A cure for HIV?

According to the World Health Organization and UNAIDS, over 33 million people worldwide are infected with HIV, the virus that causes AIDS. Over 2 million people die AIDS-related deaths each year. HIV/AIDS has enormous social and economic impact, particularly in developing countries. Despite over 30 years of research into HIV, an effective method of prevention (besides condoms) and a cure have not been found. Currently, once someone become infected with HIV they can take a combination of anti-retroviral drugs on a strict regimen, which should suppress the virus for several years. Eventually, the patient develops AIDS which typically leads to death within 1 year. It is thought that antiretroviral therapy can increase survival time by 4-12 years, but the patient would still eventually develop AIDS.

It is really difficult to treat HIV for several reasons. The virus replicates very fast (in less than 2 days) and doesn’t always make a perfect copy when it replicates. This leads to mutations that can allow the virus to become resistant to the antiretrovirals, or to escape the immune system. All of these mutated virus also replicate quickly, so someone infected with HIV will have millions of copies of different versions of HIV. In addition, HIV infects (and kills) CD4+ T cells, which are a very important part of the immune system. So, while your immune system is trying to fight a constantly changing invader, the invader is also killing those cells that have a key role in fighting it. What is really cool is that some genetic combinations provide protection from infection or suppress HIV replication. One that is called Δ32 CCR5 deletion is present in a small percentage of Caucasians descended from Western Europeans, and also prevents infection with bubonic plague.

I have only found 1 case where someone was cured of HIV. An HIV-positive patient with acute myeloid leukemia was given a hematopoietic stem cell transplant (basically a bone marrow transplant). Since this patient had both AML and HIV there wouldn’t be very many (or maybe even any) treatment options available, so this situation provided the opportunity to try something new. The doctors decided to give them a hematopoietic stem cell transplant using cells from a donor that had the Δ32 CCR5 deletion. The transplanted cells would not be infected with HIV, and should be able to destroy any remaining HIV-infected cells in the patient. So far, HIV suppression has been observed in this patient, and they have stopped taking antiretrovirals!

Walker et al (http://jvi.asm.org/content/86/10/5719.abstract) were interested in creating a gene therapy vector that could provide protection from HIV infection. They created a gene therapy vector that would induce the Δ32 CCR5 deletion, in addition to expressing TRIM5α (shown to prevent HIV replication) and a TAR decoy (which should prevent HIV replication).

To determine if this gene therapy vector could be clinically relevant, it needs to be tested in an animal model, which is difficult for HIV. HIV is the HUMAN immunodeficiency virus, which means it can only infect humans. This has posed a huge problem for HIV researchers, but a pretty cool solution has been found – you can create mice that have a human immune system (there will be a blog about how to do this soon, because I’m going to learn how to make my own franken-mice). These mice can be infected with HIV and the infection is similar to what is observed in people.

Walker et al isolated CD34+ hematopoietic stem cells and infected them with the gene therapy vector, then injected the cells into mice. These stem cells developed into immune system cells, including the CD4+ T cells that HIV can infect. The CD4+ T cells appeared functionally normal and contained the gene therapy vector.

Once they verified everything was working as expected, they infected the mice with HIV and monitored the mice. They found that the mice that received the gene therapy vector had significantly enhanced survival of CD4+ T cells after HIV infection. However, the level of HIV virus in the blood was not changed. This suggests that the gene therapy vector was able to keep the CD4+ T cells alive, but didn’t stop HIV from replicating.

This study is a good start for using gene therapy as HIV prevention, but follow-up work on why the HIV levels in blood were unchanged should be undertaken. It is also important to realize that in this study they were sort of putting the cart before the horse – they gave the mice the gene therapy vector before HIV infection. To build on this study they should infect mice with HIV then give them a bone marrow transplant with hematopoietic stem cells that contain the gene therapy vector to see if the HIV infection is cured – it would be more clinically relevant that way. This sort of treatment would be a long way from the clinic, particularly since you’re dealing with a treatment option that could be highly controversial, since it involves stem cells and gene therapy. I am definitely going to keep my eyes on this field!

Christina