HIV: Basic Research IS the Force behind Translational Research

AIDS is a humongous problem. It is a epidemic with ~33 million infections worldwide. To put that in perspective using numbers that make sense to people ~1 in every 200 people in the world are infected. We have individual classes at my university that on average should have 2.5 HIV+ students.


To date, there is no cure, and no vaccine.


If you live in a rich country like the USA, there is a treatment called HAART. If you live in a poor country, well you are pretty much dying of a nasty opportunistic infection. However, even in a rich country ~50% of all patients fail HAART therapy in the first year. This is due to toxicity (the drugs can have real nasty effects) and resistance (HIV doesn't like to be kept in check). So even in the countries with the best health care (not the US) treating HIV is hit or miss, but mostly miss.


This is our problem, we need new therapeutics. Well a vaccine would be better and we are working on it, but until then new therapeutics are desperately needed. This is the translational side of the equation, getting better treatments to the 1.1 million HIV+ patients in the US alone. (BTW ~21% are undiagnosed, hope you didnt have sex with one of those 231,000 people recently.)


Ok, here is where basic science comes in.


First, let's introduce epidemiology:  the study of factors affecting health in a population.


Well, we know a bunch of things about HIV infections (which many characters besides epidemiology generated). For example, HIV binds to a protein receptor on cells called CD4. Not many cells are CD4+ cells, but those that are are infected and killed by HIV. A critical type of T-cell is CD4+, aptly termed the CD4+ T-cell. CD4+ T-cells are the directors in the movie called "The Immune System." So when the CD4+ T-cells are killed by HIV, the movie comes to a screeching halt and then some generally benign microbe comes along and kills you.


Now not only does HIV bind to CD4, it also binds a co-receptor: a protein called CCR5, which is also found on CD4+ T-cells (and a few other cells). What's important, and we can thank epidemiology, is that ~1% of all people carry a mutant form of CCR5 (called CCR5∆32) that is not expressed. People are diploid, they have 2 copies of every gene, so of those 1% many have the mutant copy and the normal, wild-type, copy (the are heterozygotes CCR5∆32/CCR5). However, a small fraction of the population carries both mutant alleles (CCR5∆32/CCR5∆32) and do not express CCR5 on any cell. Based on epidemiological studies CCR5∆32/CCR5∆32 individuals are resistant to HIV and CCR5∆32/CCR5 individuals showed delayed onset of disease.


So what does this information get us? Well maybe a drug could be made that blocks CCR5 from HIV or inhibits CCR5 expression. Enter Maraviroc. Maybe we could help someone using this information. Well in 2006 an HIV+ patient came down with leukemia (like shit isn't bad enough). One treatment for leukemia (at least certain types) is a bone marrow transplant (BMT). Basically you destroy the patients immune system, which is where the leukemic cells come from, with radiation and/or chemicals and then restore the immune system with bone marrow, the source of the cells of the immune system, from a healthy donor. Here the doctors got clever and found a CCR5∆32/CCR5∆32 individual for a donor. 


WHAMOO, the HIV+ patient is currently free of HIV and leukemia. w00t!!11!leventy!!1


However, BMTs suck and most patients would opt for the HAART therapy over a BMT. But the point is that this fucking worked!!! Some basic epidemiology set on top a large set of immunology, cell biology, and virology led to a fucking cure! Not treatment, CURE! Basic research for the translational win.


Now let's be real, this approach is not going to be used to treat the current 33 million, I mean 32,999,999 HIV+ patients. Many if not most patients would refuse this treatment even if cost effective. So what can we do now.


Let's introduce molecular biology, biochemistry and genetics: the study of molecules and inheritance in living cells.


If we can get rid of CCR5 in HIV+ patients, we have a cure. Well, many years basic biochemistry, genetics, and molecular biology have identified proteins that cleave DNA called nucleases. These fields also identified a protein motif called a zinc finger that binds to specific DNA sequences. Finally some nucleases are in fact zinc finger DNA nucleases. Now if we take our knowledge of zinc fingers, we should be able to make a zinc finger nuclease that cuts DNA at a specific DNA sequence. Like a specific DNA sequence in the CCR5 gene. This would allow us to make human cells CCR5∆ in the laboratory.


Let's introduce cell biology, cancer biology, and stem cell biology: the study of the properties of cells in general, in cancer, or pluripotent.


Based on the work in these fields, we know how to get at least certain cells from people grow them in the laboratory and manipulate them. We know how to introduce new bits of DNA, such as DNA that encodes our zinc finger DNA nuclease that targets CCR5. So we can take some cells from an HIV+ patient, make them CCR5∆, put them back in and in principle cure the patient of HIV. This also avoids issues of donor:patient incompatibility since the cells come from you not a donor.


But how can we test this?


Let's introduce zoologists, immunologists, and veterinary scientists: those who studies animals the immune system and diseases of animals, respecitvely.


We know a lot about the mouse, and in many ways the mouse is like a human (although in many ways its not, which may be the focus of a future post). Further, we can destroy the immune system of a mouse, just like we can a human, and do some things to give the mouse a more human immune system. Sounds very Dr. Moreauian doesn't it. I mean, why would we want to make a mouse with a human-like immune system? Well, for one mice don't get HIV. They can't catch it, don't transmit it, and basically suck as a model to study. If we have mice running around with human CD4+ T-cells, instead of mouse CD4+ T-cells, well they can be infected with HIV and come down with AIDS. So we can use a humanized-mouse to actually see if this CCR5∆ stem cell, made using a zinc finger nuclease, treatment is a viable approach. This is translational research at its best.


and you know what? A study by Holt et al (see below) suggests this approach fucking works!!! 


Translational research is da bomb!! But only if we forget that all of this research is the culmination of years of research by diverse labs using diverse organisms learning basic biology. Basic research is da fucking bomb!!!


 Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Holt N, Wang J, Kim K, Friedman G, Wang X, Taupin V, Crooks GM, Kohn DB, Gregory PD, Holmes MC, Cannon PM. Nat Biotechnol. 2010 Jul 2. [Epub ahead of print].


Can the new humanized mouse model give HIV research a boost. Shacklett BL. PLoS Med. 2008 Jan 15;5(1):e13

This post was inspired by a seminar given by Dr. Cannon the senior author of the Holt study given months before it was pubished.