Chemotherapy

HIV Vaccines

An important consideration for vaccine development is the factthat the immune system has not shown much capability in copingwith natural infections. In some 60 million HIV infectionsworldwide, there is not a single known case in which theimmune system has eradicated the virus. Obstacles to developinga vaccine for HIV are formidable, and the landscape is nowlittered with unsuccessful vaccine trials. The rapid mutation rate of HIV makes it difficult to develop a vaccine that is effectiveagainst all mutational variants of the virus that appear duringthe course of an infection. Furthermore, the virus hasdeveloped clades that differ substantially from one geographicarea to another, and each would probably require an appropriatevaccine.

Ideally, a vaccine would produce antibodies that would preventinfection. The virus resists antibodybinding until a last-second exposure just before attachment andentry into the host cell. For persons already infected, a successfulcell-mediated-type vaccine would be necessary to control the progressionof the disease. To be considered successful, however, thevaccine would have to stimulate the production of CTLs that aremore effective than those produced in response to a natural infection.Cells infected by HIV, it happens, are not very susceptible toattack by CTLs. There is also the problem of a persistent, butimmunologically invisible, viral population in the form ofproviruses and latent viruses. Finally, a vaccinewould have to be affordable in regions of the world where economicsubsistence is often marginal. All in all, the development ofan HIV vaccine is a formidable task. Some experts believe that noHIV vaccine is possible that will confer nearly complete protection,such as those for smallpox or measles. It is thought that amore practical goal may be to develop a vaccine with more modestgoals than "sterilizing immunity." Perhaps a vaccine would

stimulate cell-mediated immunity in already infected persons and help the patient's existing immune system to clear the virus.

Much progress has been made in using chemotherapy to inhibitHIV infections. The first target of anti-HIV drugswas the enzyme reverse transcriptase, an enzyme notpresent in human cells. These nucleoside reverse transcriptaseinhibitors are analogs of nucleosides and cause the termination ofthe synthesis of viral DNA by competitive inhibition.There are other drugs that inhibit reverse transcription but

are not analogs of nucleic acids; these are the so-called non-nucleoside reverse transcriptase inhibitors.

To reproduce, the virus makes use of certain protease enzymes that cut proteins into pieces, which are then reassembled into the coat of new HIV particles. Drugs called protease inhibitors inhibit this enzyme and are now in use.

For infection to take place, the virus must accomplish a series of steps. It must attach to the cell's CD4 receptors, an interplay between the gp120 spike on the virus and the coreceptor must occur, and finally there must be a fusion with the cell to allow viral entry into the cell. One of the newer anti-HIV drugs, grouped as fusion inhibitors, targets the gp41 region of the viral envelope.

After fusion has been completed, reverse transcription produces a double-stranded cDNA version of HIV, which enters the nucleus. Within the nucleus, the complex containing the cDNA must be integrated into the host chromosome to form the HIV provirus. This step requires an enzyme, HIV integrase, which is a target for drugs called integrase inhibitors. Several other points of attack for anti-HIV drugs exist, and drugs such as maturation inhibitors, targeted at these are under investigation or are in clinical trials.

Because of the increasing number of drugs that control reproduction of the virus, at least temporarily, HIV infection is almost at the stage where it can be considered a treatable chronic disease-assuming that the treatment is affordable. The rapid reproductive rate and frequent occurrence of drugresistant mutations dictates that multiple drugs, given simultaneously, must be used. The current treatment is termed highly active antiretroviral therapy (HAART). This therapy consists of administering drug combinations; one of the most common combinations is two nucleoside analog reverse transcriptase inhibitors plus either a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor. Patients are often required to take as many as 40 pills a day on a complex schedule, which must be adhered to rigorously because the virus is unforgiving. Even so, resistant strains of the virus are likely to emerge. As one scientist put it, drug resistance in HIV is driven by selective pressures that Darwin never imagined. Experience has also shown that eliminating all viruses in latent form in lymphoid tissue is especially difficult. The number of HIVs in circulation is often reduced to fewer than can be detected, but this is not the same as eradication. A caution is that a patient with a viral load at an undetectable level might still be infective. Frequent testing for viruses is required to follow effectiveness of the treatment. Arise in numbers probably indicates development of a resistant population.

One clearly successful application of chemotherapy has been to reduce the chance of HIV transmission from an infected mother to her newborn. The administration of even one nucleoside reverse transcriptase drug alone reduces the

incidence.

Дата добавления: 2014-01-11