THE FUTURE OF HIV TREATMENT
New discoveries of how HIV works continue to fuel research on devising ways to counter HIV. For example, scientists are testing drugs and vaccines that act to prevent HIV from replicating its genes, to inhibit assembly of virus proteins into new viruses, and to block the entry of HIV into immune system cells. While no one of these new treatments can cure AIDS, these new approaches offer the first real hope for individuals infected with HIV who have not developed AIDS.

COMBINATION DRUG THERAPY
A variety of drugs inhibit HIV in the test tube. There are two basic kinds. The most widely used are AZT and its analogs, which inhibit virus nucleic acid replication. A second basic kind of anti-HIV drug are so-called protease inhibitors, which inhibit the cleavage of the long protein chains encoded by HIV genes into functional segments. This chopping of long protein strands into segments is critical to multiplication of HIV, because the segments are key virus components: 1. the interior membrane, called a capsid, 2. reverse transcriptase, the enzyme which reads the virus genes, and 3. the envelope, or outer membrane.

When combinations of these two kinds of drugs were administered to people with HIV over the last year, their condition was markedly improved. A combination of a protease inhibitor and two AZT analog drugs entirely eliminated the HIV virus from many of the patients' bloodstreams. Importantly, all of these patients began to receive the drug therapy within three months of contracting the virus. Researchers believe that the earlier people receive treatment for HIV, the better chance they have at fighting AIDS. This is simply because the longer the virus is in the body, the more time it has to mutate to alternative drug-resistant forms.

We do not yet know if this combination therapy will actually succeed in eliminating HIV from the body. As researchers suspected, while the virus disappeared from the bloodstream, traces of it can still be detected in lymph tissue of the patients. Scientists hope that these copies of the virus are defective and unable to reproduce, and that as the study continues, the lymph cells with HIV will just die off.

USING A DEFECTIVE HIV GENE TO DEVELOP VACCINES AND DRUG THERAPY
Recently, five people in Australia who are HIV positive but have not developed AIDS in 14 years were found to have all received a blood transfusion from the same HIV positive person, who also has not developed AIDS. This led scientists to believe that the strain of virus transmitted to these people has some sort of genetic defect that prevents it from effectively disabling the human immune system. In subsequent research, a defect was found in one of the nine genes present in the AIDS virus. This gene is called nef, named for "negative factor," and the defective version of nef in the six Australians seems to be missing some pieces. Viruses with the defective gene do not reproduce as much, allowing the immune system to keep the virus in check.

This finding excites those developing a vaccine against AIDS. Before this, scientists have been unsuccessful in trying to produce a strain of AIDS that can elicit an effective immune response. The Australian strain with the defective nef gene has the potential to be used in a vaccine that would arm the immune system against this and other strains of HIV.

Another potential application of this discovery is its use in developing drugs that inhibit HIV proteins that speed virus replication. It seems that the protein produced from the nef gene is one of these critical HIV proteins, because viruses with defective forms of nef do not reproduce, as seen in the cases of the six Australians. Research is currently underway to develop a drug that targets the nef protein.

CHEMOKINES AND CAF
In the laboratory, chemicals called chemokines appear to inhibit HIV infection by binding to and blocking the CCR5 and CXCR4 coreceptors necessary for the virus to gain entry to the cell. As you might expect, people long infected with the HIV virus who have not developed the disease prove to have high levels of chemokines in their blood. The search for HIV-inhibiting chemokines is intense. Not all results are promising. Researchers report that in their tests, the levels of chemokines were not different between patients in which the disease was not progressing and those in which it was rapidly progressing. More promising, levels of another factor called CAF (CD8+ cell antiviral factor), are different between these two groups. Researchers have not yet succeeded in isolating CAF, which seems not to block receptors that HIV uses to gain entry to cells, but, instead, to prevent replication of the virus once it has infected the cells.

Research continues on the use of chemokines in treatments for HIV infection, either increasing the amount of chemokines or disabling the CCR5 receptor. However, promising research on CAF suggests that it may be an even better target for treatment and prevention of AIDS.

One problem with using chemokines as drugs is that they are also involved in the inflammatory response of the immune system. The function of chemokines is to attract white blood cells to areas of infection. Chemokines work beautifully in small amounts and in local areas, but chemokines in mass numbers can cause an inflammatory response that is worse than the original infection. Injections of chemokines may hinder the immune system's ability to respond to local chemokines, or they may even trigger an out-of-control inflammatory response. Thus, scientists caution that injection of chemokines could make patients more susceptible to infections, and they continue to research other methods of using chemokines to treat AIDS.

DISABLING HIV CORECEPTORS
Scientists have found that a mutation in the gene that codes for the HIV coreceptor CCR5, consisting of a 32-base pair deletion, appears to block or inhibit HIV infection. Individuals homozygous for the mutated gene allele who have been exposed to HIV or are at high risk of HIV infection have not developed AIDS. Furthermore, individuals heterozygous for the mutated allele may have some protection and may develop the disease more slowly. In one study of 1955 people, scientists found no individuals who were infected and homozygous for the mutated allele. The allele seems to be more common in Caucasian populations (10% to 11%) than in African American populations (2%), and absent in African and Asian populations.

Treatment for AIDS involving disruption of CCR5 looks promising, as research indicates that people live perfectly well without CCR5. Attempts to block or disable CCR5 are being sought in numerous laboratories.