November 28, 2002. Copyright 2002. Graphic News. All rights reserved.

New weapons in war against HIV

LONDON, November 28, Graphic News: Since AIDS (Acquired Immunodeficiency Syndrome) appeared two decades ago, the virus that causes the disease has claimed the lives of nearly 22 million men, women and children and invaded the bloodstreams of 42 million more.

Early in the epidemic, researchers pinpointed a virus -- Human Immunodeficiency Virus (HIV) -- as the cause of AIDS, but the intimate relationship that viruses form with a host cell made them impossible to eradicate through traditional drug therapies. 

The AIDS epidemic pushed researchers to develop new approaches to the virus problem. In 1987 there was just one product, Glaxo WellcomeÕs AZT (azidothymidine), to fight the HIV virus -- and it didnÕt work very well. Subsequently a cocktail of AZT with a new drug, 3TC (lamivudine) was found to reduce the amount of virus in the blood. These drugs, both in a class called Ònucleoside reverse transcriptase inhibitorsÓ (NRTIs), blocked reverse transcriptase, one of the three enzymes HIV requires for replication. This multidrug cocktail, introduced in 1996, was the first Òhighly active antiretroviral treatment,Ó also known as HAART.

Initially NSTIs were one of three classes of drugs -- the others being Òprotease inhibitorsÓ (PIs) and Ònon-nucleoside reverse transcriptase inhibitorsÓ (NNRTIs) -- that were a landmark in the fight against viral diseases.

PIs shut down viral replication by preventing a second viral enzyme, protease, from cutting viral proteins into shorter pieces needed by HIV to make new copies of itself, and NNRTIs work by blocking reverse transcriptase directly. But the virus is a constantly moving target, mutating and developing resistance to antiviral drugs.

ÒAIDS has had a remarkable impact on medicine in ways that never could have been anticipated,Ó said Dr. Mark Feinberg, of Emory University Vaccine Research Centre in Decatur, Georgia, United States. Currently, Dr. Feinberg is conducting Phase I clinical trials on an HIV-1 DNA vaccine.

ÒItÕs not just that we came up with new drugs. ItÕs much more profound than that. WeÕve been pushed to learn and be creative because of the AIDS epidemic. ItÕs led to changes in the way we think about treating infectious diseases, auto-immune diseases and malignancies in general.Ó

Scientists are now making discoveries that could lead to several novel advanced therapies seen as vital because, as the AIDS pandemic enters its third decade, viral resistance is countering the success of HAART.

Five additional arrows have been added to the scientistsÕ quiver: Fusion inhibitors, nucleotide analogues, integrase inhibitors, so-called Òzinc fingerÓ inhibitors and antisense drugs.

Fusion inhibitors -- the most advanced of which are T-20 and T-1249, made by Trimeris Inc in partnership with Roche, and now in Phase III testing -- prevent the virus from attaching to a new cell and breaking through the cell membrane.

Nucleotide analogues, like Gilead Sciences IncÕs Tenofovir, also block the reverse transcriptase enzyme. Integrase inhibitors tackle the third enzyme, integrase, which inserts the double-stranded DNA copy of the RNA genome into the chromosomes of an infected cell. Once there the hijacked cell becomes a factory churning out multiple copies of HIV. One integrase inhibitor, Shionogi and Glaxo WellcomeÕs S-1360, is currently in Phase II trials.

The inner core of HIV, called the nucleocapsid, contains so-called Òzinc fingers,Ó chains of amino acids which package HIV genetic material into newly budding virions, or new HIV viruses. One zinc finger inhibitor -- azodicarbonamide (ADA) -- has been tested in a Phase I/II trial.

Finally, antisense drugs which mirror part of the HIV genetic code can lock onto the virus to prevent it from functioning. One antisense drug, HGTV43 by Enzo Therapeutics, is currently starting Phase II trials.
/ENDS

Sources: Journal of the American Medical Association, New Mexico AIDS Education and Training Center