- Category: Search for a Cure
- Published on Thursday, 28 August 2014 00:00
- Written by Liz Highleyman
An additional 2 people with long-term HIV infection have no evidence of infectious virus or viral genetic material following bone marrow stem cell transplants to treat leukemia or lymphoma, researchers reported at the 20th International AIDS Conference last month in Melbourne. While these individuals remain on antiretroviral therapy (ART) and therefore cannot be considered functionally cured, they offer further evidence that HIV may be controlled off ART in some cases.
Several approaches are being explored in research towards a cure for HIV. The Berlin Patient, Timothy Brown, has remained free of detectable HIV for several years after receiving bone marrow transplants to treat lymphoma from a donor with an uncommon genetic mutation (CCR5-delta-32) that makes T-cells resistant to HIV infection.
Given this proof-of-concept, researchers have studied other HIV positive people undergoing bone marrow transplants to treat cancer. Bone marrow contains stem cells that give rise to all immune cells, including the CD4 T-cells targeted by HIV. It is unclear whether Brown's apparent cure was due to the donor's genetic mutation, the process of ablating or killing off the cancerous immune cells, a graft-vs-host reaction in which transplanted immune cells attack the recipient's body, or some other factors.
Kersten Koelsch and David Cooper from the University of New South Wales and colleagues presented posters at AIDS 2014 and at the preceding International AIDS Society Towards a Cure symposium describing 2 Australian men treated at St. Vincent's Hospital in Sydney who underwent allogeneic (self-donated) hematopoietic stem cell transplants. Unlike Brown, these patients received reduced-intensity conditioning prior to transplantation using milder chemotherapy that enabled them to remain on ART throughout the process.
The first patient (age 47), who received a transplant due to non-Hodgkin lymphoma in 2010, was CCR5-delta-32 heterozygous, meaning he had 1 copy of the protective mutation. The second (age 53), who underwent transplantation due to leukemia in 2011, had normal CCR5 genes. The first patient experienced grade 2 (moderate) graft-vs-host disease and reactivation of cytomegalovirus (CMV) infection, while the other had only a mild skin reaction.
Following bone marrow transplantation both men have no detectable HIV RNA in their blood plasma and no detectable HIV DNA by PCR in peripheral blood mononuclear cells (PBMCs) or CD4 T-cells according to sensitive tests. Neither shows CD4 T-cell responses to HIV antigens. One has only traces of HIV antibodies, while the other has absent antibodies.
"Assessment of the HIV-1 reservoir size in these 2 patients after allogeneic [bone marrow transplantation] with reduced-intensity conditioning shows undetectable HIV-1 RNA and DNA in peripheral blood and absent CD4+ T cell responses to HIV-1 antigen," the researchers concluded. "We also found a profound reduction in HIV-1 antibody detectability in both patients by Western blot."
While these results appear promising, a similar pair of bone marrow transplant patients in Boston experienced HIV relapse several months after stopping ART. Both men also received reduced-intensity conditioning and stayed on antiretrovirals during transplantation. After extensive testing over 3-4 years showed continued undetectable plasma HIV RNA, no HIV DNA in PBMCs, and no evidence of virus in lymph nodes or gut tissue, the patients underwent carefully monitored analytic treatment interruptionsto see if the virus would return. As Timothy Henrich from Brigham and Women’s Hospitalreported at this year's Retrovirus Conference and in the July 22 Annals of Internal Medicine, both men did eventually experience viral relapse, at 4 and 8 months after stopping ART.
While the Boston results were disappointing, the men were able to remain off ART for many weeks, indicating that some aspect of the transplant procedure helped them control HIV longer than would be expected without treatment. These late relapses despite undetectable HIV suggest that even a tiny amount of residual virus in reservoirs is enough to rekindle infection, making researchers more cautious about interrupting therapy in the Australian patients.
"This is another example of where the transplant can drive the amount of virus to levels that we simply cannot detect," Cooper told the Australian Associated Press. "But if we stopped the antiretroviral therapy, there would be a very strong chance that it would come back."
Yet each new case like this adds to the body of knowledge that may one day allow people with HIV to stay off ART for extended periods without disease progression.
"Cure research is looking for a way to move forward and my view is that this is a very important clue, that an immune response produced by bone marrow transplantation has such a strong anti-HIV effect," Cooper added. "We're going to use this as a model for cure research and see if we can develop some therapies that mimic what were doing with bone marrow transplantation."
KK Koelsch, WJ Hey-Cunningham, SC Sasson, et al. Allogeneic bone marrow transplantation in two HIV-1 infected patients shows no detectable HIV-1 RNA or DNA, and a profound reduction in HIV-1 antibodies. 20th International AIDS Conference. Melbourne, July 20-25, 2014. Abstract LBPE21.
Australian Associated Press. Two men with HIV 'cleared' in Sydney. SBS. July 19, 2014.
K Moskvitch. Cancer treatment clears two Australian patients of HIV. Nature. July 18, 2014.