LEARNING THE SECRETS OF THE HIV VIRUS
The secrets of the AIDS virus, HIV (for Human Immunodeficiency Virus), like many advances in science, have been revealed by painstaking and laborious analysis of mountains of data. One of the first tasks confronting AIDS researchers was to gain a better picture of our viral foe by learning the full nucleotide sequence of HIV's genes. About 9000 nucleotides long, the HIV virus has nine genes. Three of the genes (called gag, pol, and env) encode the protein parts of the virus, as well as other proteins necessary to replicate its genes within a human cell. The other six HIV genes are much smaller than these three, and seem to have regulatory functions, controlling when and how the three principle genes are used.

The Achilles heel of the HIV virus became evident when researchers began to examine more carefully the proteins produced by gag, pol, and env. It turns out, and this proves to be a key point of vulnerability, that each of these three gene encodes not one, but several proteins. The product of each gene, called a polyprotein, is first manufactured in the cell as a single very long protein chain. Then a special enzyme called a protease cleaves the polyprotein into specific fragments, each of which carries out a particular roles in assembling the complete HIV virus.

gag The gag polyprotein is cleaved into four capsid proteins. At the core of the virus are two small capsid proteins, p7 and p9, associated with two copies of the HIV genome. Surrounding this is an inner core of capsid protein p24, and an outer core of capsid protein p17.

pol The pol polyprotein is cleaved into three enzyme proteins. Buried in the virus core with the virus genes is the enzyme reverse transcriptase which replicates the genes. The pol gene also encodes an integrase enzyme that allows HIV to enter and leave human chromosomes, and a protease enzyme that cleaves the polyprotein products of gag, pol, and env into functional segments.

env The env polyprotein is cleaved into two envelope proteins. The outer covering of the virus, its envelope, is acquired from the host cell as the virus buds out. Anchored to this outer envelope are the two virus envelope proteins, gp41 and gp120.

POINTS OF ATTACK
The structure of the AIDS virus is thus a protein-wrapped package, with layers of protein surrounding the core of genes like the wrapping of a golf ball. The details of the structure of HIV suggest two likely avenues of attack, two approaches that might produce a successful anti-HIV therapy.

The most obvious approach, first tried more than a decade ago, is to try to prevent the HIV virus from replicating, using drugs such as AZT that mimic the subunits of DNA but gum up the molecule. The HIV reverse transcriptase enzyme is fooled by these mimics, inserting them into the genes it is replicating. The gene molecule that results cannot function, its structure poisoned by the mimic elements inserted into it.

A second approach, only apparent after the polyprotein organization of HIV became known, is to try to prevent the HIV virus from cleaving its three polyproteins into functional segments, using protease inhibitors that prevent this cleavage. The HIV protease is blocked by these protease inhibitors, so that it never cuts the polygenes into useful pieces. As a result, there are no capsid, envelope, and other HIV proteins available to assemble into new viruses.

COMBINATION DRUG THERAPY
Administered alone, no one drug seems to do the job. The initial effects are beneficial, but resistant viruses soon arise, so the benefit is short-lived. The key insight that has led to a more successful therapy was the realization that few cells will become resistant to two drugs simultaneously, and no one cell can become simultaneously resistant to three! In just the same way, it is very unlikely (but possible) that you will win the lottery, and also very unlikely (but possible) that you will be struck by lightning -- but the chances that you will be struck by lightning on the day you win the lottery are vanishingly small. By combining three drug therapies, each effective in its own right, the likelihood that any one virus will become resistant to all three is similarly vanishingly small.

The drugs selected for combination therapy were two AZT analogs and a protease inhibitor. Mixtures of these three drugs have been administered to people known to be infected with HIV over the last two years. From the outset, the treatment has seemed to be very effective. The 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.

INITIAL SUCCESS
With the widespread use of combination therapy in the last two years, AIDS deaths have plummeted. In New York City AIDS deaths have fallen fully 48 percent last year. The New York figures are particularly encouraging, as New York has been a center of HIV infection from the outset of the epidemic. Although it has only 3% of the United States population, it has 16% of the AIDS cases. Of the more than 100,000 New Yorkers who have been diagnosed with AIDS, more than 66,000 have died. Any treatment that halves this staggering death rate in New York City is a great success in the battle against AIDS, and preliminary national figures seem to show a similar sharp decline.

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 of