A GENERAL INTRODUCTION TO VIRUSES
Let's first consider viruses in a general sense. There are many different kinds of viruses which cause many diseases. Individual viruses may differ in their exact compositions and mechanisms for growth, but all viruses have some properties in common.
WHAT ARE VIRUSES?
Viruses are the simplest microorganisms that exist. Here are some of the common features of viruses:
- Viruses are obligate intracellular parasites. This means that viruses cannot replicate and make more of themselves outside of cells. In fact, a pure preparation of virus particles will not grow. In the case of humans, this means that viruses must replicate in some tissue or cell type in our bodies.
- Virus particles consist of:
- Genetic material. Viruses carry genetic material in the form of nucleic acids. For some viruses, the nucleic acid is DNA, the same as the genetic material of the cells in our body. For other viruses, the nucleic acid is RNA, which is related chemically to DNA --more about this later. The genetic material of a virus specifies virus proteins. These virus proteins may be structural proteins that make up the virus particles , enzymes that help carry out biochemical processes necessary for virus growth, or they may be regulatory proteins. Some viral regulatory proteins are used by the virus to select expression of particular virus genes at different times or under different conditions. Other viral regulatory proteins may be used by the virus to help take over the cell and convert it into an efficient "factory" for producing virus.
- A system for protecting the genetic material and introducing it into a cell. Viruses must protect their genetic material when they leave one cell and move to another -- either within tissues of an infected individual, or from an infected individual to an uninfected one. Naked DNA or RNA is quite fragile, and vulnerable to attack by numerous agents. Thus, viruses carry genes that direct production of a protein coat that surrounds the genetic material. In addition, some (but not all) viruses also direct synthesis of a viral envelope which surrounds the virus genetic information and protein coat. Viral envelopes resemble the membranes that make up the outer surfaces of our cells. These membranes contain proteins that are virus-specified. For viruses that contain envelopes, the envelope proteins are very important for the initial phases of infection, since they are exposed on the outside of the virus particle.
- Viruses are dependent on cells for:
- Energy metabolism. Energy is required for most biochemical processes to take place. In the case of viruses, such processes include those responsible for production of the virus proteins and genetic material. However, viruses themselves do not carry the machinery necessary for generating energy. Instead, they rely upon the machinery of the cell that they infect.
- Protein synthesis. Proteins are synthesized in cells by a complex system of molecules and sub-cellular particles, using instructions from the genetic material. Again, viruses carry the genetic instructions but do not carry the machinery for synthesis of proteins. They depend upon the cell protein synthesis machinery.
- Nucleic acid synthesis. Many viruses may also depend on the cell machinery for synthesis of virus-specific nucleic acids. These nucleic acids may be used for expression of viral proteins (mRNA -- see below), or they may be the virus genetic information itself.
HOW DO WE INFECT A HOST?
In order for a virus to infect an individual, it must come into contact with a susceptible cell. It is important to remember that most of our body is covered with skin, which is designed to protect us from infection: skin is quite touch, and the outer layers of skin cells are actually dead. Thus most viruses cannot infect and grow in cells of the outer layers of the skin. These are some of the important routes into the body that viruses use (Figure 4-2):
- The respiratory tract. Viruses can be carried into the respiratory tract through the air that we breathe. Once they are brought into the body by this route, they can infect cells in any part of the respiratory tract, including the nose, wind pipe, bronchial tubes and lungs. Examples of viruses which infect the respiratory tract are influenza and the common cold.
- The oral cavity and digestive tract. If viruses are taken in with food or water, they can potentially infect cells of the mouth and other parts of the digestive system, including the large and small intestines. One form of liver inflammation or hepatitis ("infectious" or type A hepatitis) is an example of this category, as are various diarrheas.
- The genital tract. During sexual intercourse, it is possible to introduce viruses into the female or male genital tract from an infected partner. Suck infections are classified as venereal diseases. If sexual intercourse involves anal penetration, it is also possible to introduce viruses into the anus, rectum and lower intestines by this route as well. Genital herpes virus is an example of an infection of the genital tract.
- Breaks in the skin. If the protective layer of skin is broken by a cut or scratch, then viruses may be able to enter directly into tissues or the blood stream. Bites from animals or insects also fall into this category. For example, rabies is spread by bites from infected animals such as dogs or squirrels, and yellow fever is spread by bites from infected mosquitoes. Transfusions and IV drug abuse are another example this category. In these cases, viruses that contaminate blood or blood products can be introduced into individuals during intravenous transfusions with blood or blood products, or during intravenous drug abuse involving shared needles. An example of this is another form of hepatitis, hepatitis B.
It is important to remember that any individual type of virus
will use some but not all of these routes of infection. A key to
controlling viral infections is understanding the particular
routes of spread that the virus of interest uses. We shall see
how this is determined in Chapter 6. Once a virus has entered an
individual and established infection at a primary site,
the infection can spread to secondary sites in the body as
well. Disease symptoms may result from infection at the primary
site, the secondary sites, or both.
A TYPICAL VIRUS INFECTION CYCLE
Let's look at what happens if a purified virus preparation is used to infect some susceptible cells in the laboratory. A typical result is shown in Figure 4-3. If the amount of infectious virus is measured over a period of time, it is seen to fall after an initial lag period, remain low for a period of time, and then rise to even higher levels. The period during which the amount of infectious virus is low is referred to as the eclipse period. The virus infection cycle can be divided into several events:
- Adsorption (binding) of the virus to the cell. When a virus infects, it must first bind to the cell. This binding is a very specific interaction between the virus particle and some protein (or other molecule) on the cell surface. This protein is referred to as the virus receptor. At first it might seem strange that cells have receptors for viruses, since this would seem to be disadvantageous to the uninfected host. However, this is due to the fact that viruses have evolved so that they are able to bind to a protein that is normally present on the uninfected cell. The distribution of the receptor protein among different cells in the body will influence the kinds of cells that the virus can infect. We will see that this is an important consideration for HIV Infection and development of AIDS.
- Penetration of the virus into the cell and uncoating of the viral genetic material. Once the virus particles have bound to the surface of the cell by attaching to a receptor protein, they are brought into the cell. This penetration process is an active one, which requires expenditure of energy by the cell. Once the virus particle has been taken into the cell, the protective protein coat is removed, exposing the viral genetic material. The genetic material is now ready to be expressed. This uncoating of the virus accounts for the drop in infectious virus assayed because the uncoated virus cannot withstand the assay conditions.
- Expression of the viral genetic material. This
occurs during the eclipse period, when the amount of
infectious virus in the culture appears low. Several
events take place during the eclipse phase:
- Organization of the infected cell for virus expression. The cell machinery may be altered to favor efficient expression of virus genes. This often occurs at expense of the cell's own metabolic processes, and may ultimately lead to death of the infected cell.
- Replication of the viral genetic material. The virus programs the machinery necessary to generate more copies of its own genetic material. In some cases, this may rely on machinery from the uninfected cell, but in other cases, the virus may specify proteins that are necessary for the process.
- Synthesis of proteins for virus particles. Proteins that make up the virus coat, as well as those in the viral envelope are synthesized, from instructions in the viral genetic information. Once these proteins are synthesized, all of the components necessary for formation of a new virus particle are present within the infected cell.
- Assembly of virus particles and release from the cell. Virus particles are assembled in the infected cell from the new genetic material and viral proteins. As this occurs, the amount of infectious virus in the culture will increase and surpass that at the stare of the infection. Typically, an infected cell will release hundreds or thousands of new virus particles, which can spread to infect other cells.
Depending on the virus, there are different fates for an
infected cell. For many viruses, the infected cell is killed (or
lysed) at the end of the infection. These viruses are called lytic.
Other viruses do not kill the infected cell, but they establish a
persistent or carrier state where the cell survives and
continually produces virus particles. These viruses ate called non-lytic.
Some viruses can also establish a state called latency in
cells. In these situations, the virus genetic material remains
hidden in the cell, but no virus is produced. At a later time,
the latent virus can become reactivated, and the cell will
begin to produce infectious virus particles again, as in the case
of cold sores caused by a herpes virus. As we shall see, all of
these fates probably play an important role in HIV infection and
the development of AIDS.
HOW DO WE TREAT VIRAL INFECTIONS?
Once virus infections become established, they are very difficult to treat. This contrasts with the wide variety of antibiotics that are available to treat infections by other microorganisms such as bacteria and fungi. Antibiotics take advantage of the fact that there are differences in some of the biochemical machinery of these very simple microorganisms compared to highly developed organisms such as humans. These antibiotics specifically inhibit processes carried out by the bacteria or fungi, but they do not affect similar processes in higher organisms. For instance the antibiotic streptomycin inhibits the machinery used to make proteins in bacteria, but not in humans. Unfortunately, since viruses rely on the cell to carry out most of their metabolic processes, it is difficult to find drugs similar to classical antibiotics that will block virus .growth without killing the infected cell.
However, in a few cases, compounds that specifically inhibit a viral process have been identified. These compounds are called antivirals, and they hold the key for future treatment of viral infections. As we shall see, there is one anti-viral which inhibits HIV infection to some degree and slows up the progress of AIDS, azidothymidine. At the present time, the basic treatment for a virus infection is to manage the symptoms and wait for the viral infection to run its course. Management of symptoms can include treatment to reduce fevers (for instance aspirin), classical antibiotics (to prevent secondary infections by bacteria in a weakened individual), and bed rest.
Since treatment of virus infections currently not is particularly effective, the best approach to managing viral disease is to prevent the initial infection. One powerful method is public health and sanitation methods to intervene in the epidemiological cycle of the virus, as described in Chapter 2. Another important approach the use of is viral vaccines, as described in Chapter 3. If immunity to a virus can be induced by the vaccine before the virus is encountered, then it will not be able to establish a foothold. Most of you are probably familiar with some of the best-known virus vaccines, which include the smallpox vaccine developed by Edward Jenner (the first vaccine), rabies vaccine developed by Louis Pasteur, and polio vaccines developed by Jonas Salk and Albert Sabin.
THE LIFE CYCLE OF A RETROVIRUS
HIV belongs to a class of viruses called retroviruses. Let's examine the life cycle of a typical retrovirus.
Before considering the retrovirus life cycle, it is important to discuss the central dogma for genetic information flow in cells. The central dogma states that genetic information flows in this direction:
DNA----> RNA ----> Protein
That is, the genetic information is carried in DNA as a sequence of nucleotide bases. In higher organisms the DNA is organized into chromosomes that are located in the nucleus of the cell. When a gene is "expressed," the information from the DNA base sequence is copied or transferred (transcribed) to a related molecule called RNA using the DNA molecule as a pattern. The RNA (which is called messenger RNA or mRNA) then moves from the cell nucleus to the cytoplasm. Once in the cytoplasm, the messenger RNA is used as a blueprint for the formation of proteins (translation). The proteins then carry out most of the important functions for the cell.
The structure of a retrovirus is shown in Figure 4-4. The genetic information of a retrovirus is RNA. This RNA is covered with a viral protein coat; together the viral RNA and coat protein make up a core particle. The core particle is surrounded by a viral envelope, which contains membrane lipids and viral envelope protein.
The life cycle of a retrovirus is shown in Figure 4-5. The retrovirus first binds to the surface of an uninfected cell by recognizing a cell receptor. After binding, the virus particle is brought into the cytoplasm of the cell. During this process, the viral envelope is removed, leaving the core particle. Once this happens, a unique virus-specified enzyme called reverse transcriptase is activated. This enzyme reads the viral RNA and makes viral DNA. The host cell lacks such an enzyme. The viral DNA then moves to the nucleus of the cell, where it is incorporated (or integrated) into the host cell's DNA in the chromosomes. Once this viral DNA is integrated into the chromosome, it resembles any other cell gene. As a result, the normal cell machinery reads the integrated viral DNA to make more copies of viral RNA. This viral RNA is then used for two purposes: 1) some of the viral RNA moves to the cytoplasm and functions as viral messenger RNA to program the formation of viral proteins; 2) the rest of the viral RNA becomes genetic material for new virus particles by moving to the cytoplasm and combining with viral proteins. These virus particles are formed at the cell surface and leave the cell by a process called budding.
There are several important characteristics of the retrovirus life cycle. First, most retroviruses do not kill the cell that they infect. Second, the fact that these virus integrate their DNA into host chromosomes means that they establish a stable carrier state within the infected cell. As a result, once cells are infected with most retroviruses, they will continually produce viruses without dying. For some retroviruses, a latent state may also be established, in which the retroviral DNA is integrated into the host chromosomes, but it does not program formation of new virus particles . However, at a later time (sometimes years later), the latent viral DNA may become activated by some means, and virus will be produced. This latency process is probably important in AIDS. The viral enzyme reverse transcriptase carries out an unusual process in converting the viral RNA genetic information into DNA. This is the reverse of genetic information flow according to the central dogma of molecular biology. This is the reason the enzyme is called reverse transcriptase. This is also where retroviruses get their name -- "retro" is from the Latin word for reverse.
In terms of their genetic material, all retroviruses have three genes. These genes code for:
- coat proteins which make up the inner virus (core) particle. The virus gene that specifies these proteins is called the gag gene.
- the enzyme reverse transcriptase, as well as some other enzymes used in virus replication. The gene that codes these enzymes is the pol gene.
- the proteins of the viral envelope. The gene that codes for these proteins is the env gene. A protein coded by the env gene is responsible for binding of the virus to the cell receptor.
THE AIDS VIRUS
The virus that causes AIDS is Human Immunodeficiency Virus (HIV). Other names that have been used previously for HIV include HTLV-III, LAV and ARV. HIV belongs to a sub-group of retroviruses called lentiviruses (meaning "slow" viruses, since they often cause disease extremely slowly); other lentiviruses have been found in such diverse species as cats, sheep, goats, horses and monkeys. Actually, the virus responsible for the great majority of AIDS cases in the United States, Europe and Africa; is called HIV-1. Recently, a second virus related to HIV-1 has been isolated in Africa, HIV-2 (see Chapter 6). HIV-2 also appears to cause AIDS. In this book, we will refer to the AIDS virus simply as HIV, and this; will almost always mean HIV-1.
Several features about the structure or replication of HIV are important, as shown in Figure 4-6a:
- The nature of the HIV receptor. The cell receptor that HIV binds to is the CD4 surface protein. As described in Chapter 2, CD4 protein is present on T-helper lymphocytes. In fact, this is the predominant cell type that has CD4 protein. In addition, some macrophages also have CD4 protein as well. Most other cells in the body do not contain CD4 protein. As a result, the main cells that HIV can infect are T-helper lymphocytes and macrophages.
- Extra genes. As for all retroviruses, HIV contains
the three genes for coat proteins, reverse transcriptase,
and envelope proteins. In addition, HIV contains; genes
that specify four or five additional proteins.
These proteins are regulatory proteins that give HIV
finer levels of control and a more versatile life cycle.
Two of the best-known of these genes are:
- tat, which is an up-regulator or amplifier of viral gene expression in the infected cell, and
- rev, which shifts the balance from production of viral regulatory proteins to proteins that make up virus particles.
- These extra genes are probably important in allowing the virus to establish a latent or inactive state in some infected cells, followed by reactivation at later times.
- Killing of T-helper lymphocytes. In contrast to most retroviral infections, infection of T-helper lymphocytes with HIV results in cell death (Figure 4-6b). Considering the pivotal role that T-helper lymphocytes play in both humoral and cell-mediated immunity (see Chapter 3), it is possible to understand how infection with HIV can ultimately lead to collapse of the immune system.
- Non-lytic infection of macrophages. When HIV infects macrophages, it follows a course that is typical of other retroviruses, in that the infected macrophages are not killed (Figure 4 a, b). In most cases, the macrophages continue to produce HIV virus particles, while other macrophages establish a latent state of HIV infection. These infected macrophages art the main reservoir of infection in an HIV-infected individual. This also explains how many years can elapse between the time of initial infection and development of clinical AIDS symptoms.
THE EFFECTS OF HIV INFECTION IN INDIVIDUALS
Let's now consider the results of HIV infection at the level of infected people. The routes of HIV infection will be covered in Chapters 6 and 7, so we will start at the time a person becomes infected. There will be a detailed description of AIDS as a clinical disease in the next chapter, but an overview is useful at this point.
The progression of events after HIV infection is shown in Figure 4-7. After HIV infection, there are generally very few initial symptoms -- perhaps a mild flu-like illness or swollen glands. Most individuals then remain fret of any clinical symptoms for variable lengths of time -- up to many years. Individuals who are HIV-infected but who do not show any signs of disease are referred to as asymptomatic. It is generally difficult to detect infectious HIV virus in infected asymptomatic individuals. Indeed, even as individuals develop signs of clinical symptoms, they have quite low levels of infectious HIV. One of the puzzles about HIV is how it can cause such devastating disease with such apparently low levels of circulating virus. During the asymptomatic period, individuals generally produce antibodies to HIV. Unfortunately, these antibodies are not sufficient to prevent continued HIV infection as the disease progresses. However, they provide a useful diagnosis for HIV infection, as we shall see below.
As time passes, many HIV-infected individuals begin to experience symptoms of HIV infection. Some initial symptoms include persistent enlarged lymph glands (lymphoadenopathy syndrome or LAS), and fevers or night-sweats. As the disease worsens, a continuum of progressively mere serious conditions develop as the immune system weakens, ultimately resulting in full-blown or frank AIDS. During the early periods of the AIDS epidemic , doctors also used a classification called ARC or AIDS-related Complex. Individuals were classified as having ARC if they showed fewer of the characteristic opportunistic infections or cancers (see below) than patients with frank AIDS. The term ARC is used less frequently today after the' progressive nature of HIV infection has become apparent. The progression from ,asymptomatic infection to AIDS is accompanied by a progressive depletion of T-helper lymphocytes by HIV infection. Ultimately , there is a profound lack of T-helper lymphocytes, which results in the failure of both humoral and cell-mediated immunity.
The clinical manifestations of AIDS will be covered in detail in Chapter 5. They can be summarized briefly here:
- Opportunistic infections. These are infections by microorganisms that normally do not cause problems in healthy individuals. However, in individuals with weakened immune systems, these microorganisms can take hold and cause devastating infections. One important opportunistic infection a pneumonia caused by a fungus microbe called Pneumocystis carinii (PCP pneumonia).
- Cancers. Cell-mediated immunity also plays an important role in defense against development of cancers (immune surveillance -- see Chapter 3). HIV-infected individuals develop several cancers with very high frequency. One example of an AU)S-related cancer is Kaposi's sarcoma.
- Weight loss. Many AIDS patients suffer from profound weight loss or wasting. The mechanism for this is not understood yet.
- Mental impairment. HIV can also establish infection in the nervous system. This can result in muscle spasms or tics. More serious, infection of the central nervous system can result in AIDS-related dementia, in which individuals lose the ability to reason.
Individual AIDS patients may suffer from one or more of these manifestations. Indeed, recurrent bouts with different opportunistic infections or cancers may be experienced. Since the major problem in AIDS is a loss of T-helper lymphocyte function, monitoring of the numbers of T-helper lymphocytes is important in clinical monitoring of HIV-infected individuals. Doctors can perform a test for these cells, and the results are reported in terms of T-helper (or T4 or CD4) lymphocyte numbers. A few years ago, the tests were frequently reported as the ratio of T-helper to T-killer lymphocytes in the blood (also T4/T8 or helper-to-suppressor ratios). An inversion of the normal T-helper/T-killer lymphocyte ratio is often an early sign of HIV infection. The likelihood that an HIV-infected individual will develop full-blown AIDS will be discussed in more detail in Chapter 6. Current estimates arc that more than 70% of HIV-infected individuals will develop AIDS with an average time to disease of eight or more years.
THE AIDS ANTIBODY TEST
Within a year of the isolation of HIV as the causative agent of AIDS, a test was developed which determines if an individual has been exposed to HIV. The procedure is to test whether an individual has antibodies to HIV virus proteins. These antibodies appear in those who have been previously infected with HIV and made antibodies against the virus (set Chapter 3).
The most common HIV antibody test is called an ELISA test, shown in Figure 4-8. In an ELISA assay, virus protein is first attached to a small laboratory dish. A serum sample is prepared from the blood of the individual to be tested, and placed in the dish containing bound HIV viral proteins. If HIV-specific antibodies are present in the serum, they will become tightly bound to the dish by way of the HIV proteins. The serum is then removed, and the dish is washed -- during this procedure, only antibodies specific for HIV will be retained. The dish is then reacted with a stain that will detect any human antibodies. Thus, dishes which were exposed to serum containing HIV-specific antibodies will be stained, while dishes from antibody-negative serum samples will be unstained. This procedure has been automated, so that many blood samples can be tested at once. The current ELISA tests are better than 99% accurate. That is, less than 1% of HIV-negative individuals incorrectly score as positive by the ELISA test. Likewise, less than 1% of HIV antibody-positive serum samples are missed by the test.
POTENTIAL PROBLEMS WITH THE HIV ANTIBODY TEST
Although this test has been extremely important in furthering our knowledge of how the virus spreads and causes disease, there are several potential problems as well:
- False positives. These are individuals who are not
HIV-infected, but who test antibody-positive in the ELISA
assay. Clearly this can be an extremely frightening
experience. The frequency of false positives is between
one in one hundred (1%) to one in one thousand (0.1%)
uninfected individuals.
- This is a particular problem in populations with low frequencies of HIV infection are tested. In these cases, many of the individuals who score positive will be false positives. This is one of the arguments against routine HIV antibody screening of the general US. population, where current prevalences of infection are less than 1% -- many of the individuals identified as antibody-positive in such a mass screening would actually be false positives.
- Because of the significant false positive rate for the ELISA test, a second more specific test for HIV antibodies is also used, the Western blot test. This technique has a lower incidence of false positives than the ELISA assay. In practice, serum samples that score antibody-positive by the ELISA test are generally re-tested by the Western blot procedure. Serum samples are considered positive if they are found to contain HIV-specific antibodies by both tests. New, and improved tests (more sensitive and/or more accurate) for HIV infection art currently undergoing development.
- False negatives. An equally important problem is
individuals infected with HIV but who do not score
positive in the HIV antibody test. Such individuals fall
into two categories:
- Recently infected individuals. As was discussed in Chapter 3, the immune system has a lag period between initial exposure to an antigen and the production of antibodies. In the case of HIV infection, this lag can range up to six months. Thus individuals who have been recently infected with HIV will not score positive in the antibody test.
- Infected individuals who never mount an immune response. Since the immune response varies from person to person, a few infected individuals do not produce antibodies to HIV. There are rare but documented cases of individuals who remain antibody-negative but spread HIV infection to their sexual partners.
WHAT THE HIV ANTIBODY TEST DOES NOT TELL YOU
The HIV antibody test measures whether an individual has circulating antibodies to HIV. However, the test specifically does not indicate if an antibody-positive individual still harbors infectious virus. some individuals who art exposed to HIV may raise a successful immune response and completely eliminate the infection. Current estimates are that somewhere between 10% and 30% of HIV antibody-positive individuals do not shed infectious virus anymore.
There is however a typical progression of the AIDS disease with respect to initial exposure to the AIDS virus. This can be correlated to the appearance of HIV antibodies in the bloodstream as shown below.
HOW DOES HIV EVADE THE IMMUNE SYSTEM?
One of the paradoxes about HIV infection is that most infected individuals contain HIV antibodies, but the disease eventually occurs in most cases, even in the presence of these antibodies. This means that HIV antibodies are unable to prevent onset of AIDS. This may be due to several factors. First, the levels of antibodies raised might be insufficient to block spread of infectious virus. In addition, antibodies can be produced against different parts of the virus. Only some of these antibodies (neutralizing antibodies) can inactivate virus and prevent infection. Finally, several unique features of HIV infection provide the virus with ways to evade the immune system. These include:
- High mutation rates for HIV envelope protein. The HIV envelope proteins are on the outside of the virus particle, and they are important in attaching the virus to the cell receptor. As such, they are the most important targets for neutralizing antibodies. However, HIV shows an unusually high mutation rate for its env gene, so that the exact amino acid sequence of the envelope proteins changes quite rapidly during successive cycles of infection. Changes in the makeup of HIV envelope proteins have even been observed over time within the same person. Thus, even though an infected individual may raise neutralizing antibodies to the initial infecting virus, those antibodies may not be able to neutralize subsequent viruses with mutated envelope proteins. Thus HIV can keep one step ahead of the immune system and continue infection.
- HIV can establish latent states in some cells. In
these cells, the viral DNA is maintained, but virus
proteins are not expressed. As a result, these latently
infected cells will not be recognized or attacked by the
immune system, but remain as reservoirs for infectious
virus. At later times, the virus may be activated from
these cells. Macrophages are probably the major cells
that carry latent HIV, since initial HIV infection does
not kill them. In addition, T-helper cells latently
infected with HIV may also exist, although in fewer
numbers than latently infected macrophages.
- Reactivation of latent HIV from carrier cells may also be important in AIDS progression. Infection of cells carrying latent HIV with certain other viruses such as herpes simplex or cytomegalovirus will reactivate the HIV. In addition, other stimuli to the immune system (such as infection with other microorganisms) can result in production of factors that reactivate HIV. These secondary infections may be important cofactors in AIDS progression.
- HIV can carry out infection by cell-to-cell spread. That is, if an HIV-infected cell comes into contact with an uninfected cell, the virus may pass to the uninfected cell directly. Naturalizing antibodies are unable to prevent this process, since they can only attack virus when it is outside cells .
These properties of HIV also pose another problem. Vaccines are our front line of defense against most virus infections, as described earlier in this chapter. However, the ability of HIV to evade the immune system means that it will much more difficult to design an effective anti-HIV vaccine.
AZIDOTHYMIDINE (AZT), AN EFFECTIVE THERAPEUTIC AGENT IN AIDS
One effective drug has been developed against HIV infection and AIDS so far, azidothymidine or Retrovir). The effectiveness and use of AZT will be described more in Chapters 5 and 6. However, let's consider its mode of action here.
Azidothymidine is very similar in chemical structure to thymidine, one of the- building blocks of DNA. However, when AZT is incorporated in place of thymidine during the DNA assembly process, it aborts further DNA assembly because of its structure. This inactivates any growing DNA molecule which has incorporated AZT. During HIV infection, if AZT is present, HIV reverse transcriptase will readily incorporate it into the viral DNA. This will inactivate the viral DNA. It is important that the enzymes responsible for making the chromosomal DNA of the cell (cellular DNA polymerases) do not efficiently incorporate AZT into DNA. As a result, the cell can continue to grow and make its genetic material, but HIV cannot replicated efficiently. Thus, AZT is a selective poison for HIV. it exploits an "Achilles heel" of the virus -- reverse transcriptase. This enzyme plays no role in the uninfected cell, but it is vital to the virus. An agent that affects this enzyme will have no effect on the uninfected cell, but will inhibit virus infection. This is shown in Figure 4-9.
LIMITATIONS OF AZT
While AZT is an effective drug in AIDS treatment, it has some limitations:
- Toxic side effects. Normal cellular DNA polymerases do not efficiently incorporate AZT into DNA in comparison to HIV reverse transcriptase -- the basis for the drug's selectivity. However, cellular DNA polymerases do incorporate some AZT into cell DNA at low levels. During prolonged treatment, this can lead to death of normal cells. Anemia is a common side effect in individuals taking AZT, and results from killing of blood cells by the drug.
- Inactivity in macrophages. When AZT is taken up by a cell, it must be modified chemically (phosphorylated) before it can be incorporated into DNA. This modification takes place in T-helper lymphocytes, so the drug is effective against HIV infection in these cells. However, there are some indications that this modification may not take place efficiently in macrophages. in this case, AZT will not be incorporated into viral DNA as efficiently in infected macrophages, and it may not prevent infection in these cells. This is of particular concern, since macrophages are probably the reservoirs of infection in HIV-infected people.
The effectiveness of AZT in treating AIDS patients has a very important implication. Even in individuals who are already infected, prevention of continued HIV infection improves the clinical status. Thus, other drugs that selectively inhibit HIV reverse transcriptase are likely to be useful therapeutic agents, particularly if they can overcome some of the limitations of AZT. Moreover, the other HIV proteins are all potentially "Achilles heels" for the virus as well. Agents that interfere with the action of any of these proteins may also be useful therapeutic agents. AIDS researchers are devoting a great deal of effort to developing new anti-HIV drugs.
WHERE DID HIV COME FROM?
Molecular biologists have examined the genetic structure of HIV (actually HIV-1 and -2) in great detail, and compared it to the structure of other retroviruses of the lentivirus sub-class. From these studies, it is clear that HIV shares a common origin with other lentiviruses, and it evolved from a common ancestral retrovirus over thousands of years.
Epidemiology studies tell us that the HIV that exists today probably evolved to its current form in central Africa one hundred or so years ago. Fifteen to twenty years ago, it spread into high density populations in the Western world and Africa., leading to the AIDS epidemic. Recent changes in human social behavior such as the sexual revolution may have also contributed to the spread of AIDS.
Numerous apocryphal stories as to the origin of HIV have circulated since the beginning of the AIDS epidemic. These include: HIV was the result of germ warfare research by the CIA; HIV was a laboratory accident involving recombinant DNA; HIV resulted from a plot between Israel and South Africa, HIV resulted from sexual relations between humans and sheep; HIV resulted from sexual relations between humans and monkeys. None of these are true.
This page ©Copyright
Peter B. Berget
All Rights Reserved