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Finding a cure for HIV infection; promise or reality?
(Note: all the sources listed in the "Balanced" section)
Anti-retroviral therapy (ART), or highly-active-antiretroviral therapy (HAART), is effective in halting progression of HIV infection. However, the HIV virus, despite of the treatment, remains hidden in the human body. In 2017, existing medications for the treatment of HIV infection such as Gilead’s Genvoya and Merck’s Isentress had annual sales of $3.67 billion and $1.2 billion, respectively. Notwithstanding their commercial success, these medicines do not cure the disease. The HIV virus often remains hidden in the human body in reservoirs such as dendritic cells, macrophages, and CD4+ lymphocytes. Since HIV was first detected in 1983, the medical community have intensively searched for a cure for HIV infection.
The Story of the Berlin Patient. In 2007, Timothy Ray Brown, an American studying in Berlin, Germany, was treated with a hematopoietic stem cell transplant. Two years earlier, Mr. Brown had been diagnosed with a type of blood cancer known as acute myeloid leukemia (AML). Besides its cancer diagnosis, Timothy was infected with the Human Immunodeficiency Virus (HIV). Dr. Gero Hütter, a German doctor from the Charité Hospital, Berlin University of Medicine, performed the transplant. At the time, Dr. Hütter had never treated an HIV patient before Timothy, but he had learnt about a rare genetic mutation causing natural resistance to HIV infection. Based on this information, Dr. Hütter found a stem-cell donor carrying this specific mutation. He performed the transplant on Mr. Brown using these mutated cells.
The procedure resulted in a surprising outcome as Timothy’s HIV infection disappeared after the transplant. The HIV virus could not be detected on his blood, not even with the most sensitive diagnostic techniques such polymerase chain reaction (PCR) methods. Timothy Ray Brown was cured of his HIV infection. He became famous in the medical community. Timothy is now known as the Berlin patient (https://www.youtube.com/watch?v=f6DXqGZt_Fw). The story of the Berlin patient triggered significant interest in both academy and industry, setting off a golden rush to find a sterilizing cure for HIV infection. Timothy’s transplant treatment was done from a donor carrying a mutation in a gene known as CCR5, which happens to be the site of entry utilized by HIV virus to infect immune system cells (New England Journal of Medicine 2009, 360, 692-698). The CCR5 protein receptor is expressed on the surface of lymphocytes T, which are the predominant target cell for the virus. Two cell receptors, CD4+ and CCR5, are utilized by HIV to enter the cell. The virus cannot enter and infect cells with a defective CCR5 receptor. As a result, HIV cannot find a home, the patient’s viral load gradually decreases, and eventually the virus fizzles out. This is probably what transpired during Mr. Brown’ treatment procedure. The fact of the matter is that the virus became undetectable in Timothy’s body. He stopped taking any medication for HIV, although he continued to undergo treatment for his blood cancer. Since then, Timothy has remained HIV negative. He has been cured from his HIV infection.
Scientists Believe CCR5 is The Adequate Target to Find a Cure. There is a body of evidence in the medical literature supporting the premise that preventing the entry of HIV into cells by blocking the virus interaction with the CCR5 cell surface receptor (HIV site of entry) is the right approach to find the elusive cure for the disease. Persons who carry two copies (alleles) of mutated CCR5 (homozygous for mutation delta 32) are fully resistant to HIV infection (Cell 1996, 86:367-377). HIV patients who carry one mutated CCR5 allele plus a normal copy of CCR5 (heterozygous patients) show slower disease progression, when compared to patients carrying two normal alleles of CCR5 (Annals of Internal Medicine 1997, 127:882-890).
In recent years, the CCR5 receptor has been an important target for the biotechnology and pharmaceutical industries. Pfizer’s Maraviroc (Selzentry), a drug inhibitor of CCR5, was approved by FDA in 2007. The drug blocks HIV viral replication (Journal of Translational Medicine 2011, 9 (Suppl 1:S9). At the time, this FDA approval validated the importance of CCR5 as a target in HIV area. However, treatment with Maraviroc has not become a cure for HIV infection, far from it. Instead, the drug is being currently used for the treatment of graft-versus-host disease, a complication of bone marrow transplantation.
Although targeting CCR5 with a drug inhibitor, such as Maraviroc, did not result in a cure for HIV infection, the consensus among scientists is that replacing a patient’s lymphocytes with “mutated-CCR5 resistant cells” could potentially become a sterilizing treatment. Sangamo Therapeutics (NASDAQ: SGMO, Market Cap $1.36 billion) is developing SB-728-T as a novel drug for the treatment of HIV infection. This candidate medicine is based on genome editing of CCR5 gene in lymphocytes T. The treatment is designed to render these T lymphocytes resistant to the virus. These genetically modified cells are subsequently grown outside of the human body (ex vivo), and then infused back into HIV patients to repopulate the immune system. Sangamo’s SB-728-T is currently in Phase II clinical trials. In February this year, Sangamo’s management announced the start of a collaboration with Case Western Reserve University, based in Cleveland, to advance this technology. Another biotechnology company targeting CCR5 is CytoDyn Inc. (CYDY, Market Cap $133 million). CytoDyn is developing an antibody, PRO140, which binds to CCR5 receptor blocking HIV cell entry and inhibiting viral replication.
Berlin Patient Results Have Been Difficult to Reproduce. Eleven years have passed since the Berlin patient was cured. Despite of many attempts in other HIV patients, the results have not been easy to reproduce. Dr. Hütter had treated other patients with the same procedure. These patients, like Timothy Brown, have been diagnosed with blood cancer, and were concomitantly infected with HIV virus. Unfortunately, the results of these treatment attempts have been negative. Unlike the case of the Berlin patient, these newly treated patients have not been cured. In one of these trials, six cancer patients, carrying HIV virus, were treated with stem cell transplantation from donors with mutated CCR5. Unfortunately, they all died within 12 months. The causes of death were infections, graft-versus-host disease (an autoimmune complication of the transplant), and recurrent blood cancer (New England Journal of Medicine 2014, 371(25) p2437-2438). Many other physicians have also tried this treatment procedure, but have not been successful in their attempts as patients often die of the bone marrow transplant, or relapse years after treatment (HIV virus restart replicating again in immune system cells). These negative results have cast doubts on the promise of finding a cure for this illness.
What is Next in The Field, Is Stem Cell Transplant Still an Option. The prevailing view among scientists in the HIV field is that a potential cure is now an achievable goal. Recent advances in gene therapy, combined with superior stem cell transplantation techniques, should help bringing this new technology to the forefront of HIV treatment.
- The Berlin patient was the first patient cured by stem cell
- Long-term control of HIV by CCR5 Delta32/Delta32 stem cell transplantation (Hütter, G., et al, New England Journal of Medicine 2009, 360, 692-698)
- Hematopoietic stem cell transplantation for HIV cure (Kuritzkes, D.R., The Journal of Clinical Investigation 2016, 126 (2) p432-437)
- More on shift of HIV tropism in stem cell transplantation with CCR5 mutation (Hütter G., Kordelas L., et al, New England Journal of Medicine 2014, 371(25) p2437-2438)
- Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection (Liu R, et al, Cell 1996, 86:367-377)
- Association between CCR5 genotype and the clinical course of HIV-1 infection (de Roda Husman AM, et al, Annals of Internal Medicine 1997, 127:882-890)
- (Gilliam BL, et al, Journal of Translational Medicine 2011, 9 (Suppl 1:S9)
- Making inroads toward eliminating latent HIV reservoirs
- CytoDyn, Inc. (CYDY) HIV targeting with CCR5 antagonist
- Could gene editing fight the AIDS
crisis? Scientists poised to re-try the risky procedure 10 years after it cured
the Berlin Patient, but had disastrous results in every other trial
- Gene therapy could revolutionize HIV
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