New Light Shed on HIV-1 Reservoir Reductions After Stem Cell Transplant

By Will Boggs MD

October 16, 2018

NEW YORK (Reuters Health) - Several factors underlie a profound reduction in the HIV-1 reservoir in patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) for hematologic disease, researchers report.

Previous studies have found substantial reductions in the latent HIV-1 reservoir after allo-HSCT, including complete HIV-1 eradication in one case where the donor had a homozygous mutation in the HIV coreceptor CCR5.

In an effort to understand mechanisms underlying these reductions, Dr. Javier Martinez-Picado from IrsiCaixa AIDS Research Institute, Badalona, Spain and colleagues in the IciStem Consortium analyzed reductions in HIV latency and viral-specific humoral responses in 23 HIV-1-infected persons who had viral suppression due to combination antiretroviral therapy (cART) and high-risk hematologic disease that required allo-HSCT.

As reported October 15 online in Annals of Internal Medicine, all 23 participants achieved complete standard chimerism in peripheral blood and bone marrow in the first 12 months after allo-HSCT. One patient had delayed achievement of complete T-lymphocyte chimerism, and four patients had posttransplant graft-versus-host disease (GVHD).

Five of six participants with comprehensive biologic studies had undetectable HIV RNA in blood, and all six had undetectable HIV in CSF and cells from bone marrow, lymph node, and ileal biopsy specimens.

All five participants with undetectable HIV reservoirs had peripheral blood progenitor cells as the graft source. The only participant with a detectable HIV reservoir was the patient who had mixed chimera in T cells; this individual received a cord blood transplant with a conditioning regimen that contained antithymocyte globulin.

After allo-HSCT, all participants lost one or more antibody bands, and a longer interval after transplant seemed to be associated with greater antibody clearance among those receiving cART.

In a mouse model, none of the mice infused with cells from the six allo-HSCT recipients had detectable virus in plasma or cell-associated HIV DNA in the blood or spleen after 4 to 13 weeks of follow-up, suggesting that immediate viral rebound was not likely after discontinuation of cART in these transplant recipients.

"Allo-HSCT resulted in a profound long-term reduction in the HIV reservoir," the researchers conclude. "Such factors as stem cell source, conditioning, and a possible 'graft-versus-HIV-reservoir' effect may have contributed. Understanding the mechanisms involved in HIV eradication after allo-HSCT can enable design of new curative strategies."

Dr. Andrew D. Badley from Mayo Clinic, Rochester, Minnesota, who earlier reported significant reductions in the HIV-1 reservoir in an HIV-infected individual following allogeneic stem cell transplantation (ASCT), told Reuters Health by email, "ASCT (using wild-type CCR5 donors) causes significant reductions in the amount of detectable HIV by multiple measures when ART is continued in the peritransplant setting. Other reports have shown, however, that these reductions in HIV do not equate to HIV cure, as when an analytic treatment interruption is performed HIV eventually rebounds, often after periods of as long as 10 months."

"What this tells us is that ASCT alone significantly reduces HIV reservoirs, but does not eliminate them and, thus, alone is insufficient to cure HIV," he said. "It remains possible that ASCT plus another intervention could further reduce reservoir size, possibly to levels in which a cure is realized."

"For an intervention that reduces HIV reservoir size in a meaningful way to be applicable to the majority of people infected with HIV, that intervention must be simple safe and scalable," Dr. Badley said. "ASCT is not, so these results are of limited relevance to those without an underlying hematologic malignancy."

Dr. Gero Huetter from Universitaetsklinikum Carl Gustav Carus der TU Dresden, Germany, recently reviewed stem cell transplantation as a strategy for curing HIV/AIDS. He told Reuters Health, "Targeting HIV reservoir either by medical options or direct immunological effects by HIV-specific T-cells is still a promising approach to improve or replace common ART treatment. The question is still how sustained a reduction of the reservoir can be."

"To our knowledge, allotransplantation has the deepest effect on reservoir; however, it is not able the purge the reservoir this way, so it's hard to believe that other options have more success," he said by email.

Dr. Huetter added, "In this report all patients are still on cART. Therefore, the negative test results either by ultrasensitive PCR or viral outgrowth in animal models should be regarded with caution. The ultimate test to prove eradication would be a treatment interruption."

Dr. Martinez-Picado did not respond to a request for comments.


Ann Intern Med 2018.