By Ben Burwitz, Ph.D., PQ Monthly
Antiretroviral drugs are currently our front, and last, line of defense against HIV. Many patients with HIV take antiretroviral drugs, but may not understand the mechanisms by which these drugs suppress HIV replication. This article discusses the different classes of antiretroviral drugs and how they work to maintain the health of HIV patients. However, before we go into the drugs, a quick review of the human cell:
1) Deoxyribonucleic acid (DNA) is the genetic code for all cell proteins. DNA is found in the nucleus, segregated from the rest of the cell where protein construction occurs.
2) Ribonucleic acid (RNA) is an intermediate molecule between DNA and protein. Because DNA is segregated in the nucleus, RNA molecules are built off the DNA template and exported out of the nucleus, where they themselves provide a template for protein building.
3) Proteins are the building blocks of the cell. They perform nearly all of the tasks required for life including cellular replication and signaling. Proteins are also the building blocks of viruses, such as HIV.
All viruses, including HIV, must hijack host cells in order to replicate. HIV achieves entry into the host cell by first recognizing two specific proteins on the cell surface called CD4 and CCR5. Once HIV binds to these proteins it fuses to the cell membrane and injects its viral genome into the cell. Fusion inhibitors block this first step in the HIV life cycle by preventing HIV recognition of CCR5 or by inhibiting HIV fusion with the cell.
Examples: Selzentry, Fuzeon
Reverse Transcriptase Inhibitors
HIV belongs to a family of viruses termed retroviruses. All retroviruses must insert their own genome into the host genome in order to replicate. The HIV genome is RNA, which is unable to insert into the DNA genome of the host. Therefore, HIV must transform its genome from RNA into DNA once inside the host cell. This is performed by a viral protein named reverse transcriptase, which enters the newly infected cell along with the viral genome. Reverse transcriptase inhibitors work by inhibiting the function of reverse transcriptase directly, or by causing the production of faulty HIV DNA genomes that are unable to insert into the host genome.
Examples: Atripla, Truvada, Combivir, Trizivir, Retrovir
Once the HIV genome is successfully transformed from RNA to DNA, it is ready to insert into the host genome. In order for this to occur, the HIV genome must be guided into the nucleus where a viral protein named integrase facilitates its insertion into the host genome. Integrase inhibitors do exactly what their name implies. They disrupt the function of integrase and prevent insertion of the HIV genome into the host genome.
Examples: Isentress, EVG
The HIV genome encodes for all of the proteins necessary to construct new viruses. Once inserted in the host genome, the same rules described above for protein synthesis apply. The newly formed HIV proteins, however, must be cut by the viral protein protease in order to take the correct structure for virus assembly. Protease inhibitors block this last step of protein processing and prevent the proper assembly of infectious viruses.
Examples: Prezista, Reyataz, Lexiva/Telzir
These four drug classes each target a different step in the HIV life cycle. The first antiretroviral drug was the reverse transcriptase inhibitor Retrovir, which was approved by the FDA in 1987. In the early days of antiretroviral therapy, doctors had limited options in the number of drugs available to them. In fact, until 1995 only reverse transcriptase inhibitors were available. Subsequently, in many patients the replication of HIV was not completely suppressed. The side effects of these drugs also prevented some patients from adhering to the strict regimens required for full HIV suppression. In combination, these problems led to strains of HIV resistant to antiretroviral drugs. As more and more antiretroviral drugs became available, it was found that combinations of drugs could more fully suppress HIV replication and prevent the formation of drug-resistant HIV strains. This was termed Highly Active Antiretroviral Therapy (HAART). Today there are a number of HAART regimens available to patients, each of which comprises a different combination of antiretroviral drugs.
The concept of drug-resistance is important because it has ramifications at the population level. HIV drug-resistance can be compared to bacterial resistance against penicillin. Due to the prevalent use of penicillin following its discovery, many bacterial strains have become resistant, leading to the discovery of other antibiotics, such as ampicillin. In the same way, drug-resistant strains of HIV have expanded within the population and have been the driving force behind the antiretroviral pharmaceutical pipeline. In the end, drug manufacturers are in a biological arms race with a rapidly adapting HIV.
Antiretroviral drugs do more than suppress HIV replication. Patients on HAART also show improvements in immune system function and are therefore less likely to succumb to secondary infections. Additionally, the life span of HIV patients has improved drastically as the success of HAART has improved. In fact, a 20-year old infected with HIV today can expect to live to an average age of 69, assuming proper adherence to their HAART regimen . These life expectancies will continue to rise as more HIV therapies are discovered and employed. However, it is important to note that HAART cannot cure patients with HIV. This is why the search for an HIV vaccine remains a top global health priority. For now, we must continue fighting HIV with all our HAART.
Ben Burwitz is an HIV researcher at Oregon Health and Science University. He received his Bachelors of Science in molecular biology in 2004 and his Doctor of Philosophy in cellular and molecular pathology in 2010, both from the University of Wisconsin.