By Barry C. Fox, M.D., University of Wisconsin
No safe and effective cure for HIV currently exists, but scientists are working hard to find one, and remain hopeful. There are various kinds of drugs that have been used and are still being used to try treat HIV and AIDS. Let us take a look at what these drugs are and how they work.
The HIV virus is a retrovirus. This means its genetic material is RNA instead of DNA. Once the virus enters a CD4 cell—a type of immune cell in our bodies—it uses an enzyme called reverse transcriptase to implant its RNA genetic code into the DNA of the CD4 cell. It also encodes for the production of HIV RNA, which is used to create daughter viruses from the very DNA that it just disrupted. The HIV virus also tricks the invaded cell into using its own DNA to signal the production of proteins and enzymes that are essential for the HIV virus survival.
Also, by implanting its RNA in the DNA of the CD4 cell, it’s also able to pass along this genetic blueprint material to newly dividing CD4 cells. By the way, the virulence potential of HIV-1 is illustrated by its incredibly rapid genetic change in a short period of time. It evolves one million times faster than the DNA of mammals.
This is a transcript from the video series An Introduction to Infectious Diseases. Watch it now, on Wondrium.
AZT for HIV Treatment
What progress have we made toward managing this terrible disease? The first drug breakthrough came when Jerome Horwitz, a scientist studying cancer, developed Zidovudine, also known as AZT. In 1964, it was originally designed to be used as a cancer drug, but it was a failure. Twenty-five years later it was surprisingly found by other scientists to have anti-retroviral activity, and it became the first ART medicine. This was the first treatment to give hope to HIV patients.
The earliest nationally sponsored drug trials for HIV was in the 1980s, where AZT was compared to placebo. Patients had to set their watches for the middle of the night to take their medication every four hours. While AZT was found to be effective, it only made a small dent in the viral load in the blood. AZT reduced the viral load by one logarithm, for example, from one million down to 100,000 virus particles. Also, when used alone, resistance rapidly developed. Also, AZT was not without several significant side effects, especially nausea.
However, due to the crisis state of the HIV and AIDS pandemic, and for humanistic reasons, this drug was approved within 20 months, rather than the usual 8 to 10 years.
Learn more about the life cycle of a virus.
There are six classes of ART drugs currently in use, matching six targets in the HIV virus replication cycle. At the beginning of the virus replication, HIV must enter the host cell.
Entry inhibitors and fusion inhibitors act to block this attachment and movement into the cell. A receptor on the cell membrane known as CCR5 is crucial for HIV viral attachment. Virus RNA is guided into the host DNA by an enzyme known as integrase. Integrase inhibitors are another weapon for restricting viral replication.
NRTI and NNRTI Drugs
The drug classes known as NRTI and NNRTI focus their attention on the most important enzyme in RNA and DNA synthesis, reverse transcriptase. NRTI stands for nucleoside reverse-transcriptase inhibitors, and are the oldest therapies, and include AZT. They are nucleoside analogs, or building blocks of DNA.
But they lack an oxygen and hydrogen atom at the core sugar structure, so once they are incorporated into replicated viral DNA, the reversed transcriptase enzyme is forced to terminate the addition of more amino acids, and halts protein and enzyme synthesis.
Another class of ART, known as NNRTI, also inhibits the reverse transcriptase enzyme, but it accomplishes this task by physically putting themselves in the pathway of the enzyme in order to block DNA synthesis.
Another drug class is known as the protease inhibitors, and they act by binding to HIV protease. This enzyme is responsible for allowing the virus to exit the host cell. This leads to the inability of HIV virus to exit.
By combining drugs of different classes, we’re able to suppress viral replication at different points in the HIV life cycle. For example, combining nucleoside analogs with different drugs that mimic DNA structure increases the chances of the blockade of viral reverse transcriptase. A combination of at least three ART medications at one time is the current standard of care.
Learn more about the dynamic world of infectious diseases.
Revising ART Regimens
The recommended first and second line ART regimens undergo revision nearly every 6 months and need to be published online due to the rapid changes in the ART science. The goal of combination therapy is a 3- to 5-fold logarithmic reduction in the viral load of the blood, attempting to drive the viral burden down to under 100, and even to undetectable levels. However, the virus is still present in the body in lymph nodes and other sites known as hidden sanctuaries.
Since there are between one and 10 billion HIV viruses replicating daily, there is a large and rapid turnover of genetic material, and hence a high probability for the potential of drug-resistant mutant viruses to emerge. HIV reverse transcriptase also has a high error rate in its reading of its genetic code, so this enhances the potential for mutations and for drug resistance.
Mutations and Drug Development
Finally, if patients are not adherent to taking all the doses of their medications, this can result in sub-therapeutic drug levels, which greatly increases the risk of drug mutations. In fact, the odds of being infected with an HIV virus without mutations that encode for drug-resistant is becoming increasingly rare.
You should be aware that sometimes mutant HIV virus is not necessarily more virulent. In fact, the mutant virus can be weak enough that it will not have a long-term survival advantage, and hence becomes clinically insignificant. The capacity for rapid mutations re-enforces the need for continued aggressive pharmaceutical development in the field.
Common Questions about HIV Treatment and Anti-Retroviral Therapy
HIV uses an enzyme called reverse transcriptase to implant its RNA genetic code into the DNA of the CD4 cell. It also encodes for the production of HIV RNA, which is used to create more viruses. The virus also tricks the invaded cell into using its own DNA to signal the production of proteins and enzymes that are essential for the survival of the virus.
In 1964, AZT was a failed a cancer drug. Twenty-five years later it was surprisingly found by other scientists to have anti-retroviral activity, and it became the first ART medicine to be used for treating HIV.
There are six classes of ART drugs currently in use, matching six targets in the HIV virus replication cycle.