I was shocked to last summer of the Malaysian Airlines flight MH 17 that crashed over Ukraine, carrying among its passengers six AIDS researchers. Here is my [overdue] tribute: a brief summary of our progress toward eradicating HIV from this planet.
Human Immunodeficiency Virus (HIV) in brief:
HIV is a retrovirus of the genus lentivirus. Retroviruses carry their genetic material in the form of RNA, and then reverse transcribe this RNA when inside the host cell to create viral DNA. The DNA is then incorporated into the host genome. Lentiviruses are special in that they infect cells at any time, while other viruses can only do so during cell division. For this reason, lentiviral vectors can be used to deliver copies of a correct gene to people with a mutated version. HIV in particular infects several types of immune cells, including CD4 T cells. In humans, this results in a continual failure of the immune system over time, which progressively increases patient susceptibility to infections and cancers. If left untreated, average life expectancy after the time of infection is 9 to 11 years. Fortunately there exist many kinds of effective treatments called antiretroviral therapy (ART). You can read about these drugs and how they inhibit different steps of the viral life cycle here. Unfortunately, these treatments are not capable of completely curing an HIV patient.
If you Google “HIV cure,” you’ll find all kinds of interesting stuff. For example, a compound found in bee venom, melittin, pokes holes in lipid bilayers and thus can kill the human immunodeficiency virus by destroying its outer envelope. The melittin can be delivered with nanoparticles, which are already known to be safe in humans. The figure at right illustrates this delivery system. The nanoparticles (purple) are modified with small molecular “bumpers” (red ovals) that prevent human cells from coming into contact with the melittin (green), but allow the much smaller virus to get close enough that the bee venom compound can rip it apart. A PLOS ONE journal article detailing a study of the safety of melittin as a virucide can be found here. This particular possibility is really exciting because unlike other existing therapies, it directly attacks the physical virus. I just hope that if this is pursued as an HIV solution, it can be synthesized in a lab and won’t have to be obtained via mass bee sacrifice.
While there’s no cure currently available, there exist individuals that have a natural resistance to HIV, called “elite controllers.” Such individuals are infected with HIV but do not need to take ART because they are naturally able to maintain a CD4 count greater than 500. You can read about several different types of genetic variations that confer this natural resistance here, but I’ll focus on one in particular: the CCR5-delta-32 mutation, which nullifies the CCR5 gene. This gene normally encodes a surface cell receptor protein on CD4 immune cells, which the HIV virus uses to gain entry into the host cell. Clinical trials have already been conducted in humans to modify the CCR5 gene with gene therapy methods, so this viral entryway can be deleted in HIV patients without the natural mutation. It has been determined to be a safe therapy within the limits of one clinical study published last year in the New England Journal of Medicine. Efforts are currently underway to improve the therapy with newer and more reliable gene editing methods. I’m not sure when this treatment will come widely available, and it hasn’t permanently cured anyone yet, but it definitely reduces viral loads and increases CD4 cell counts. Read more here.
There actually is one person who is confidently said to have been functionally cured of HIV (he has had undetectable levels of viral genetic material and a normal CD4 cell counts for more than six years now). This is Timothy Brown, also known as the second “Berlin patient.” Interestingly, however, the exact mechanism by which he was cured still eludes the researchers of the world. I’ll detail his treatment briefly. Brown was diagnosed with acute myeloid leukemia more than a decade after he contracted HIV. His doctor had heard that patients with the CCR5-delta-32 mutation have natural resistance to HIV, and found a bone marrow donor that carried two copies of that mutation, meaning that he did not make any of the CCR5 receptor. After undergoing radiation which killed all Brown’s white blood cells (eliminating the cancer), he underwent two separate bone marrow transplants from the aforementioned donor (the second one was required because of a leukemia relapse). This allowed his immune system to start over with CD4 T cells which lacked the CCR5 receptor. One article describes a study that made some progress in elucidating why this treatment worked so well; researchers think that the foreign cells from the donor killed any of Brown’s immune cells which survived chemotherapy, allowing his immune system to truly start over again after the transplant.
One other person may have been cured, using a transplant of blood from the umbilical cord of someone carrying that very important CCR5 mutation, but this is said with hesitance, because the “Barcelona patient” was HIV free for only three months before dying of cancer.
Relying on transplants is not the answer for the majority of the HIV-positive population. It’s simple a matter of supply and demand; to find someone with 2 copies of the CCR5-delta-32 mutation is rare, and to hunt these individuals down and ask them to donate their bone marrow is unfair. Most experts agree that a cure must involve some combination of immune system therapy, gene therapy, and drug therapy to force the HIV out of hiding so it can be destroyed.
There’s one more thing that I’m really excited about, and perhaps you have already thought about it yourself. If gene therapy has been used in a human to modify the CCR5 receptor, why can’t it be used to delete the viral DNA from the infected cells as well? Well, a research group at Temple University School of Medicine in Philadelphia has asked this very question, and they seem to have an answer. Their study, published last summer, details how they successfully eliminated the HIV virus from cultured human cells for the first time with high-fidelity gene editing methods. Unfortunately, this therapy is not yet ready to go into clinical trials. An article from the Temple University School of Medicine website details the main obstacles: “The researchers must devise a method to deliver the therapeutic agent to every single infected cell. Finally, because HIV-1 is prone to mutations, treatment may need to be individualized for each patient’s unique viral sequences.” But imagine what a potent combination it will be when we can use gene therapy to both prevent infection by deleting the CCR5 receptor, and for erasing the viral DNA for those cells which have already been infected!
While we wait with great anticipation and hope for the cure for HIV, the World Health Organization (WHO) is making great progress towards providing universal access to antiretroviral therapy; they aim for all the world’s HIV victims to get access to ART by the end of 2015.
Even without a cure, we should be proud with how far we’ve come. Remember how I said that without treatment, HIV victims will live on average only 9-11 years post-infection? Well, successfully treated HIV-positive individuals now have a normal life expectancy. That’s no insignificant achievement.
So, thank you to all the AIDS researchers of the world!! It’s an exciting time to be alive.