An avalanche of media coverage has been loosed by the recently announced case of an individual who may have been “functionally cured” of HIV infection. The term functional cure has entered the lexicon due to the impossibility of formally proving that HIV has been entirely eradicated from the body; due to that limitation, long-term absence of detectable virus without therapy has been adopted as a reasonable definition of a cure, prefixed with the “functional” caveat. The individual in this case is a 40 year old, HIV-infected American living in Berlin who had been on successful antiretroviral therapy prior to developing acute leukemia. The treatment for this condition involves bone marrow transplantation, which carries a 30% risk of mortality and is frequently associated with post-procedure complications. Due to the individual’s HIV infection, his doctors found a donor who was homozygous for the delta32 mutation, which completely abrogates expression of CCR5 (the major HIV co-receptor) on cells. Preparation for transplantation involves chemotherapy and radiation to essentially wipe out the immune system in order to prevent transplant rejection (with the salutary side effect of also depleting HIV-infected immune cells). The donor cells successfully engrafted but leukemia initially returned, requiring a second transplantation. Since that time – now close to two years ago – the individual has been free of leukemia, and HIV has remained undetectable without further antiretroviral treatment.
As can be gleaned from the press articles, opinions are divided on the significance of what has occurred. Some researchers have suggested it is a “proof of principle” that gene therapies with the capacity to block CCR5 expression could be curative. However, a 1999 review of bone marrow transplants in people with HIV (abstract below) identified two similar instances in which virus did not reappear after the procedure, so the contribution of the delta32 status of the donor in this current case is uncertain (although it is also possible that the prior examples also involved delta32 donors, unbeknownst to the doctors). The 1999 review also offers a grim perspective on the mortality associated with the procedure: the longest documented survival was around 300 days. While cynics might question whether AIDS professionals (including this writer) have their own self-serving reasons to express skepticism about cure claims, the complexity and danger of bone marrow transplantation clearly severely limits its use. It also must be stressed that while the individual is said to be “recovering,” there are no details available regarding his current health.
Despite the many caveats, the case may be able to inform the pursuit of a safer curative strategies. The Foundation for AIDS Research (amfAR) has already sponsored a small meeting of experts to discuss the subject, attended by Mark Schoofs who wrote the first mainstream media article in the Wall Street Journal last week. One lesson may be that depleting HIV reservoirs to very low levels – if it can be done safely – will be beneficial, perhaps tipping the balance in favor of the host such that any residual virus can be controlled. If the individual remains well enough and is willing to undergo further evaluation, additional analyses to look for HIV in tissues will be important, along with evaluations of HIV-specific immunity. The presence of HIV-specific T cells carrying the donor delta32 mutation would suggest that sufficient viral activity has occurred after the transplantation procedure to induce new immune responses while, conversely, the absence of such responses might add to the evidence that HIV has been rendered completely inactive. Given that the case is now under the spotlight, the doctors involved will hopefully be forthcoming with updates as more information becomes available.
Med Hypotheses. 1999 Mar;52(3):247-57. Links
Could bone marrow transplantation cure AIDS?: review.
Huzicka I.
First Medical Faculty of Charles University, Prague, Czech Republic.
Despite recent use of potent antiretroviral drugs, the goal of eradication of human immunodeficiency virus (HIV) and restitution of the immune system has not been achieved. The present work reviews the literature on syngeneic or allogeneic bone marrow transplantation (BMT) in patients infected with HIV and in patients with acquired immune deficiency syndrome (AIDS). Thirty-two such attempts have been reported between 1982 and 1996. In two cases, HIV was eradicated and previously positive polymerase chain reaction (PCR) for viral DNA and RNA became negative. One patient had transient disappearance of HIV by PCR and several more, including one who underwent xenotransplantation of baboon bone marrow, experienced clinical and laboratory improvement. These results correlate with use of intensive pre-transplant cytoablative conditioning with chemotherapy and radiotherapy. Curative mechanisms of conditioning include elimination of several cell populations: infected cells, cells susceptible to infection, uninfected chronically activated cells responsible for autoimmune phenomena, and exhausted haemopoietic and lymphopoietic progenitors. They are repopulated by donor-derived cells that could mount a successful antiviral response through cytotoxic T lymphocytes. Non-specific graft-versus-host effect of allogeneic bone marrow would also help eliminate residual reservoirs of virus, especially macrophages. Protection of repopulating cells from infection could be achieved by a combination of antiretroviral agents and gene therapy strategies may be of additional benefit.
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