Learning how the virus grows and develops has been crucial to developing medicines that control HIV infection. This knowledge has enabled drug discovery researchers to devise ways to interfere with the virus at critical points in its life, preventing it from infecting more of the patient’s white blood cells.
The resulting drugs—often referred to as highly active antiretroviral therapies (HAART)—manage AIDS well. Unfortunately, they don’t completely eliminate the virus that causes it. In other words, they’re not a cure. In addition, HIV’s high mutation rate means it rapidly evolves resistance to drugs that once kept symptoms at bay. For this reason, HAART typically combines different drugs, which is the “cocktail” approach. This strategy takes advantage of the fact that viruses are unlikely to develop resistance to multiple drugs simultaneously. Researchers continue working on new drugs that can fight infection when resistance emerges.
Let’s look at how some current HIV medications interrupt key stages of the viral lifecycle.
ONE VIRUS, MANY DRUGS
Existing HIV drugs work to prevent T-cell infection, viral replication, or the assembly and release of new viral particles. Examples of these strategies include:
Preventing infection: HIV wipes out the immune system because it infects a critical type of white blood cell, helper T-cells. To gain entry to the T-cells, HIV binds a protein called CCR5 on the surface of those cells. Drugs that interfere with that interaction can prevent infection and are called CCR5 inhibitors. Currently, there is only one CCR5 inhibitor on the market—Maraviroc (Pfizer, New York), a small molecule drug. CytoDyn (Vancouver, WA) has a monoclonal antibody inhibitor of CCR5, leronlimab (PRO 140), which has successfully completed Phase III clinical development.
- Another way to prevent infection is to block the HIV surface protein, GP120, from binding to the CCR5 receptor. GlaxoSmithKline ViiV Healthcare (North Carolina, US) has developed Fostemsavir, which FDA approved in July 2020. It is a small molecule that targets GP120, the portion of the viral surface protein that enables HIV to bind to and enter T-cells. Its developers believe that the bit of GP120 that Fostemsavir targets mutate slowly, perhaps reducing the chances that resistant strains of the virus will emerge. Peptide therapeutics also work on GP120. Roche’s Fuzeon interferes with the ability of a portion of GP120 to fuse with the T-cell membrane.
- Blocking viral replication: As described earlier, two steps are critical for viral replication: conversion of the viral RNA genome into DNA by the viral enzyme reverse transcriptase(RT) and insertion of this DNA into the host cell genome by the viral enzyme integrase. The first antiviral drug approved by the FDA for the treatment of HIV in 1987, AZT, inhibited RT. Since then, many others have been approved, including Viread and Emtriva, both marketed by Gilead Sciences (Foster City, CA). Click here for a complete list of RT inhibitors.
Integrase inhibitors include Isentress (Merck & Co.), Vitekta (Gilead Sciences), Tivicay (ViiV Healthcare), and Biktarvy (Gilead Sciences). All RT and integrase inhibitors are small-molecule drugs.
- Disrupting viral assembly: After replication of its genome and production of new proteins, the final step of the HIV lifecycle is the assembly of new viruses. This process depends on a specific kind of viral protein called a protease. This enzyme processes newly made viral proteins so that they can form new viral particles. Inhibiting the HIV protease enzyme means no new viral particles. Small molecule protease inhibitors on the market include Prezista (Janssen Therapeutics), Tipranavir (Boehringer Ingelheim), and Lexiva (GlaxoSmithKline).
- The diagram below shows where in the HIV lifecycle each of these types of drugs acts.
These drugs have profoundly improved the lives of people with AIDS worldwide. However, the as-yet-undiscovered cure for AIDS may arise instead out of biotech.
The journey to control HIV/AIDS has been fraught with challenges, but remarkable strides have been made. From understanding the intricate lifecycle of the virus to developing potent drugs that target its weaknesses, the medical community has dramatically improved the prognosis and quality of life for those affected by the disease. As we reflect on the vast array of current treatments, it is crucial to remember that the relentless pursuit of a definitive cure continues. The synthesis of knowledge, innovation, and collaboration will, we hope, one day lead to a world free of HIV/AIDS.
FREQUENTLY ASKED QUESTIONS
1. WHAT IS HIV, AND HOW DOES IT DIFFER FROM AIDS?
HIV stands for Human Immunodeficiency Virus. The virus can lead to acquired immunodeficiency syndrome, or AIDS. Unlike some other viruses, the human body can not get rid of HIV completely, so once someone has HIV, they have it for life. AIDS is the final stage of HIV infection, and not everyone who has HIV will develop AIDS.
2. HOW DOES HAART MANAGE AIDS?
HAART stands for highly active antiretroviral therapies. These therapies target the virus at multiple points in its lifecycle, reducing its ability to replicate and infect new cells. By combining different drugs in a “cocktail,” the virus is less likely to develop resistance.
3. WHY IS THE COMBINATION OR “COCKTAIL” APPROACH USED IN HIV TREATMENT?
Due to HIV’s high mutation rate, it can rapidly evolve resistance to single drugs. Combining different drugs ensures that even if the virus becomes resistant to one, the other drugs can still act against it.
4. WHAT ARE CCR5 INHIBITORS?
CCR5 inhibitors are drugs that prevent HIV from entering T-cells by blocking its interaction with the CCR5 protein on the surface of these cells.
5. HOW DO INTEGRASE INHIBITORS WORK?
Integrase inhibitors block the enzyme that HIV uses to integrate its genetic material into the host cell’s DNA, effectively stopping the virus from replicating.
6. WHAT IS THE CURRENT STATUS OF A CURE FOR HIV/AIDS?
While there are effective treatments like HAART that can manage HIV/AIDS, a definitive cure is still elusive. Researchers are exploring innovative methods such as gene therapy and genome editing in the quest for a cure.