Nearly 38 million men, women and children are living with HIV worldwide. Of these, at least 24 million are keeping the virus in check with anti-HIV drugs, but these must be taken daily for a lifetime. If treatment is stopped, the virus invariably springs back to active infection. Only two people have been cured of HIV to date, both through bone marrow transplant with genetically HIV-resistant cells, a risky and toxic procedure that is not realistic for wide-spread use.
A major obstacle to long-term control and cure of HIV is the persistence of HIV in reservoirs, or hidden depots of virus within the body. HIV is able to hide quietly inside a patient’s own immune cells (CD4+ T cells), undetected by the immune system. Because of the long lifespan of these cells, the reservoir persists throughout the life of an individual. Current anti-HIV treatments can inhibit active viral replication but cannot eliminate these pockets of long-lived, HIV-harboring cells.
The HIV reservoir has proven to be extremely persistent. As a result, development of novel paradigm-shifting approaches will likely be required for successful long-term control and cure of HIV. Moreover, a focus on low-cost techniques with a broad reach will be crucial to making make HIV cure technology accessible to all 38 million people living with HIV, no matter who they are and where they live.
The Berlin Patient
In 2009, a paradigm shifting approach was published in the New England Journal of Medicine, demonstrating the functional cure of HIV by administration of high-dose chemotherapy followed by transplantation of HIV-resistant hematopoietic cells from an unrelated donor. While the procedure was performed to cure a hematologic malignancy, not to eliminate HIV, the results were compelling in that the Berlin Patient was able to stop antiretroviral therapy without recurrence of readily detectable virus.
The unrelated donor cells were HIV resistant by virtue of homozygosity for the Δ32 mutation in the HIV co-receptor CCR5, which plays a critical role in the infectivity of HIV. Individuals homozygous for the CCR5Δ32 allele, in which deletion of a 32-bp segment results in a nonfunctional receptor for HIV, rarely become infected despite repeated high-risk exposures.
The outcome for the Berlin Patient provides important proof of principle that latent reservoirs of HIV can be eradicated using nontraditional methods. However, this approach can not be used broadly for treating HIV, both because of the extreme risks involved with bone marrow transplantation and because CCR5Δ32 homozygous, HIV-resistant donor cells are very limited. An analysis performed at the Fred Hutchinson Cancer Research Center of 1273 donors determined that we will identify an HLA-matched HIV-resistant donor for only 0.1-0.4% of patients.
TIMOTHY RAY BROWN
"THE BERLIN PATIENT"
Timothy Ray Brown (March 11, 1966 – September 29, 2020) is an American considered to be the first person cured of HIV/AIDS. Brown was called "The Berlin Patient" at the 2008 Conference on Retroviruses and Opportunistic Infections, where his cure was first announced, in order to preserve his anonymity. He chose to come forward in 2010. "I didn't want to be the only person cured," he said. "I wanted to do what I could to make [a cure] possible. My first step was releasing my name and image to the public."
Timothy was born in Seattle, Washington, on March 11, 1966, and raised in the area by his single mother, Sharon, who worked for the King County sheriff's department. He journeyed across Europe as a young adult and was diagnosed with HIV in 1995 while studying in Berlin. In 2006, he was diagnosed with acute myeloid leukemia. On February 16, 2007, he underwent a procedure known as hematopoietic stem cell transplantation (also called a bone marrow transplant) to treat leukemia. A team of doctors in Berlin, Germany, including Gero Hütter, performed the procedure.
From 60 matching donors, they selected a [CCR5]-Δ32 homozygous donor, an individual with two genetic copies of a rare variant of a cell surface receptor. This genetic trait confers resistance to HIV infection by blocking attachment of the virus to the cell. Roughly 1% of people of European or Western Asian ancestry have this inherited mutation, but it is rarer in other populations. The transplant was repeated a year later after a leukemia relapse.
Over the three years after the initial transplant, and despite discontinuing antiretroviral therapy, researchers could not detect HIV in Brown's blood or in various biopsies. Levels of HIV-specific antibodies in Timothy Brown's blood also declined, suggesting that functional HIV may have been eliminated from his body.
The procedure met with some skepticism in the scientific community. Some AIDS researchers sought to test Mr. Brown’s blood samples for themselves. Some questioned whether, if he was indeed free of HIV, the virus could still recur. Experts noted as well that bone marrow transplants were risky, expensive and unlikely to be available for wide use.
Timothy was originally known only pseudonymously, as the “Berlin Patient.” But he became a reluctant public figure when he decided to reveal his identity.
“At some point, I decided I didn’t want to be the only person in the world cured of HIV,” Mr. Brown told the website ContagionLive. “I wanted there to be more. And the way to do that was to show the world who I am and be an advocate for HIV”.
He added, “My story is important only because it proves that HIV can be cured, and if something has happened once in medical science, it can happen again.”