A diverse array of viruses occurs among animals.

A good way to gain a general idea of the

characteristics of these viruses is to look at one animal virus in detail. Here we examine the virus
responsible for a comparatively new and fatal viral disease, Acquired Immunodeficiency
Syndrome (AIDS).
AIDS is caused by HIV
The disease now known as AIDS was first reported in the United States in 1981, although a few
dozen people in the United States had likely died of AIDS prior to that time and had not been
diagnosed. Frozen plasma samples and estimates based on evolutionary speed and current
diversity of HIV strains trace the origins of HIV in the human population to Africa in the 1950s.
It was not
long before the infectious agent, a retrovirus, was identified by laboratories in France. Study of
HIV revealed it to be closely related to a chimpanzee virus (simian immunodeficiency virus,
SIV), suggesting a recent host expansion to humans from chimpanzees in central Africa.
Infected humans have varying degrees of resistance to HIV. Some have little resistance to
infection and rapidly progress from having HIV-positive status to developing AIDS and
eventually die. Others, even after repeated exposure, fail to become HIV-positive or may become
HIV-positive without developing AIDS. One hypothesis to explain this great variability in
susceptibility is genetic variation among these groups due to the selective pressure put on the
human population by the smallpox virus (Variola major) over the centuries. Because of
successful vaccination and
immunization, smallpox has been eradicated from the human population; however, before its
eradication, it caused billions of deaths worldwide.
HIV infection compromises the host immune system
The HIV virus targets cells that are critical to the immune response. Immune cells are
characterized based on the proteins they display on their surface. The relevant cells targeted by
HIV are cells that express the antigen CD4, thus CD4+ cells. The specific cell type infected by
HIV is T-helper cells, which are critical to regulating the immune response, and their action is
described in chapter 51. HIV infects and kills the CD4+ cells until very few are left. Without
these crucial immune system cells, the body cannot mount a defense against invading bacteria or
viruses. AIDS patients die of infections that a healthy person could fight off. These diseases,
called opportunistic infections, normally do not cause disease and are part of the progression
from HIV infection to having AIDS. Clinical symptoms typically do not begin to develop until
after a long latency period, generally 8 to 10 years after the initial infection with HIV. Some
individuals, however, may develop symptoms in as few as two years. During latency, HIV
particles are not in circulation, but the virus can be found integrated within the genome of
macrophages and CD4+ T cells as a provirus (equivalent to a prophage in bacteria).

HIV testing
HIV tests do not test for the presence of circulating virus but rather for the presence of antibody
against HIV. Because only those people exposed to HIV in their bloodstream at one time or
another
would have anti-HIV antibodies, this screening provides an effective way to determine whether
further testing is needed to confirm HIV-positive status.
The spread of AIDS
Although carriers of HIV have no clinical symptoms during the long latency period, they are
apparently fully infectious, which makes the spread of HIV very difficult to control. The reason
HIV remains hidden for so long seems to be that its infection cycle continues throughout the 8-
to 10-year latency period without doing serious harm to the infected person because of an
effective immune response. Eventually, however, a random mutational event in the virus or a
failure of the immune response allows the virus to quickly overcome the immune defense,
beginning the course of AIDS.
HIV infects key immune-system cells
The way in which HIV infects humans provides a good example of how animal viruses replicate.
Most other viral infections follow a similar course, although the details of entry and replication
differ in individual cases
Attachment
When HIV is introduced into the human bloodstream, the virus particles circulate throughout the
body but only infect CD4+ cells. Most other animal viruses are similarly narrow in their
requirements; hepatitis goes only to the liver, and rabies to the brain. This tissue tropism is
determined by the proteins found on a cell surface and on a viral surface. For example, the
common cold virus uses the ICAM-1 membrane protein as a receptor to enter cells. ICAM-1 is a
protein that is up-regulated (increased) in times of immune activation and stress. So, the more
inflammation and stress in an area, the more receptors exist for the virus to enter a cell and
continue the disease process.
How does a virus such as HIV recognize a target cell? Recall from chapter 4 that every kind of
cell in the human body has a specific array of cell-surface glycoprotein markers that serve to
identify them to other, similar cells. Invading viruses take advantage of this to bind to specific
cell types. Each HIV particle possesses a glycoprotein called gp120 on its surface that precisely
fits the cell-surface marker protein CD4 on the surfaces of the immune system macrophages and
T cells. Macrophages, another type of white blood cell, are infected first. Because macrophages
commonly interact with CD4+ T cells, this may be one way that the T cells are infected.
Entry of virus
After docking onto the CD4 receptor of a cell, HIV requires a coreceptor such as CCR5, to pull
itself across the cell membrane. After gp120 binds to CD4, it goes through a conformational
change that allows it to then bind the coreceptor. Receptor binding is thought to ultimately result
in fusion of the viral and target cell membranes and entry of the virus through a fusion pore. The
coreceptor, CCR5, is hypothesized to have been used by the smallpox virus as was mentioned
earlier in this section.
Replication
Once inside the host cell, the HIV particle sheds its protective coat. This leaves viral RNA
floating in the cytoplasm, along with the reverse transcriptase enzyme that was also within the
virion. Reverse transcriptase synthesizes a double strand of DNA complementary to the virus
RNA, often making mistakes and introducing new mutations
 HIV Replication Cycle
Evolution of HIV during infection
During an infection, HIV is constantly replicating and mutating. The reverse transcriptase
enzyme is less accurate than DNA polymerases, leading to a high mutation rate. Eventually, by
chance, variants in the gene for gp120 arise that cause the gp120 protein to alter its second-
receptor partner. This new form of gp120 protein will bind to a different second receptor, for
example CXCR4, instead of CCR5.
AIDS treatment targets different phases of the HIV life cycle
The federal Food and Drug Administration (FDA) currently lists 34 antiretroviral drugs that are
used in AIDS therapy. These target four aspects of the HIV life cycle: viral entry, genome
replication, integration of viral DNA, and maturation of HIV proteins. Of these, the vast majority
are inhibitors of the replication enzyme, reverse transcriptase, and the protease that is involved in
maturation of proteins. Only two drugs block viral entry: one that blocks the fusion of virus with
the cell membrane, and one that blocks the chemokine coreceptor CCR5. A single drug has also
been approved that targets the integrase protein that integrates the viral genome into a
chromosome.
Reverse transcriptase inhibitors
The first drug licensed for clinical use was AZT, a reverse transcriptase inhibitor. This class of
drugs falls into two categories: nucleotide or nucleoside reverse transcriptase inhibitors (NRTI)
such as AZT, and nonnucleoside reverse transcriptase inhibitors (NNRTI). These drugs are
selective for HIV (or other retroviruses) because reverse transcriptase is not a cellular enzyme.
So although the NRTI drugs affect cellular enzymes, they inhibit reverse transcriptase at much
lower doses. Nineteen RT inhibitors are currently approved by the FDA.
Protease inhibitors
The second class of drugs discovered to be effective in AIDS treatment were the protease
inhibitors. These drugs target a protease that cleaves a polyprotein into the smaller proteins
necessary for viral replication and assembly. Some of these drugs are actually a good example of
the concept of rational drug design. Drug designers started with the protease enzyme, then
targeted drugs at transition state analogues of this enzyme. There are now 11 of these drugs that
have received FDA approval.
Blocking viral entry
Two drugs have been approved by the FDA that block the entry of HIV into the cell. One of
these, the fusion inhibitor, was approved in 2003. The drug blocks the fusion of the viral
envelope with the plasma membrane of a target cell. This entry also requires recognizing the
CD4 receptor protein, and a coreceptor such as CCR5. The coreceptor blocker was approved in
mid-2007.
Integrase inhibitors
A number of companies have been working on drugs targeting the viral integrase protein. This
protein catalyzes the integration reaction of the viral genome. Two drugs that target this protein
have been approved.
Combination therapy
The most successful form of therapy has been to use combinations of the previously discussed
drugs.
Vaccine development for HIV has been unsuccessful
A large amount of effort has been put toward developing an anti-HIV vaccine. Thus far, this has
been totally unsuccessful. A recent large-scale international HIV vaccine trial was halted when
an
early examination of data indicated that the vaccine was essentially useless for preventing
infection or lowering viral load. This has led to a retooling of clinical trials to have periodic
examination of data instead of waiting for endpoints, but has not helped in terms of the vaccine
itself. This vaccine was a subunit vaccine in which a specific HIV protein was engineered into an
adenovirus vector.
Although the high mutation rate of HIV has always been seen as a problem for vaccine
development, it appears that the reason for vaccine failures may be more basic, and harder to
surmount. A vaccine needs to produce a strong cellular immune response, and thus far no trial
HIV subunit vaccine has done this. The only type of vaccine in an animal system that has been
shown
to provide protection against infection was a vaccine made from attenuated SIV. Unfortunately
over time, the attenuated virus was able to mutate into an infective virus, and the experimental
animals eventually developed simian AIDS.