Cause for caution on HIV cure report

6 February 2009. Related: Cure-related research, Basic science and immunology.

Richard Jefferys, TAG

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 positive 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 [1] 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 in November. [2]

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.

Source: TAG basic science blog (14 November 2008)
http://www.treatmentactiongroup.org/basicsciblog.aspx

References:

1. Huzicka I. Could bone marrow transplantation cure AIDS?: review. Med Hypotheses. 1999 Mar;52(3):247-57. PMID: 10362285.
   http://www.ncbi.nlm.nih.gov/pubmed/10362285
2. Schoofs M. A Doctor, a Mutation and a Potential Cure for AIDS. Wall Street Journal. (7 November 2008).
   http://online.wsj.com/article/SB122602394113507555.html