The virus which causes AIDS manages to survive in the very hostile environment of the human immune system. It does this by forming an extremely polymorphous population in which at least one individual is capable of resisting any given attack. The result is Darwinian evolution on a time-scale of about one week.
Viruses and lentiviruses
At the beginning of the 20th century, pioneer virologists believed all diseases of viral origin involved the inflammation and destruction of the infected organs. However, this proved to be true only for so-called "acute" viral infections which are short-lived and whose clinical symptoms disappear when the virus is destroyed by our immune defennses. This original virus theory had to be re-examined when it was discovered that certain viruses cause chronic infections and are capble of surviving in the organism for long periods of time without damaging tissue.
Thus, in the 1950s, the concept of slow viral infection was developed. Slow viral infection involves a very long and preliminary asymptomatic incubation period before clinical symptoms of the disease appear. Today, many "slow" viruses have been identified. HIV (Human Immunodeficiency Virus), the AIDS virus, belongs to one family of these persistent viruses, the lentiviruses (or retroviruses).
"Acute" and "chronic" viral strategies
Acute and persistent infections are, in fact, two different strategies used by viruses that live in the very hostile environment of the immune systems in higher animals.
Broadly speaking, the "acute" strategy takes advantage of the initial quiet period, the first weeks following the invasion while the body is preparing the immune response. The virus uses this time to reproduce and/or to be transmitted to another individual, before it is destroyed by the immune system. Therefore, for this kind of virus, rapid reproduction and maximal contagiousness are essential from the outset. "Acute" viruses are treated by shortening the time required for the immune response, for example by "alerting" the immune system in advance with a vaccine that provokes the needed antibodies.
The essential problem for lentiviruses, however, involves resisting immune system attacks from the organism in which it must live. This kind of virus does not need to be contagious to survive in the long-term. It only has to be transmitted before the death of its host. The virus's long-term survival is guaranteed when it is transmitted naturally through sexual contact or during childbirth, as is the case with HIV.
Lentiviruses represent a major challenge to immune response and render vaccination problematic.
Viral infection and immunity
There are two components to the body's immune response. The so-called "humoral" response primarily involves the production of antibodies (or immunoglobulins) which are capable of fixing themselves specifically to the invading microoorganism in the blood and lymph. The cellular response relies heavily on lethal white blood cells, called cytotoxic T lymphocytes, that destroy infected cells. Since lentiviruses spend a large part of their life cycle inside cells where antibodies cannot reach them, an organism infected by a lentivirus must depend on the second weapon in the immune response: the cellular response.
Cytotoxic T lymphocytes (commonly kown as "T-cells") can identify and destroy infected cells. But the organism pass a high price for this protection: in destroying the virus' ecosystem, the organism attacks its own cells. The situation is all the more dramatic because the virus sometimes escapes T-cell attack and the cells destroyed are a pure loss for the organism.
 |
| Viruses realted to HIV are found in numerous animal species. They are all derived from a single common ancestor, but do not necessarily produce diseases like AIDS. None of them except the primate varieties can infect humans. |
Features of immune response
The immune response is provoked when a foreign protein, known as an antigen, is detected in the organism. Response is highly specific: a killer lymphocyte is "programmed" for a certain antigen and cannot recognize the enemy if it changes shpae. Therefore, a virus which constantly modifies its proteins can escape the immune response.
This kind of high genetic variability is one of the essntial features of HIV. This variability results from errors during virus reproduction: the enzymes that copy viral genes sometimes do not produce exact copics. Each error, or mutation, results in a structural variation in the virus. For HIV, there is about one mutation per copy. Every HIV virus is thus unique and, even though all members of the viral population that cause AIDS are related, they are all different. Within these populations we can sometimes even find important differences in biological properties between viruses, particularly in regard to the kinds of cells they infect (cellular tropism), their toxicity (cytopathogenic effect), and the speed with which they replicate.
This diversity of properties within the viral population gives the virus an extensive adaptive capacity. At least one individual virus will always manage to survive any attack to the population as a whole, and it will be the forefather of future populations.
Rapid evolution of the virus
The evolutionary schema of HIV -mutation followed by natural selection- is unique in two ways. The first is the viral ecosystem, which in this case is the organism of the infected host, where the primary predator threatening the survival of the virus is the immune response. The second is the rapidity of viral evolution, due to the high percentage os errors during viral replication, as well as to the "solidarity" among individuals infecting any single cell.
The high rate of reproductive errors produces a large number of so-called "defective" individuals that can eventually threaten the viral population's vital functions. To deal with this risk, the virus can maintain its population at a sufficient level, while individuals infecting the same cell can exchange certain proteins and even genes.
All these mechanisms enable HIV to form extremely polymporphous populations always maintaining its vital functions, and to rely on this variability to survive in the highly selective environment of the organism.-8
Antiviral strategies
Given the rate of replication errors, there is a probability of about 10 per reproductive cycle that a virus can survive any attack which can be avoided through a single mutation. The most effective means for reducing this probability is to use vaccines and drugs to attack multiple viral targets so that a combination of mutations are required before a resistant generation of mutants can arise. The virus' probability of surviving is estimated at 10-6 per cycle when two mutations are required, at 10-15 for three, at 10-29 for four, and so on. Resistnace to AZT, the first antiviral drug used against HIV, requires two or three mutations, in other words a period of about six months.
It would be unreasonable to expect the antiviral drugs currently available to provide complete cures, but progress in handling and, above all, in combining these drugs should enable us to more effectively slow the infernal cycle that leads to AIDS.
Pierre Sonigo
Director of Research, CNRS
Cochin Institue of Molecular Genetics
No hay comentarios:
Publicar un comentario