The ?Berlin Patient? May Not Be The Answer As HIV Research Progresses Toward A Cure

Timothy Ray Brown has been cured of HIV while 30 million men and women worldwide are still fighting to survive this disease. Why?

More and more often when I tell people that I work in a lab that is developing a vaccine against HIV, I get this response:

?Didn?t they find a cure for that??

The answer is yes and no. ?Yes, you probably did see CNN coverage that hailed the medical breakthrough that ?cured? Brown of his infection. ?But, that?s not the end of the story. ?I?ll explain here why Brown?s experience is not the cure for which those 30 million people have been waiting. ?Instead, I will share some of the most recent advancements in HIV prevention and vaccine development that give us hope for a solution in the near future.

This year we recognize 30 years of history since the discovery of the HIV epidemic. ?At the same time, we acknowledge that we have struggled to find a practical cure for this devastating disease. ?In 2009 around 1.8 million people worldwide died from AIDS and 2.6 million more (56,000 in the U.S.) became infected with HIV. ?Until we find a cure, 30 children will die every hour as a result of AIDS.

The urgency is undeniable. ?So, how close are we to a cure?

As recently as May of this year, virologist, Robert Weiss said,

?Much as I would love to see one, the word ?cure? can lead to false hopes. ?I don?t believe you can cure HIV infection??

Though I respect his desire to lower expectations, I choose not to be quite so pessimistic. However, if you?re looking for answers based on the ?Berlin patient,? as Timothy Brown was known prior to revealing his identity, you may be barking up the wrong tree. ?Brown, a 40-year-old American living in Germany, allowed doctors the exceptional opportunity to apply cutting edge science and technology to his condition, despite the risks.

You see, Brown had not only contracted HIV, he also developed leukemia 10 years after his infection. ?So, when hematologist Dr. Gero H?tter, at the Charit? Hospital in Berlin, began to deliberate treatments for Brown?s cancer, he also thought about dealing with his HIV condition. ?A stem cell transplant was the common treatment for Brown?s type of leukemia. ?To lay the groundwork for the transplant, Brown?s leukemic blood cells would have to be removed. ?This was done with radiation and a drug regimen that wiped out not only the cancerous white blood cells but also most or all of his immune cells. ?Because HIV largely resides in these cells, the procedure denied the virus a place to live and replicate. ?The brilliance of Brown?s treatment came in the next phase of the process.

Dr. H?tter was aware of a genetic mutation that makes some people naturally resistant to HIV infection. ?The mutation occurs in approximately 1-2 percent of white Americans and Western Europeans. ?It affects a gene that encodes a protein found on the surface of white blood cells. ?The CCR5 protein, as it is called, allows the HIV virus to attach to cells and inject its genetic material, leading to the production of more viruses [1]. ?Individuals who carry the ?delta32 mutation? in the CCR5 gene do not produce a functional protein; therefore HIV cannot use this pathway to infect their immune cells. ?There is a disadvantage to having the defective CCR5 gene; an increased susceptibility to West Nile virus (WNV). Despite the slight risk posed by WNV, H?tter thought this mutation could be the key to Brown?s HIV treatment.

H?tter screened over 13 million people on his donor list. ?He found 232 people who matched Brown?s tissue type, a necessity to reduce complications with the transplant. ?He then went one step further and screened those donors for the delta32 mutation in the CCR5 gene. ?Cells from Sample #61, which were positive for the delta32 mutation, were transplanted into Brown?s immune-depleted body.

His new immune system was not only free of leukemic cells, but also was HIV resistant. ?H?tter and Brown then waited to see if he would remain HIV-free. ?He did. ?Two years after his treatment, biopsies taken from his brain, gut and other organs remained HIV-negative. ?The scientific community, at first reluctant to accept H?tter?s assertion, finally agreed that Brown was indeed cured of HIV [2].

While this was unprecedented, the media coverage of Brown?s story resulted in some overly optimistic expectations in regards to HIV treatments. ?These media mistakes provided an opportunity to take stock of what we had learned from Brown?s experience and to decide how we should proceed in the search for a cure.

There are several reasons why Brown?s case is not likely to be translatable to the millions of others whose lives are threatened by this disease. ?Brown and H?tter took extreme measures and suffered dangerous setbacks in order to achieve this outcome. ?These risks were necessary because of the virus?s ability to rapidly evolve to avoid most treatments.

Many people may not be as fortunate as Brown. First, Brown had been highly successful at controlling his infection using antiretroviral therapy. ?In order to undergo leukemia treatments, he agreed to stop taking his HIV drugs. ?This led to a dangerous spike in his viral load. ?Fortunately, after receiving the stem cell transplant, the virus went to undetectable levels and remained so. ?For the record, no one has ever stopped taking HIV drugs without experiencing a reemergence of the virus.

Second, the risk of dying from the stem cell transplant alone ranges from ~10% to as high as 40%. ?This is not a risk most would accept given current success controlling HIV infection using antiretroviral drug treatments. ?Third, tests on Brown?s blood revealed that he was carrying variants of the virus that were capable of infecting white blood cells without relying on the CCR5 protein. ?No one knows why those viruses never infected the transplanted cells. ?Finally, Brown experienced neurological and intestinal side effects from the stem cell treatments. ?These complications led to temporary blindness and memory problems. ?At one point, Brown was in an induced coma so doctors could deal with his complications. He continues to undergo therapy to recover his balance as well as to restore his normal speaking capabilities.

To summarize, Timothy Ray Brown is what some would call a medical miracle. ?Despite the rational approach taken by Dr. H?tter, the medical science that ?cured? him of HIV and preserved his life relied on some uncontrollable circumstances, like finding a tissue match with the delta32 mutation and avoiding infection of the transplanted cells. ?Some would say Timothy Ray Brown is simply a lucky guy.

So how will additional research bring us closer to a practical cure?

We should explore less risky variations on H?tter?s approach. ?For example, zinc-finger nuclease technology developed by Sangamo Biosciences (SB) may solve at least one of the challenges. ?Zinc-finger nucleases (ZFN) are molecular scissors that can be engineered to cut DNA in specific locations of the genome. ?SB scientists have generated a ZFN that cuts the CCR5 gene. ?Through complex genetic engineering techniques, they were able to use this ZFN to recreate the delta32 mutation in donor cells. ?This means that the tissue types from random donors no longer limit scientists. ?Instead, researchers can take stem cells from the patient, engineer them to be HIV-resistant and transplant them back into the patient. ?This would reduce the risk of developing graft-versus-host disease, which is what doctors believe caused some of Brown?s side effects.

What?s the likelihood of this working?

SB and their collaborators recently presented the results of a trial in which they transplanted such engineered cells into HIV patients who had low white blood cell counts. ?In this proof-of-concept study, the patients tolerated the cells with only mildly adverse reactions and the cells actually began to healthily increase the number of white blood cells in all patients.

The costs of these treatments are extremely expensive. ?At current rates, it would be cost-prohibitive to deploy these strategies on the scale needed to address the global HIV epidemic. ?So, we must wait for additional breakthroughs, both scientific and economic.

Where should we look in the meantime?

Just last month, researchers from the University of Washington?s International Clinical Research Center showed that antiretroviral medications taken as daily preventive therapy significantly reduced the risk of HIV transmission. ?The pre-exposure prophylaxis treatments (PrEP) reduced new HIV infections by at least 63 percent among mostly single women and men. According to the study, the drug was 77.9 percent effective among participants who took the medication regularly. ?While that is very promising news, few people want to take drugs perpetually as prophylaxis against HIV. ?So, we must continue to seek other approaches.

The earlier quote from Dr. Weiss was actually the first part of an argument for investments in vaccine research.

Weiss completes his thought by expressing optimism,

?I would prefer to see a vaccine so we can stop people being infected in the first place.?

As an HIV vaccine researcher at the National Cancer Institute with access to the most recent data, I can tell you that there have been some promising advancements toward the development of an effective HIV vaccine. ?For example, the National Institutes of Health recently announced that it plans to expand a vaccine investigation in the U.S. that showed protective capabilities beyond what was expected. The study, which is funded by the National Institute of Allergy and Infectious Diseases (NIAID), is increasing its enrollment from 1350 to 2200 HIV-negative men and transgender women who have sex with men. ?The expansion was prompted by a major HIV vaccine trial in Thailand that showed for the first time, in 2009, that an HIV vaccine lowered the rate of infection by 31.2% compared with the placebo. ?While most protection occurred among low-risk participants, the results showed significant protection (3.7%) even among high-risk participants. ?This is the first evidence of any human vaccine trial effectively lowering the risk of contracting HIV.

These accomplishments suggest that we are on the right path to defeating this horrible disease. ?Though a cure may still be eluding us, preventive measures have greatly improved. ?Prevention programs built on these discoveries will save lives while we continue to learn how to fight this elusive virus. We should take pride in the effort that has brought us here. ?It has taken years of commitment from scientists and policymakers to secure funding for these projects. It is important that we continue to support them as they make it possible to find a cure.

This is where I ask you to let your voice be heard. ?While Congress is looking to cut waste wherever they see it, remind your representatives that this area of research does not fall under that category.

Critical scientific publications referenced in this article:

[1] Samson M, et al. (August 1996). ?Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene?. Nature 382 (6593): 722?5.

[2] H?tter G, et al. (2009). ?Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation?. N Engl J Med 360 (7): 692?698.

Images: Picture 1: HIV daughter particles being shed from an infected T cell, National Institutes of Health; Picture 2: HIV budding: Scanning electron micrograph of HIV-1 budding (in green) from cultured lymphocyte, Photo by C. Goldsmith.

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