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AIDS And Retroviruses

Today, tens of millions of people around the world are going to die young
because they are infected by HIV, the virus that causes AIDS. The primary AIDS
virus is HIV-1, which can be spread via sexual intercourse or drug use
(activities, which result in body fluid exchange like blood and semen). HIV can
also be passed from mother to child and can also be acquired during blood
transfusions. AIDS, Acquired Immune Deficiency Syndrome, is a virus that causes
a loss of protection against disease causing microorganisms. People who are
infected by AIDS usually have a decline in the number of T-cells that are
responsible for their immune system. Because the virus reproduces by a reversed
transcriptase enzyme, it can quickly make a copy of its virus and so, it is
difficult to treat with its infinite reproductions. However, scientists have now
came up with a combination of drug called “cocktail drugs” to slow
down the development of the virus in different life cycles. Introduction HIV,
the Human Immunodeficiency Virus, is a disease that merits international
concern, study, and research. The diseases that infect individuals over the
world are causing theme to lose the functionality of their immune system and
finally succumb to one or more opportunistic diseases. AIDS viruses are
unbelievably small particles, invisible under an ordinary microscope, but
observable with an electron microscope. All the viruses are tiny packets of
genetic material, composed of either DNA or RNA and are surrounded by a
protective envelope of protein. HIV belongs to a group of especially tricky
viruses called retrovirus. It reverses the usual flow of genetic information
within the host cell. Retroviral RNA is copied, using its reverse transcriptase
enzyme, into a complementary single strand of DNA. This single-strand retroviral
DNA is then copied into double-stranded retroviral DNA inside the cell’s
cytoplasm. This retroviral DNA migrates into the host cell’s nucleus and becomes
integrated into the host cell DNA. It is then a provirus. (Hyde & Forsyth,
1996) 1.0 Retroviruses 1.1 History There are two strains of HIV, HIV-1 and
HIV-2. HIV-1 is the more prevalent form and also the one that causes the greater
pathology. HIV-2 is a lesser found strain that is endemic to countries in West
Africa. Presently, the majority of those infected with HIV are infected with the
HIV-1 strain. When the infection progresses, the patient is diagnosed with
acquired immunodeficiency syndrome (AIDS). The first well-documented case of
AIDS was found in San Francisco and New York in 1981. A young gay man in San
Francisco was found to be suffering from a severe fungal infection to which he
had little immune reaction. In fact, his immune system did not appear to respond
to any disease. Then he developed Pneunocystis carinii pneumonia (PCP), a type
of pneumonia that is caused by parasite. This disease is usually found only
among severely malnourished individuals or people whose immune systems have been
impaired by drugs such as those used in the treatment of cancer or in connection
with organ transplants. The young man died by the end of the year. Retroviruses
are classified into many different categories, but Lentivirus is responsible for
human immunodeficiency virus (HIV-1). (Armstrong, 1990) 1.2 T-Cells A
characteristic feature of AIDS is the progressive decline in the number of
circulating CD4 T lymphocytes . Various strains of HIV are cytopathic for cells
from cultured CD4 cell lines suggesting that direct killing, among other
mechanisms, may contribute to depletion of CD4 T-cells in HIV-infected persons.

Cell killing may also be involved in other aspects of HIV pathogenesis,
including the induction of neurological dysfunctions. The molecular events that
mediate HIV-induced cytopathology have not yet been elucidated, although env
gene products have been implicated by many lines of evidence. Studies funded in
the previous years of this grant indicate that HIV, like several other cytolytic
viruses, mediates changes in plasma membrane-associated ion transport systems.

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Scientists proposed studies focus on defining HIV proteins, which mediate the
changes in ion flux. Their study found out that one of the HIV proteins may be
involved is the transmembrane protein (TM). Among the regions of TM, there are
carboxyl terminal sequences involved. These sequences have the potential to form
a strongly amphipathic helix enriched in arginine, a motif shared with
monovalent cation channels. HIV also have affects the potassium and sodium ion
transport systems. (Armstrong,1990) 1.3 Structure of AIDS virus There is
considerable diversity between various types of retrovirus; the following is a
generalized description of the particle. There is a universal nomenclature for
retrovirus proteins: Protein Function Matrix matrix protein (gag gene); lines
envelope Capsid capsid protein (gag gene); protects the core; most abundant
protein in virus particle Nucleocapsid capsid protein (gag gene); protects the
genome; forms the core Protease Essential for gag protein cleavage during
maturation Integrase Encoded by the pol gene; needed for integration of the
provirus Surface glycoprotein The outer envelope glycoprotein; major virus
antigen Transmembrane protein The inner component of the mature envelope
glycoprotein Reverse transcriptase Reverse transcribes the RNA genome; also has
RNAseH activity Retroviruses have enveloped particles and vary in sizes and
shapes, but are usually 100nm in diameter. The envelope carries a virus-encoded
glycoprotein, which forms spikes in the membrane. There are certain
structural/functional similarities between the envelope glycoprotein and the
influenza haemagglutinin. The mature protein is cleaved into 2 polypeptides:
? The outer envelope glycoprotein is the major antigen of the virus,
responsible for receptor binding, linked by disulphide bonds to: ? The
trans-membrane glycoprotein holds the SU protein in the envelope, responsible
for membrane fusion. Inside the membrane is the matrix protein, rather
amorphous. Capsid is the most abundant protein in the particle making 33 per
cent of the total weight. Inside the capsid is the core, which contains RNA,
genome+NC and protein+RT+IN. All retrovirus genomes consist of two molecules of
RNA, a 5′ cap and a 3′ poly-A (equivalent to mRNA). Retrovirus genomes have 4
unique features: ? They are viruses that are truly diploid. ? They
are the only RNA viruses whose genome is produced by cellular transcriptional
machinery, that is, without any participation by a virus-encoded polymerase.

? They are the only viruses whose genome requires a specific cellular RNA
(tRNA) for replication. ? They are the only RNA viruses whose genome does
not serve directly as mRNA immediately after infection. These two molecules are
physically linked by hydrogen bonds. (Retroviruses [Online]) 1.4 Replication
Shortly after infection, only low amounts of parental infectious material can be
identified, this is the so-called eclipse phase. At this stage, genome
replication has been initiated but progeny viruses are not yet released. There
is then a maturation phase when viral material accumulates exponentially in the
cell or surrounding medium. After a few hours cells infected with lytic viruses
become metabolically disordered and viral production ceases. Titres then slowly
drop. Cells infected with non-lytic viruses can continue to produce viral
particles indefinitely. Infection of a cell may be: ? productive, the
cells are permissive for viral replication and virion progeny are released.

? abortive, the cells are non permissive for a viral function and virion
particles not produced. ? restrictive, the cell is transiently permissive
and a few virus are produced. Viral production then ceases but the genome
persists. This is one of the reasons why some people do not develop AIDS. The
replication cycle of HIV is shown: Source: “Retrovirus” (Online) There
are several steps involved in the HIV cycle: Source: “AIDS fact sheet”
(Online) ? Attachment Virus attachment consists of specific binding of a
viral attachment protein (VAP) to a cellular receptor. Receptor molecules can be
proteins (glycoproteins), or the sugar residues present on glycoproteins or
glycolipids. Some complex viruses, for example, Poxviruses and Herpesviruses may
have more than one receptor-binding protein, therefore, there may be alternative
routes of uptake into cells. The expression or absence of receptors on the
surface of cells largely determines the tropism of most viruses, that is, the
type of cell in which they are able to replicate. ? Penetration Unlike
attachment, viral penetration is an energy-dependent process; that is, the cell
must be metabolically active for this to occur. Three mechanisms may be
involved: ? Translocation of the entire virion across the cell membrane
? Endocytosis of the virus into intracellular vacuoles. ? Fusion
of the viral envelope with the cell membrane, which requires the presence of a
viral fusion protein in the virus envelop. ? Uncoating A general term for
the events which occur after penetration, in which the capsid is removed and the
virus genome exposed, usually in the form of a nucleoprotein complex. This can
happen when retrovirus cores are highly ordered nucleoprotein complexes which
contain, in addition to the diploid RNA genome, the reverse transcriptase enzyme
responsible for converting the viral RNA genome into the DNA provirus. This
process occurs inside the core particle. For viruses that replicate in the
cytoplasm, the genome is simply released into the cell, but for viruses that
replicate in the nucleus, often with associated nucleoproteins, must be
transported through the nuclear membrane. This is achieved by interactions of
the nucleoproteins or capsid with the cytoskeleton. At the nuclear pores, the
capsid is stripped off, and the genome passes into the nucleus. ? Gene
Expression Control of viral replication is achieved by tight regulation of gene
expression and the methods used depend on nature of the virus genome/replication
strategy. One advantage of monocistronic mRNAs is that various proteins can be
produced in different amounts, rather than in a constant ratio. Non-segmented
genomes tend to produce polycistronic mRNA, which is translated to form a
polyprotein, processed by proteolytic cleavage to form the mature gene products.

To utilize the cellular machinery, viral mRNAs must contain control signals
which are recognized by the cell. ? Assembly This involves the assembly
of all the components necessary for the formation of the mature virion at a
particular site in the cell. During this process, the basic structure of the
virus is formed. ? Release For lytic viruses, release is a simple process
– the cell breaks open and releases the virus. Enveloped viruses acquire the
lipid membrane as the virus buds out through the cell membrane. Virion envelope
proteins are picked up during this process as the virus is extruded. Budding may
or may not kill the cell, but is controlled by the virus – the physical
interaction of the capsid proteins on the inner surface of the cell membrane
forces the particle out through the membrane: ? Maturation The stage of
the life cycle at which the virus becomes infectious. Usually involves
structural changes in the particle, often resulting from specific cleavage of
capsid proteins to form the mature products, which frequently leads to a
conformational change in the capsid, or the condensation of nucleoproteins with
the genome. For some viruses, assembly and maturation are inseparable, whereas
for others, maturation may occur after the virus particle has left the cell.

(Retroviruses [Online]) 2.0 Transcription The transcription of RNA in AIDS is
caused by reverse transcriptase enzyme. This enzyme changes HIV’s genetic
material (RNA) into the form of DNA. This step has to occur before HIV’s genetic
code gets combined with an infected cell’s own genetic codes. Within the host
cell nucleus, proviral DNA, when activated, produces new strands of RNA. Some
RNA is used as mRNA to produce proteins for making HIV. Other RNA becomes
encased within the viral core proteins to become the new viruses. The RNA
strands that are splices become the mRNA strands used in protein synthesis. The
unspliced RNA strands serve as new viral strands that are encased in their
protein coats (capsids) to become new viruses that bud out of the cell. Source:
“Retrovirus – Transcription” (Online) There are two distinct phases of
transcription follow the HIV infection of an individual cell. Firstly, the RNA
strands produced in the cell’s nucleus are snipped into multiple copies of
shorter sequences by cellular splicing enzymes. When they reach the cytoplasm
they are only about 2,000 nucleotides in length. These early-phase short
transcripts encode only the virus’ regulatory proteins. The regulatory proteins
and the structural genes that constitute the rest of the genome are among parts
that are left behind. In the second, or late phase, two new size classes of RNA
move out of the nucleus and into the cytoplasm. (Cozic ; Swisher, 1991) 3.0
Treatment Although scientists have not came up with sufficient treatments for
AIDS, researchers have found several ways to suppress HIV reproductions: 3.1 Tat
Toxoid Robert Gallo, a co-discoverer of HIV has published significant findings
using an experimental vaccine for an AIDS-like illness in rhesus macaques
(monkeys). The vaccine did not prevent infection, but did weaken the disease
with undetectable viral loads, CD4 counts that remained within normal limits,
and other parameters, when compared to control animals. Tat is a protein
produced by HIV that has been linked with several components of HIV disease. In
laboratory tests, immune cells treated with Tat have a lesser response to new,
foreign antigens (infections) and can enhance HIV growth in those cells. Tat
also increases levels of fas ligand on immune mononuclear cells, a precursor to
apoptosis (programmed cell death). This is thought to be one possible component
that leads to decreased CD4 counts. Lastly, Tat increases the number of
chemokine (intercellular “messengers”) receptors on immune cells that
HIV partly uses to enter them. Scientists found out that among those monkeys,
who developed both types of immune responses to Tat, “88% were protected
against high level virus replication.” It should be emphasized, however,
that the vaccine did not protect against infection, but led to viral load levels
that were attenuated in many animals. (Drugs and AIDS, 1994) 3.2 Chinese Herbal
Medicines The Chinese herbal medicine is known as an energy balancing treatment
for people with unbalanced “yin” and “yang”. Chinese herbs
do not cure HIV infection. However, many people believed that the herbs have
helped them to improve their overall energy, or deal with the side effects of
antiviral medications. Some people have used herbs to reduce the upset stomach
or diarrhea caused by their medications. The reason for this is because Chinese
herbs generally strengthen the immune system and therefore eliminate the chance
of getting sick of an AIDS infected person. (Drugs and AIDS, 1994) 3.3 Cocktail
Drugs Cocktail drugs are known as a combination of a variety of protease
inhibitor Invirase, Nucleoside Analogues and Hivid ?, which can all help to
reduce the time to disease progression or death by more than 50 percent. These
drugs combine to attack and slow down the replication and transcription of the
RNA in the virus. Therefore, the patient can live longer because the drugs are
slowing down the speed of disease development. (Protease Works [Online])
Conclusion The true impact of AIDS is now fully known for many years for it
produced profound changes in society. Although there are still questions in the
minds of some individuals about whether AIDS should be treated as a medical or a
moral problem, an increasing number are asking what can be done to best serve
the dignity, liberty, and health of those who are infected, as well as to
prevent new infections in the name of public health. While it is the duty of the
infected not to spread the virus, it is the responsibility of the community to
provide education, compassion, and support.


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