In the 1980’s diagnosis with HIV was a death sentence. In 1995 in the USA, it was the highest cause of death in the age range 25-44 years. Nowadays HIV is a life sentence, but a relatively painless one. Anti-retroviral therapy (ART) has ensured that the virus is kept locked away in the host DNA, never to be seen more in most cases.
From no treatment available in 1983 to more than 40 retroviral inhibitors in 2015, with more in the works, scientists are staying one step ahead of emerging resistance. The death toll from HIV continues to plummet. Anti-retrovirals consist of a wide range of drugs that target different stages of the virus lifecycle.
Stage 1: Invasion
Maraviroc binds to the host cell receptor that the HIV virus binds to before working its way into the cell. It is not a common treatment. The binding of Maraviroc to the cell can open up a secondary binding site, allowing the HIV to attach regardless. The drug also has liver toxicity issues. It has however been approved by the FDA for human use and is a fallback when other drugs prove ineffective.
Enfuvirtide acts on the virus rather than the host cell, binding to the gp41 protein that HIV uses to attaches to the cell, inactivating it and stopping invasion of the cell before it starts. As with Maraviroc, it is used as a ‘salvage therapy’ rather than the first port of call due to its high cost and the fact it can only be administered as an injection.
Stage 2: Transcription
HIV is a retrovirus, which means that the virus genome is made of RNA rather than DNA. In order to replicate it needs to transcribe the RNA code into the DNA used by mammalian cells for genomic content. Mammalian cells only transcribe DNA to RNA, not the other way around. The protein needed to transform the RNA into DNA has to be provided by the virus. It makes a good place for scientist to target as the fact that it is not a protein seen in humans reduces the risk of side-effects.
The Nucleoside (or Nucleotide) analogue reverse transcriptase inhibitors (NRTI). NRTIs are specialised nucleosides, the building blocks of DNA, lacking the essential hydroxy group on its 3’ end. Lack of this group prevents it from binding to another nucleoside and stops the construct of the DNA strand cold. Without this DNA strand the virus is unable to trick the host cell into replicating viral the viral genome. The NRTIs are the most effective anti-retroviral therapies and include some of the oldest anti-retroviral among their number. Examples include zidovudine (ZDV), abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), and tenofovir (TDF).
Non-nucleoside analogue reverse transcriptase inhibitors (NNRTI). NNTRIs are drugs that target the viral reverse transcriptase directly rather than targeting the process. By binding the viral protein near the active site they change the structure of the active site, so it cannot bind nucleosides and catalyse the formation of DNA from the RNA viral genome. Examples include nevirapine (NVP), efavirenz (EFV), etravirine (ETR) and rilpivirine (RPV).
The virus is not able to change the building blocks of DNA so resistance to NRTIs is uncommon, however, it can change the structure of the reverse transcriptase protein. HIV-2 is naturally resistant to NNRTIs.
Stage 3: Integration
A viral infection that destroys all the cells it is able to infect does not have a long lifespan. To ensure it lives to fight another day, the virus does not destroy all the T-cells in invades. In some instead of taking over the cellular machinery to make thousands of copies with the transcribed DNA, it inserts its own DNA into the host cell genome using a viral protein known as an integrase.
In 2007, the drug raltegravir (RAL) was approved by the FDA. Raltegravir binds in preference to the native substrate, i.e. if there is any raltegravir nearby the integrase will select that before the host genome it is meant to target. In this way, it uses up all the integrase before the virus can insert into the genome. In 2014 two more integrases inhibitors were approved for use, elvitegravir (EVG) and doultegravir (DTG).
Stage 4: Virus production
Once the viral DNA has been transcribed and integrated the virus needs to then make more copies of itself. It does this by tricking the host cell to replicate the viral RNA genome and proteins in preference to its own functions, killing the cell in the process. The viral proteins are made as one long peptide (protein) chain called the gag/pol precursor and this is cut up by a viral protease (enzyme that cuts proteins) to separate the individual proteins into their active form.
The protease inhibitor antiretroviral drugs target this stage of the virus lifecycle, preventing the protease activity and activation of viral proteins. Protease inhibitors include lopinavir (LPV), indinavir (IDV), nelfinavir (NFV), amprenavir (APV) and ritonavir (RTV). Due to high mutation rates of the viral genome and high tolerance for mutation in the viral protease, this category of drugs suffers the most from emerging resistance.
The drugs are used as combinations to target multiple stages in the viral cycle and reduce the incidence of resistance. They are used in combination to target the virus at all stages of infection, commonly 2 NRTIs in combination with either a NNRTI, a protease inhibitor or an integrase inhibitor.
Different combinations are preferred for different situations. One of the earliest NRTIs Zidovudine (first approved 1989) has been shown to be incredibly effective in reducing the viral load in pregnant women to prevent transmission to the baby during birth. Use of Zidovudine has reduced transmission of HIV to the baby during birth from 30% of cases down to 2%.
The pre-exposure prophylaxis (PrEP), taken by those at high risk of encountering HIV is a combination of tenofovir and emtricitabine marketed as a one dose combination therapy under the name of Truvada® by Gilead Sciences. This drug has been shown to be safe for people ages 12 years and older and in various studies have shown that a daily dose reduces the risk of contracting HIV by up to 75% in high-risk individuals. Truvada is also recommended for post-exposure prophylaxis (PEP) though this can vary depending on doctor, socio-economic considerations and regional resistance, other combination therapies can be equally effective.
The first one dose combination therapy was developed by GlaxoSmithKline in 2007. Called Combivir® it contained a combination of lamivudine (3TC) + zidovudine (ZDV). As of February this year, eleven other single dose combination therapies had become available. This may seem a small breakthrough but it increases the likelihood that people will continue to take their medications and stay virus free, reducing the costs to the healthcare system, increasing peoples work life and reducing the risk of spreading via sexual contact. These miracle pills did what antibiotics did in the 1950’s, turned a killer into a mere inconvenience. With ongoing research this inconvenience lessens each year and with the blessing of hindsight we know how to reduce the threat of resistance. With good management, extensive education and ongoing research, AIDS may one day join smallpox and polio as a disease of interest only to historians.