A Cure for AIDS

The theme for World AIDS Day of last year, “The Time to Act Is Now,” was a call to turn ideas into action. It was well served by data from that year: the goal, access to antiretroviral therapy (ART) for 15 million HIV positive people worldwide by 2015, was exceeded. As a consequence, some 4.2 million deaths have been averted over the past decade, but 60% of people living with AIDS are still without access to ART. This highlights the importance of two things: the clinical and global health strategies of World AIDS Day on December 1, 2016 and its theme, “Access Equity Rights Now,” and the research outlined in this special topic issue of AIDS Patient Care and STDs. “Equity rights” include ensuring comprehensive treatment, prevention, access to care without stigma or discrimination, and support services. Much of this is still limited among resource-poor nations, but even in the US the care cascade is distressingly incomplete. ¹

This is not to deny the dramatic changes in HIV therapeutics. Recent cultural projects have explored what it was like to be HIV positive in the US three decades ago. “So much death. It was painful and confusing and horrific,” according to Neil Greenberg, a choreographer who recently addressed his own HIV status then and now in a dance piece for Danspace Project. ² In the late 1990s, when HIV protease inhibitors enabled administration of potent ART cocktails, everything changed. “The imperative to survive relaxed. I ran away into my life,” recalled Greenberg. ¹ At that time, coincident with my first issue of AIDS Patient Care and STDs as Editor-in-Chief in 1996, NIH researcher Dr. Robert Gallo referred to AIDS as a “clinically curable disease.” ³

That concept of a “clinically curable” disease, a functional cure by which a person, although still harboring latent virus, has a normal T cell repertoire and can anticipate a normal life span in the absence of AIDS-associated disorders, has indeed been reached. Data from two studies, SMART and ESPRIT, found that non-intravenous drug-using HIV-infected individuals who received continuous ART and had maintained normal CD4+ T cell counts and undetectable viral loads had no increased risk of death compared to the general population. ⁴

But what about a “sterilizing cure,” the type one typically envisions in speaking of a cure for pneumonia or for certain types of cancer? There is an observation period needed to define “cure,” of course. For a bacterial pneumonia, it might mean no evidence of active bacteria in the body and resolution of the lung infection over weeks. For an early stage I cancer, it might mean being cancer free, as documented by the most sensitive imaging techniques available, for 5–15 years, depending on the type of malignancy involved. But what about a person with AIDS? A cure might mean no detectable active virus, no detectable latent or silent virus residing in cell or tissue reservoirs, and no chance of transmitting virus, in the setting of an intact immune system in a person off all antiretroviral medications for a prolonged period of time. Thus far, this has happened once to one person in Berlin. But that individual provided the proof-of-concept that curing AIDS was possible.

Acceptance that this cure was real took a while. In May of 2008, I wrote an editorial, “Seeking a Cure for AIDS,” ⁵ which highlighted an intriguing poster presented at the 15^th Conference on Retroviruses and Opportunistic Infections, held in Boston 3 months earlier. ⁶ The case concerned a 40-year-old HIV-positive man, a US citizen residing in Berlin, on ART, in whom acute myeloid leukemia had developed. He underwent a conditioning regimen, FLAMSA, in preparation for a matched unrelated door hematopoietic stem cell transplant, with the goal of curing his leukemia. FLAMSA is a very potent myloablative regimen, rarely used in the US, which included three antineoplastic agents (fludarabine, Ara-C, and amsacrine), 4 Gy total body irradiation, and cyclophosphamide and antithymocyte globulin administration. The patient then received an intravenous infusion of peripheral blood CD34+ stem cells obtained from a donor selected for homozygosity for the CCR5-Δ32 mutation. CCR5 is the primary co-receptor for HIV entry into cells. ⁷ Persons lacking this receptor, as the result of a mutation found in about 4% of Scandinavians and 1.4% of Caucasian Americans, but in no persons of African, Asian, or American Indian descent, are resistant to infection by the most common types of HIV-1, i.e., those utilizing the CCR5 co-receptor.

Two such transplants from the same donor were necessary as the patient relapsed from the leukemia after the first round. The critical finding was that before transplant the patient's viral load on ART was undetectable, yet more than 15 HIV proviral DNA copies per million peripheral blood mononuclear cells were still present—his latent viral reservoir. As discussed in a recent review in this journal, that reservoir, consisting mainly of CD4+ memory T cells, is the major obstacle to an ART-mediated AIDS cure, as latent virus is resistant to current HIV medications and immune-based therapies. ⁸ But post-transplantation, although the patient had not received ART for more than 285 days at the time of the poster's publication, his viral load remained undetectable and there was no detectable HIV provirus in blood, bone marrow, or rectal mucosal biopsy tissue. At that point he still had some anti-HIV antibodies, but they too soon disappeared.

What was modestly deemed by the Berlin team “a promising approach” revolutionized AIDS research. As one group recently wrote: “Since then, the landscape has changed. HIV cure has become a key priority for AIDS researchers, for both governmental and charitable funders, and for persons living with HIV infection.” ⁹ But it was not perceived in that manner in 2008. Skepticism was widespread, if anyone paid attention to this case at all. It received virtually no notice. And so 4 months after my Editorial, in my capacity as Senior Scientific Consultant for Programs at amfAR, The Foundation for AIDS Research, I convened a think tank at the Endicott House of MIT outside of Boston, inviting prominent scientists from academia, industry, and the NIH, including the head of the Berlin team, Dr. Gero Hütter, to discuss his report. As noted in the Wall Street Journal, “The case was presented to scientists earlier this year at the Conference on Retroviruses and Opportunistic Infections. In September, the nonprofit American Foundation for AIDS Research, or AmFAR, convened a small scientific meeting on the case.… The scientists agreed that the patient is ‘functionally cured.’” As suggested by Dr. David Baltimore, its significance surpassed this unusual patient, providing “a virtual ‘proof of principle’ for gene-therapy approaches” to curing AIDS. ¹⁰

With time that “functional cure” was proven to be a true sterilizing one. ¹¹ Many amfAR-sponsored think tanks have been held in the ensuing years, with a recent focus on establishing the scientific basis for a cure by the year 2020. Making the “Berlin patient” type of cure more pragmatic will present an additional challenge.

The risk of morbidity and mortality following such a transplant is very high; it would not be undertaken unless a life-threatening condition was also involved. Even then, finding a donor who had an HLA type appropriate to the recipient, together with a homozygous deletion in CCR5, presents a huge challenge. Use of cord blood donors, whose stem cells are more forgiving in terms of requirements for HLA matching, provides some hope. Early stakeholder engagement in cure research will assist these and other efforts. ¹² But given dramatic strides in genetic engineering, it is also conceivable to modify an HIV-positive individual's own stem cells or T cells ex vivo to make them resistant to HIV, and use them in autologous transplants or cell infusion protocols, which do not carry much risk ¹³ It is ironic that HIV itself, engineered to carry the information needed to excise CCR5 and related receptors from cells, might be employed as a vector in such a scenario. ¹⁴ Many of these concepts are covered in the following series of articles in this special topic issue. They were selected from presentations at a think tank convened by amfAR in Portland, Oregon from June 24–26, 2016, entitled “Gene therapy strategies to eradicate HIV.”