

shift enhances expression of the c-myc gene.

In power myelogenous leukemia (CML) cells, a truncated

chromosome referred to as a “Philadelphia” chromosome is seen. This

chromosome has a attribute translocation that leads to

the overexpression of the bcr-abl oncogene that encodes a tyro-

sine kinase. Elevated kinase exercise will increase the speed of cell

division and inhibits DNA restore leading to leukemia. Medicine

that inhibit this kinase, reminiscent of imatinib (Gleevec), induce a

extended remission and are nicely tolerated.

(3) Some tumors have a number of copies of the mobile onco-

genes, both on the identical chromosome or on a number of tiny

chromosomes. The amplification of those genes leads to over-

expression of their mRNA and proteins.

(4) Insertion of the DNA copy of the retroviral RNA (provi-

ral DNA) close to a mobile oncogene stimulates expression of the

c-onc gene.

(5) Sure mobile oncogenes remoted from regular cells

may cause malignant transformation if they’ve been modified

to be overexpressed inside the recipient cell.

In abstract, two totally different mechanisms—mutation and

elevated expression—seem to have the ability to activate the qui-

escent “proto-oncogene” right into a functioning oncogene succesful

of remodeling a cell. Mobile oncogenes present a rationale

for carcinogenesis by chemical compounds and radiation (e.g., a chemical

carcinogen may act by enhancing the expression of a mobile

oncogene). Moreover, DNA remoted from cells handled with

a chemical carcinogen can malignantly remodel different regular

cells. The ensuing tumor cells include mobile oncogenes from

the chemically handled cells, and these genes are expressed with

excessive effectivity.

 

2. Position of Mobile Tumor Suppressor

Genes in Tumorigenesis

There’s one other mechanism of carcinogenesis involving cel-

lular genes, specifically, mutation of a tumor suppressor gene

(Determine 43–1). A well-documented instance is the retinoblas-

toma susceptibility gene, which usually acts as a suppressor

of retinoblastoma formation. When each alleles of this antion-

cogene are mutated (made nonfunctional), retinoblastoma

happens. Human papillomavirus and SV40 virus produce a

protein that binds to and inactivates the protein encoded by

the retinoblastoma gene. Human papillomavirus additionally produces

a protein that inactivates the protein encoded by the p53 gene,

one other tumor suppressor gene in human cells. The p53 gene

encodes a transcription issue that prompts the synthesis of

a second protein, which blocks the cyclin-dependent kinases

required for cell division to happen. The p53 protein additionally pro-

motes apoptosis of cells which have sustained DNA harm or

include activated mobile oncogenes. Apoptosis-induced dying

of those cells has a “tumor-suppressive” impact by killing these

cells destined to turn into cancerous.

Inactivation of tumor suppressor genes seems more likely to be

an necessary common mechanism of viral oncogenesis. Tumor

suppressor genes are concerned within the formation of different can-

cers as nicely (e.g., breast and colon carcinomas and varied

sarcomas). For instance, in lots of colon carcinomas, two genes

are inactivated, the p53 gene and the DCC (deleted in colon

carcinoma) gene. Desk 43–4 lists a number of necessary tumor sup-

pressor genes and their relationship to numerous human cancers.

Greater than half of human cancers have a mutated p53 gene in

the DNA of malignant cells.

3. Position of Mobile Micro-RNA Genes in

Tumorigenesis

Micro-RNA genes don’t encode proteins however fairly exert their

regulatory impact by being transcribed into micro-RNA that

can bind to sequences in mRNA and stop that mRNA from

being translated into proteins. For instance, there are micro-

RNAs that bind to (“silence”) mRNA transcribed from a tumor

suppressor gene. Because of this, the tumor suppressor protein is just not

synthesized, which boosts the probability of tumorigenesis.

OUTCOME OF TUMOR VIRUS INFECTION

The end result of tumor virus an infection relies on the virus

and the kind of cell. Some tumor viruses undergo their total

replicative cycle with the manufacturing of progeny virus, whereas

others bear an interrupted cycle, analogous to lysogeny, in

which the proviral DNA is built-in into mobile DNA and

restricted expression of proviral genes happens. Subsequently, malig-

nant transformation doesn’t require that progeny virus be

produced. Slightly, all that’s required is the expression of 1

or, at most, just a few viral genes. Word, nevertheless, that some tumor

viruses remodel by inserting their proviral DNA in a fashion

that prompts a mobile oncogene.

Generally, the DNA tumor viruses such because the papovavi-

ruses remodel solely cells wherein they don’t replicate. These

cells are referred to as “nonpermissive” as a result of they don’t allow viral

replication. Cells of the species from which the DNA tumor

virus was initially remoted are “permissive” (i.e., the virus repli-

cates and normally kills the cells, and no tumors are fashioned). For

instance, SV40 virus replicates within the cells of the African inexperienced

monkey (its species of origin) and causes a cytopathic impact

however no tumors. Nonetheless, in rodent cells, the virus doesn’t

replicate, expresses solely its early genes, and causes malignant

transformation. Within the “nonproductive” reworked cell, the

viral DNA is built-in into the host chromosome and stays

there by means of subsequent cell divisions. The underlying idea

relevant to each DNA and RNA tumor viruses is that solely

viral gene expression, not replication of the viral genome or

manufacturing of progeny virus, is required for transformation.

The important step required for a DNA tumor virus (e.g.,

SV40 virus) to trigger malignant transformation is expression

of the “early” genes of the virus (Desk 43–5). (The early genes

are these expressed previous to the replication of the viral genetic

materials.) These required early genes produce a set of early pro-

teins referred to as T antigens.

1

The massive T antigen, which is each obligatory and adequate

to induce transformation, binds to SV40 virus DNA on the website

of initiation of viral DNA synthesis. That is appropriate with the

discovering that the massive T antigen is required for the initiation of

mobile DNA synthesis within the virus-infected cell. Biochemically,

giant T antigen has protein kinase and adenosine triphosphate

(ATPase) exercise. Nearly the entire giant T antigen is situated in

the cell nucleus, however a few of it’s within the outer cell membrane.

In that location, it may be detected as a transplantation antigen

referred to as tumor-specific transplantation antigen (TSTA). TSTA

is the antigen that induces the immune response in opposition to the

transplantation of virally reworked cells. Comparatively little is

identified in regards to the SV40 virus small T antigen, besides that if it

is just not synthesized, the effectivity of transformation decreases.

In polyomavirus-infected cells, the center T antigen performs the

similar position because the SV40 virus giant T antigen.

In RNA tumor virus-infected cells, this required gene has

one in every of a number of totally different capabilities, relying on the retrovirus.

The oncogene of Rous sarcoma virus and a number of other different viruses

codes for a protein kinase that phosphorylates tyrosine. Some

viruses have a gene for an element that regulates cell progress (e.g.,

epidermal progress issue or platelet-derived progress issue), and

nonetheless others have a gene that codes for a protein that binds to

DNA. The conclusion is that ordinary progress management is a mul-

tistep course of that may be affected at any one in every of a number of ranges.

The addition of a viral oncogene perturbs the expansion management

course of, and a tumor cell outcomes.

The viral genetic materials stays stably built-in in host

cell DNA by a course of much like lysogeny. Within the lysogenic cycle,

bacteriophage DNA turns into stably built-in into the bacte-

rial genome. The linear DNA genome of the temperate phage,

lambda, varieties a double-stranded circle inside the contaminated cell

after which covalently integrates into bacterial DNA (Desk 43–6).

A repressor is synthesized that stops transcription of most

of the opposite lambda genes. Equally, the double-stranded

round DNA of the DNA tumor virus covalently integrates

into eukaryotic-cell DNA, and solely early genes are transcribed.

To this point, no repressor has been recognized in any DNA tumor

virus-infected cell. With RNA tumor viruses (retroviruses),

the single-stranded linear RNA genome is transcribed right into a

double-stranded linear DNA that integrates into mobile DNA.

In abstract, regardless of the variations of their genomes and within the

nature of the host cells, these viruses undergo the frequent

pathway of a double-stranded DNA intermediate adopted by

covalent integration into mobile DNA and subsequent expres-

sion of sure genes.

Simply as a lysogenic bacteriophage could be induced to enter the

replicative cycle by ultraviolet radiation and sure chemical compounds,

tumor viruses could be induced by a number of mechanisms. Induc-

tion is among the approaches used to find out whether or not tumor

viruses are current in human most cancers cells (e.g., human T-cell

lymphotropic virus was found by inducing the virus from

leukemic cells with iododeoxyuridine).

Three methods have been used to induce tumor viruses to

replicate within the reworked cells:

(1) Probably the most continuously used methodology is the addition of

nucleoside analogues (e.g., iododeoxyuridine). The mechanism

of induction by these analogues is unsure.

(2) The second methodology entails fusion with “helper” cells

(i.e., the reworked, nonpermissive cell is fused with a permis-

sive cell) wherein the virus undergoes a standard replicative

cycle. Inside the heterokaryon (a cell with two or extra nuclei

that’s fashioned by the fusion of two totally different cell sorts), the

tumor virus is induced and infectious virus is produced. The

mechanism of induction is unknown.

(3) Within the third methodology, helper viruses present a lacking

operate to enhance the built-in tumor virus. An infection

with the helper virus leads to the manufacturing of each the inte-

grated tumor virus and the helper virus.

The method of rescuing tumor viruses from cells revealed the

existence of endogenous viruses. Therapy of regular, unin-

fected embryonic cells with nucleoside analogues resulted within the

manufacturing of retroviruses. Retroviral DNA is built-in inside

the chromosomal DNA of all cells and serves because the template

for viral replication. This proviral DNA in all probability arose by ret-

rovirus an infection of the germ cells of some prehistoric ancestor.

Endogenous retroviruses, which have been rescued from the

cells of many species (together with people), differ relying on

the species of origin. Endogenous viruses are xenotropic (xeno

means overseas; tropism means to be drawn to; i.e., they infect

cells of different species extra effectively than they infect the cells

of the species of origin). Entry of the endogenous virus into the

cell of origin is proscribed because of faulty viral envelope–

cell receptor interplay. Though they’re retroviruses, most

endogenous viruses will not be tumor viruses (i.e., only some trigger

leukemia).

TRANSMISSION OF TUMOR VIRUSES

Tumor virus transmission in experimental animals can happen

by two processes, vertical and horizontal. Vertical transmission

signifies motion of the virus from mom to new child off-

spring, whereas horizontal transmission describes the passage

of virus between animals that shouldn’t have a mom–offspring

relationship. Vertical transmission happens by three strategies: (1)

the viral genetic materials is within the sperm or the egg; (2) the virus

is handed throughout the placenta; and (3) the virus is transmitted in

the breast milk.

When vertical transmission happens, publicity to the virus

early in life can lead to tolerance to viral antigens and, as a con-

sequence, the immune system is not going to eradicate the virus. Massive

quantities of virus are produced, and a excessive frequency of most cancers

happens. In distinction, when horizontal transmission happens, the

immunocompetent animal produces antibody in opposition to the virus,

and the frequency of most cancers is low. If an immunocompetent

animal is experimentally made immunodeficient, the frequency

of most cancers will increase tremendously.

Horizontal transmission in all probability doesn’t happen in people;

these in shut contact with most cancers sufferers (e.g., relations

and medical personnel) shouldn’t have an elevated frequency

of most cancers. There have been “outbreaks” of leukemia in a number of

youngsters on the similar college, however these have been interpreted

statistically to be random, uncommon occasions that occur to coincide.

HUMAN TUMOR VIRUSES

There are seven identified human tumor viruses (Desk 43–7).

Two are RNA viruses, specifically, human T-cell lymphotropic virus

and hepatitis C virus. The opposite 5 are DNA viruses, specifically,

human papillomavirus, Epstein–Barr virus, human herpesvirus

8 (Kaposi’s sarcoma virus), hepatitis B virus, and Merkel cell

polyomavirus.

1. RNA Tumor Viruses

Human T-Cell Lymphotropic Virus

There are two necessary human retroviruses: human T-cell

lymphotropic virus (HTLV), which is described right here, and

human immunodeficiency virus (HIV), which is described in

Chapter 45.

Illness

HTLV-1 causes two distinctly totally different illnesses: a most cancers referred to as

grownup T-cell leukemia/lymphoma and a neurologic illness referred to as

HTLV-associated myelopathy (also called tropical spastic

paraparesis or power progressive myelopathy). HTLV-2 additionally

seems to trigger these illnesses, however the affiliation is much less clearly

documented. (All info on this part refers to HTLV-1

until in any other case acknowledged.)

Necessary Properties

HTLV and HIV are the 2 medically necessary members of

the retrovirus household. Each are enveloped viruses with reverse

transcriptase within the virion and two copies of a single-stranded,

positive-polarity RNA genome. Nonetheless, HTLV doesn’t

kill T cells, whereas HIV does. In actual fact, HTLV does simply the

reverse; it causes malignant transformation that “immortal-

izes” the contaminated T cells and permits them to proliferate in an

uncontrolled method.

The genes within the HTLV genome whose capabilities have been

clearly recognized are the three structural genes frequent to

all retroviruses, specifically, gag, pol, and env, plus two regulatory

genes, tax and rex. Usually, HTLV genes and proteins are

much like these of HIV in measurement and performance, however the genes dif-

fer in base sequence, and due to this fact, the proteins differ in amino

acid sequence (and antigenicity). For instance, p24 is the key

nucleocapsid protein in each HTLV and HIV, however they differ

antigenically. The virions of each HTLV and HIV include a

reverse transcriptase, integrase, and protease. The envelope

proteins of HTLV are gp46 and gp21, whereas these of HIV are

gp120 and gp41.

The proteins encoded by the tax and rex genes play the identical

purposeful roles as these encoded by the HIV regulatory genes,

tat and rev. The Tax protein is a transcriptional activator, and

the Rex protein governs the processing of viral mRNA and its

export from the nucleus to the cytoplasm.

The tax gene is an oncogene and the Tax protein is required

for malignant transformation of T cells. The Tax protein acti-

vates the synthesis of interleukin-2 (IL-2; which is T-cell progress

issue) and of the IL-2 receptor. IL-2 promotes fast T-cell

progress and finally malignant transformation of the T cell.

The soundness of the genes of HTLV is far better than that

of HIV. As a consequence, HTLV doesn’t present the excessive diploma

of variability of the antigenicity of the envelope proteins that

happens in HIV.

Abstract of Replicative Cycle

The replication of HTLV is assumed to comply with a typical retrovi-

ral cycle, however particular info has been tough to acquire

as a result of the virus grows poorly in cell tradition. HTLV primarily

infects CD4-positive T lymphocytes. The mobile receptor for

the virus is unknown. Inside the cytoplasm, reverse transcrip-

tase synthesizes a DNA copy of the genome, which migrates to

the nucleus and integrates into cell DNA. Viral mRNA is made

by host cell RNA polymerase, and transcription is upregulated

by Tax protein, as talked about earlier. The Rex protein controls

the synthesis of the gag/pol mRNA, the env mRNA, and their

subsequent transport to the cytoplasm, the place they’re trans-

lated into structural viral proteins. Full-length RNA destined

to turn into progeny genome RNA can also be synthesized and trans-

ported to the cytoplasm. The virion nucleocapsid is assembled

within the cytoplasm, and budding happens on the outer cell mem-

brane. Cleavage of precursor polypeptides into purposeful

structural proteins is mediated by the virus-encoded protease.

Transmission & Epidemiology

HTLV is transmitted primarily by intravenous drug use, sexual

contact, or breast feeding. Transplacental transmission has been

hardly ever documented. Transmission by blood transfusion has

tremendously decreased in the US with the appearance of screen-

ing donated blood for antibodies to HTLV and discarding these

which can be optimistic. Transmission by processed blood merchandise,

reminiscent of immune serum globulins, has not occurred. Transmis-

sion is assumed to happen primarily by the switch of contaminated

cells fairly than free, extracellular virus. For instance, complete

blood, however not plasma, is a significant supply, and contaminated lympho-

cytes in semen are the principle supply of sexually transmitted virus.

HTLV an infection is endemic in sure geographic areas,

specifically, the Caribbean area together with southern Florida,

japanese South America, western Africa, and southern Japan.

The speed of seropositive adults is as excessive as 20% in a few of

these areas, however an infection can happen anyplace as a result of contaminated

people migrate from these areas of endemic an infection.

No less than half the folks in the US who’re contaminated

with HTLV are contaminated with HTLV-2, normally acquired through

intravenous drug use.

Pathogenesis & Immunity

HTLV causes two distinct illnesses, every with a unique sort of

pathogenesis. One illness is grownup T-cell leukemia/lymphoma

(ATL) wherein HTLV an infection of CD4-positive T lymphocytes

induces malignant transformation. As described earlier, HTLV-

encoded Tax protein enhances synthesis of IL-2 (T-cell progress

issue) and IL-2 receptor, which initiates the uncontrolled

progress attribute of a most cancers cell. All of the malignant T cells

include the identical built-in proviral DNA, indicating that the

malignancy is monoclonal (i.e., it arose from a single HTLV-

contaminated cell). HTLV stays latent inside the malignant T cells

(i.e., HTLV is usually not produced by the malignant cells).

The opposite illness is HTLV-associated myelopathy (HAM),

also called tropical spastic paraparesis or power progres-

sive myelopathy. HAM is a demyelinating illness of the mind

and spinal twine, particularly of the motor neurons within the spinal

twine. HAM is brought about both by an autoimmune cross-reaction

wherein the immune response in opposition to HTLV damages the

neurons or by cytotoxic T cells that kill HTLV-infected neurons.

Scientific Findings

ATL is characterised by lymphadenopathy, hepatosplenomegaly,

lytic bone lesions, and pores and skin lesions. These options are brought about

by proliferating T cells infiltrating these organs. Within the blood,

the malignant T cells have a definite “flower-shaped” nucleus.

Hypercalcemia as a consequence of elevated osteoclast exercise inside the

bone lesions is seen. Sufferers with ATL typically have diminished cell-

mediated immunity, and opportunistic infections with fungi

and viruses are frequent.

The medical options of HAM embrace gait disturbance, weak-

ness of the decrease limbs, and low again ache. Lack of bowel and

bladder management might happen. Lack of motor operate is far

better than sensory loss. T cells with a “flower-shaped” nucleus

could be discovered within the spinal fluid. Magnetic resonance imaging of

the mind exhibits nonspecific findings. Development of signs

happens slowly over a interval of years. HAM happens primarily in

girls of center age. The illness resembles a number of sclerosis

besides that HAM doesn’t exhibit the remissions attribute

of a number of sclerosis.

Each ATL and HAM are comparatively uncommon illnesses. The huge

majority of individuals contaminated with HTLV develop asymptomatic

infections, normally detected by the presence of antibody. Solely

a small subset of these contaminated develop both ATL or HAM.

Laboratory Analysis

An infection with HTLV is set by detecting antibodies

in opposition to the virus within the affected person’s serum utilizing the enzyme-linked

immunosorbent assay (ELISA) take a look at. The Western blot assay

is used to substantiate a optimistic ELISA outcome. Polymerase chain

response (PCR) assay can detect the presence of HTLV RNA or

DNA inside contaminated cells. The laboratory exams used to display screen

donated blood include solely HTLV-1 antigens, however as a result of there

is cross-reactivity between HTLV-1 and HTLV-2, the presence

of antibodies in opposition to each viruses is normally detected. Nonetheless,

some HTLV-2 antibodies are missed in these routine screening

exams. Isolation of HTLV in cell tradition from the affected person’s speci-

mens is just not completed.

ATL is identified by discovering malignant T cells within the lesions.

The analysis of HAM is supported by the presence of HTLV

antibody within the spinal fluid or discovering HTLV nucleic acids in

cells within the spinal fluid.

Therapy & Prevention

There isn’t any particular antiviral therapy for HTLV an infection,

and no antiviral drug will remedy latent infections by HTLV. ATL

is handled with anticancer chemotherapy regimens. Antiviral

medicine haven’t been efficient within the therapy of HAM. Cor-

ticosteroids and danazol have produced enchancment in some

sufferers.

There isn’t any vaccine in opposition to HTLV. Preventive measures

embrace screening donated blood for the presence of antibodies,

utilizing condoms to forestall sexual transmission, and inspiring

girls with HTLV antibodies to chorus from breast feeding.

Hepatitis C Virus

Continual an infection with hepatitis C virus (HCV), like hepatitis

B virus (HBV), additionally predisposes to hepatocellular carcinoma.

HCV is an RNA virus that has no oncogene and varieties no DNA

intermediate throughout replication. It does trigger power hepatitis,

which appears more likely to be the principle predisposing occasion. (Addi-

tional info relating to HCV could be present in Chapter 41.)

2. DNA Tumor Viruses

Human Papillomavirus

Human papillomavirus (HPV) is among the two viruses defi-

nitely identified to trigger tumors in people. Papillomas (warts)

are benign however can progress to type carcinomas, particularly in an

immunocompromised individual. HPV primarily infects keratiniz-

ing or mucosal squamous epithelium. (Further info

relating to HPV could be present in Chapter 38.)

Papillomaviruses are DNA nucleocapsid viruses with double-

stranded, round, supercoiled DNA and an icosahedral nucleo-

capsid. Carcinogenesis by HPV entails two proteins encoded

by HPV genes E6 and E7 that intrude with the exercise of the

proteins encoded by two tumor suppressor genes, p53 and Rb

(retinoblastoma), present in regular cells. In most cancers cells, the viral

DNA is built-in into the mobile DNA, and the E6 and E7

proteins are produced.

There are no less than 100 various kinds of HPV, lots of which

trigger distinct medical entities. For instance, HPV-1 by means of

HPV-4 trigger plantar warts on the soles of the ft, whereas

HPV-6 and HPV-11 trigger anogenital warts (condylomata acu-

minata) and laryngeal papillomas. Sure kinds of HPV, espe-

cially sorts 16 and 18, are implicated as the reason for carcinoma

of the cervix, penis, and anus.

Epstein–Barr Virus

Epstein–Barr virus (EBV) is a herpesvirus that was remoted

from the cells of an East African particular person with Burkitt’s

lymphoma. EBV, the reason for infectious mononucleosis, trans-

varieties B lymphocytes in tradition and causes lymphomas in

marmoset monkeys. It’s also related to nasopharyngeal

carcinoma, a tumor that happens primarily in China, and with

thymic carcinoma and B-cell lymphoma in the US.

Nonetheless, cells from Burkitt’s lymphoma sufferers in the US

present no proof of EBV an infection. (Further info

relating to EBV could be present in Chapter 37.)

Cells remoted from East African people with Burkitt’s

lymphoma include EBV DNA and EBV nuclear antigen. Solely

a small fraction of the various copies of EBV DNA is built-in;

most viral DNA is within the type of closed circles within the cytoplasm.

The problem in proving that EBV is a human tumor virus is

that an infection by the virus is widespread however the tumor is uncommon.

The present speculation is that EBV an infection induces B cells to

proliferate, thus growing the probability {that a} second occasion

(e.g., activation of a mobile oncogene) will happen. In Burkitt’s

lymphoma cells, a mobile oncogene, c-myc, which is often

situated on chromosome 8, is translocated to chromosome 14

on the website of immunoglobulin heavy chain genes. This trans-

location brings the c-myc gene in juxtaposition to an lively

promoter, and enormous quantities of c-myc RNA are synthesized. It’s

identified that the c-myc oncogene encodes a transcription issue,

however the position of this consider oncogenesis is unsure.

Human Herpesvirus 8

Human herpesvirus 8 (HHV-8), also called Kaposi’s sarcoma-

related herpesvirus (KSHV), causes Kaposi’s sarcoma (KS).

KS is a malignancy of vascular endothelial cells that comprises

many spindle-shaped cells and erythrocytes. It’s the most

frequent most cancers in sufferers with acquired immunodeficiency

syndrome (AIDS). KSHV is transmitted each sexually and by

saliva. A protein encoded by KSHV referred to as latency-associated

nuclear antigen (LANA) inactivates RB and p53 tumor sup-

pressor proteins, which causes malignant transformation of the

endothelial cells. (Further info relating to HHV-8 can

be present in Chapter 37.)

Hepatitis B Virus

HBV an infection is considerably extra frequent in sufferers with

major hepatocellular carcinoma (hepatoma) than in con-

trol topics. This relationship is putting in areas of Africa

and Asia, the place the incidence of each HBV an infection and

hepatoma is excessive. Continual HBV an infection generally causes

cirrhosis of the liver; these two occasions are the principle predispos-

ing components to hepatoma. A part of the HBV genome is built-in

into mobile DNA in malignant cells. Nonetheless, no HBV gene

has been undoubtedly implicated in oncogenesis. The combination

of HBV DNA might trigger insertional mutagenesis, ensuing

within the activation of a mobile oncogene. As well as, the HBx

protein might play a job as a result of it inhibits the p53 tumor

suppressor protein. (Further info relating to HBV

could be present in Chapter 41.)

Merkel Cell Polyomavirus

Merkel cell polyomavirus (MCPV) causes a carcinoma of Merkel

cells within the pores and skin. (Merkel cells are neuroreceptors for strain

and contact.) The carcinoma happens most frequently on pores and skin uncovered

to the solar such because the face and neck. Immunosuppressed indi-

viduals and the aged are predisposed to this most cancers.

Members of the polyomavirus household are small, nonenvel-

oped, double-stranded DNA viruses identified to trigger most cancers in

animals (see later part on animal tumor viruses). An infection

with MCPV is frequent, as indicated by the presence of anti-

physique to the virus in lots of wholesome blood donors. The mode of

transmission is unsure.

In carcinoma cells, the DNA of MCPV is built-in into cell

DNA. The gene for the massive T antigen is mutated so the virus

can’t replicate however the T antigen continues to be synthesized.

The T antigen causes the cell to turn into malignant by inhibiting

tumor suppressor proteins reminiscent of p53 and RB. As a result of MCPV

doesn’t replicate within the carcinoma cells, sufferers will not be infec-

tious to others.

Analysis is made by pathologic evaluation of surgical

specimens. There isn’t any virus-based laboratory take a look at clinically

accessible. There isn’t any antiviral drug or vaccine accessible.

Prevention entails lowering solar publicity, use of sunscreen,

and frequent pores and skin examinations to detect the most cancers earlier than it

metastasizes.

VACCINES AGAINST CANCER

There are two vaccines designed to forestall human most cancers:

the HBV vaccine and the HPV vaccine. The widespread use

of the HBV vaccine in Asia has considerably diminished the inci-

dence of hepatocellular carcinoma. The vaccine in opposition to HPV,

the reason for carcinoma of the cervix, was authorized to be used in

the US in 2006.

DO ANIMAL TUMOR VIRUSES CAUSE

CANCER IN HUMANS?

There isn’t any proof that animal tumor viruses trigger tumors

in people. In actual fact, the one accessible info means that

they don’t, as a result of (1) individuals who have been inoculated with polio-

virus vaccine contaminated with SV40 virus don’t have any better

incidence of cancers than do uninoculated controls, (2) troopers

inoculated with yellow fever vaccine contaminated with avian

leukemia virus shouldn’t have a excessive incidence of tumors, and (3)

members of households whose cats have died of leukemia brought on by

feline leukemia virus present no enhance within the prevalence of leu-

kemia over management households. Word, nevertheless, that some human

tumor cells, specifically, non-Hodgkin’s lymphoma, include SV40

DNA, however the relationship of that DNA to malignant transfor-

mation is unsure.

ANIMAL TUMOR VIRUSES

1. RNA Tumor Viruses

RNA tumor viruses have been remoted from numerous

species, specifically, snakes, birds, and mammals, together with nonhu-

man primates. The necessary RNA tumor viruses are listed in

Desk 43–7. They’re necessary due to their ubiquity, their

means to trigger tumors within the host of origin, their small quantity

of genes, and the connection of their genes to mobile onco-

genes (see web page 351).

These viruses belong to the retrovirus household (the prefix retro

means reverse), so named as a result of a reverse transcriptase is

situated within the virion. This enzyme transcribes the genome RNA

into double-stranded proviral DNA and is crucial to their rep-

lication. The viral genome consists of two similar molecules of

positive-strand RNA. Every molecule has a molecular weight of

roughly 2 × 106

(these are the one viruses which can be diploid

[i.e., have two copies of their genome in the virion]). The 2

molecules are hydrogen-bonded collectively by complementary

bases situated close to the 5′ finish of each RNA molecules. Additionally sure

close to the 5s′ finish of every RNA is a switch RNA (tRNA) that

serves because the primer2

for the transcription of the RNA into DNA.

The icosahedral capsid is surrounded by an envelope with

glycoprotein spikes. Some inner capsid proteins are group-

particular antigens, that are frequent to retroviruses inside a

species. There are three necessary morphologic kinds of retro-

viruses, labeled B, C, and D, relying totally on the loca-

tion of the capsid or core. A lot of the retroviruses are C-type

particles, however mouse mammary tumor virus is a B-type particle,

and HIV, the reason for AIDS, is a D-type particle.

The gene sequence of the RNA of a typical avian sarcoma

virus is gag, pol, env, and src. The nontransforming retroviruses

have three genes; they’re lacking src. The gag area codes for

the group-specific antigens, the pol gene codes for the reverse

transcriptase, the env gene codes for the 2 envelope spike

proteins, and the src gene codes for the protein kinase. There

is proof that the kinase phosphorylates sign tranduction

components that activate synthesis of cyclins that drive the cell into

S section and subsequent mitosis.

The sequences on the 5′ and three′ ends operate within the integra-

tion of the proviral DNA and within the transcription of mRNA

from the built-in proviral DNA by host cell RNA polymerase

II. At every finish is a sequence3

referred to as an LTR that’s composed of

a number of areas, one in every of which, close to the 5′ finish, is the binding website

for the primer tRNA.

After an infection of the cell by a retrovirus, the next occasions

happen: Utilizing the genome RNA because the template, the reverse

transcriptase (RNA-dependent DNA polymerase) synthesizes

double-stranded proviral DNA. The DNA then integrates into

mobile DNA. Integration of the proviral DNA is an compulsory

step, however there isn’t a particular website of integration. Insertion of the

viral LTR can improve the transcription of adjoining host cell

genes. If this host gene is a mobile oncogene, malignant trans-

formation might outcome. This explains how retroviruses with out

viral oncogenes may cause transformation.

2. DNA Tumor Viruses

Papovaviruses

The 2 best-characterized oncogenic papovaviruses are poly-

omavirus and SV40 virus. Polyomavirus (poly means many; oma

means tumor) causes all kinds of histologically totally different

tumors when inoculated into new child rodents. Its pure host

is the mouse. SV40 virus, which was remoted from regular rhesus

monkey kidney cells, causes sarcomas in new child hamsters.

Polyomavirus and SV40 virus share many chemical and

biologic options (e.g., double-stranded, round, supercoiled

DNA of molecular weight 3 × 106

and a 45-nm icosahedral

nucleocapsid). Nonetheless, the sequence of their DNA and the

antigenicity of their proteins are fairly distinct. Each bear a

lytic (permissive) cycle within the cells of their pure hosts, with

the manufacturing of progeny virus. Nonetheless, once they infect the

cells of a heterologous species, the nonpermissive cycle ensues,

no virus is produced, and the cell is malignantly reworked.

Within the reworked cell, the viral DNA integrates into the

cell DNA, and solely early proteins are synthesized. A few of

these proteins (e.g., the T antigens described on web page 353) are

required for induction and upkeep of the reworked

state.

JC virus, a human papovavirus, is the reason for progressive

multifocal leukoencephalopathy (see Chapter 44). It additionally causes

mind tumors in monkeys and hamsters. There isn’t any proof

that it causes human most cancers.

Adenoviruses

Some human adenoviruses, particularly serotypes 12, 18, and 31,

induce sarcomas in new child hamsters and remodel rodent

cells in tradition. There isn’t any proof that these viruses trigger

tumors in people, and no adenoviral DNA has been detected

within the DNA of any human tumor cells.

Adenoviruses bear each a permissive cycle in some cells

and a nonpermissive, reworking cycle in others. The linear

genome DNA circularizes inside the contaminated cell, however—in con-

trast to the papovaviruses, whose total genome integrates—

solely a small area (10%) of the adenovirus genome does so;

but transformation nonetheless happens. This area codes for a number of

proteins, one in every of which is the T (tumor) antigen. Adenovirus

T antigen is required for transformation and is antigenically

distinct from the polyomavirus and SV40 virus T antigens.

Herpesviruses

A number of animal herpesviruses are identified to trigger tumors.

4 species of herpesviruses trigger lymphomas in nonhu-

man primates. Herpesviruses saimiri and ateles induce T-cell

lymphomas in New World monkeys, and herpesviruses pan and

papio remodel B lymphocytes in chimpanzees and baboons,

respectively.

A herpesvirus of chickens causes Marek’s illness, a con-

tagious, quickly deadly neurolymphomatosis. Immunization of

chickens with a dwell, attenuated vaccine has resulted in a con-

siderable lower within the variety of circumstances. A herpesvirus is

implicated as the reason for kidney carcinomas in frogs.

Poxviruses

Two poxviruses trigger tumors in animals; these are the fibroma–

myxoma virus, which causes fibromas or myxomas in rabbits

and different animals, and Yaba monkey tumor virus, which causes

benign histiocytomas in animals and human volunteers. Little is

identified about both of those viruses.