Our understanding of Acquired Immune Deficiency Syndrome ( AIDS) and Human Immune Deficiency Virus ( HIV) has undergone rapid progress. Still, gaps in our understanding have prevented us from developing the ideal therapy or vaccine. Should we panic? The answer is no. Education has caused a decrease in the spread of AIDS in certain high-risk populations, and current therapies and vaccines add confidence that more effective treatments will be developed.
AIDS therapies have been difficult to develop for several reasons. Retroviruses, such as HIV, can integrate directly into the genetic material of the host cell. The virus can then go undetected for extended periods of time. HIV also infects a large variety of tissue and cells within the body. In particular, the virus can enter the nervous system where it is protected by the blood-brain barrier, which many helpful drugs cannot penetrate. Secondary diseases associated with AIDS, such as Kaposi's sarcoma, can lead to complications which are difficult to cure even without the virus.
Any therapeutic agent against an infection caused by a pathogen, including a bacteria, protozoan, fungus, or virus, must either kill the pathogen or stop it from multiplying, ideally without harming the infected host. It is difficult to develop such a drug against viruses because these organisms cannot replicate on their own. Simple packets of genetic material ( RNA in the case of HIV) surrounded by protein and lipid molecules, viruses infect cells and use the cell's genetic machinery to reproduce. It is difficult to distinguish between viral and host cell protein molecules. The host cell's intimate involvement in many stages of viral reproduction makes it challenging to find agents that selectively inhibit only viral protein. Harmful side effects and toxicity are also concerns.
Many scientists, including Wolfram Ostertag, Philip Furmanski (1946-), Joel Huberman, and Eric De Clerq, had studied drugs against mouse retroviruses before AIDS was discovered. In 1984, a team of researchers from the National Cancer Institute began to study these earlier experiments. Hiroaki Mitsuya and Samuel Broder (1945) began testing over 300 drugs to determine their effectiveness against HIV. A good drug should be able to interrupt the virus life cycle at any one of several stages. Strategies include blocking host cell's CD4 receptors, where HIV enters the cell. Other agents might render the virus noninfectious by preventing viral RNA and reverse transcriptase, an enzyme, from being released from their protein coat. Researchers found that one drug, azidothymidine or AZT, prevented reverse transcriptase from transcribing HIV into the host's DNA.
AZT, which is considered the "oldest" AIDS drug, does not cure or prevent AIDS, but it can slow down the disease--especially when used with other therapies that work in similar fashion, such as dideoxycytidine (ddC), dideoxyadenosine (ddA), and dideoxyinosine (ddI). AZT has also been used with other antiviral substances, including interferons, which have been effective in preventing the virus from assembling itself and budding out of the cell. The reduced budding means less virus infecting other cells and also helps keep the T cells, an important part of the immune system that protects against opportunistic infections, alive. Studies have shown that doctors and nurses treated immediately after accidental infection-on-the job with AZT dramatically reduce their risk of infection. It also has been effective in reducing the risk of HIV's transmittal from the mother during pregnancy, labor, and delivery.
There are currently many therapies at different phases of development and testing. One of the most potent therapeutic agents yet developed for HIV are the protease inhibitors. To complete its reproduction, HIV requires the use of a viral enzyme called protease, which is essential for viral particles to mature. Protease severs the parent viral protein into smaller segments, which are then reassembled into a mature and infectious viral particle. Protease inhibitors prevent this cleavage. As a result, viral particles produced in its presence are non-infectious. A number of protease inhibitors, which have been shown to be potent inhibitors of HIV strains resistant to AZT and other drugs, have been approved for clinical use. Studies have shown that HIV/AIDS patients taking protease inhibitors have increased CD4 cell counts and decreased viral load levels. Sensitive, reliable measurements of plasma viral load are a good predictor of the potential risk of AIDS development, time of death, and the antiviral action of drugs.Dextran sulfate and soluble CD4 are drugs that stop the virus from attaching to the host cell. Dextran sulfate studies in patients have included anecdotal reports of patient improvement and in elevated T-helper cells. Soluble CD4 is a genetically engineered form of CD4 that appears to block entry of HIV-1 into CD4-bearing cells. Soluble CD4's antiviral activity has been demonstrated in the test tube, but preliminary studies in patients have yet produce the same anti-viral results.
Other drugs, including ddC, ddA, ddI, Phosphonoformate, Rifabutin, and BI-RG-587, inhibit reverse transcriptase, which prevents viral DNA synthesis and stops the virus from replicating or reproducing. Ampligen is another therapeutic drug, which interferes with viral replication and is classified as an "interferon inducer." Clinical trials indicate that it may increase long-term survival in HIV patients. Finally, Ribaviran and Castanospermine show some activity in preventing HIV replication.
Although the prognosis for treatment was once grim, a new understanding of the life cycle of HIV makes it possible to design drugs that aim at specific targets. Investigators are currently developing a variety of agents to attack HIV at several different points simultaneously.
Therapies are mainly used by those people already infected with the virus. A cure or vaccine to prevent the disease, though, is the ultimate goal. Vaccination is the simplest, safest, and most effective way to prevent infectious disease. Since 1796, when Edward Jenner found that cowpox virus could serve as a smallpox vaccine, scientists have had great success against viruses. Jenner's discovery showed that the entire disease-causing organism need not be present to rally the immune system 's defenses. Only certain character parts (antigens) were needed to trigger the body to develop antibodies against the disease. Vaccines are simply used to exploit the body's ability to "remember" an antigen.
In the case of HIV, the virus's ability to hide in host cells and even change the composition of its coat makes it difficult for the body 's antibodies to find the virus and attack it. Furthermore, HIV infects the same T cell and B cells that a good vaccine must activate. Finally, the HIV virus mutates or changes its genetic composition very rapidly. This is the same reason that a vaccine to cure the common cold virus has not been developed.
Vaccine research encompasses several different strategies, including examining the proteins that coat the HIV virus in an attempt to find an approach that would help the body recognize and attack the HIV virus. Other priorities include developing genetically engineered animals for vaccine tests, developing new methods for analyzing HIV's structure, and gaining an in depth understanding of the body's immune response.Subunit vaccines are made by combining a piece of HIV with other carrier molecules or by inserting a gene for an HIV protein among the genes of another harmless virus such as adenovirus. Alan Gold and his colleagues at the George Washington School of Medicine and Health Sciences were among the first to design a subunit vaccine based on an internal part of the virus rather than on an outside part of envelope antigen. The trick is to give the body a piece of the virus so that it can recognize and produce antibodies against the infectious whole virus if the body is infected. Daniel Zagury of the University of Paris was the first to test an AIDS vaccine on humans, including himself. Lawrence Corey of the University of Washington has conducted clinical trials of a prime-boost vaccine using subunit vaccines with a canarypox primer. Preliminary results have shown that the vaccine produces both cell- mediated and humoral responses in a majority of HIV-negative volunteers.
Anti-idiotype vaccines are made of antibodies carrying the internal image of the CD4 receptor. This is supposed to activate another set of antibodies that look like the host CD4 receptor and thus compete with it for binding to the HIV. Angus Dalgleish and Ronald Kennedy are using this approach. They believe that the anti-idiotype antibodies could act as a type of decoy and tie up free virus particles in the blood. This vaccine has been shown to slow the progress of HIV infection.
A third group of vaccines uses killed or weakened HIV to cause the body to produce antibodies. This is a risky approach because the recipient of the vaccine may develop AIDS if all the HIV is not killed prior to vaccination. For this reason killed or attenuated vaccines have only been tested on people who have already been exposed to HIV, even though groups of AIDS doctors have volunteered as human guinea pigs for AIDS vaccine research.Jonas Salk, the inventor of the first polio vaccine, which was an attenuated vaccine, led colleagues at the Salk Institute for Biological Studies on this type of vaccine.
Because of its close resemblance to the intact virus, a live, attenuated virus vaccine provides better immune protection against disease than other types of vaccines that may be made from only a piece of the virus. Studies in monkeys infected with the simian immunodeficiency virus (SIV), which is similar to HIV, have led to the development of attenuated SIV vaccines. This step has served as a model for scientists trying to develop an HIV/AIDS vaccine.A major problem in developing HIV vaccines is to find a vaccine that will work against the multiple strains of the virus, some of which are more predominate in different parts of the world than others. The ultimate goal is to develop a vaccine that elicits immune responses to a variety of HIV strains. Investigators at the University of Pennsylvania have developed a vaccine that has made chimpanzees resistant to HIV infection. The vaccine, which is based on "naked" DNA encoding of HIV genes, enables the body to make viral proteins that are harmless. As a result, the immune system becomes sensitized to them, which may help prevent subsequent infection by the HIV virus. Scientists are also looking into AIDS-resistance genes, which may provide new avenues of research for developing vaccines and other therapies.
When Jonas Salk developed the polio vaccine, church bells rang and front page news heralded the triumph. Many scientists currently believe a similar scenario is possible for HIV/AIDS. However, prevention remains the best medicine. Primarily spread through sexual contact and unclean needles used by drug abusers, current prevention strategies involve education about safe sex practices and drug abuse.
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