BOSTON -- Researchers must have learned something from the two men who have become known in HIV circles as "the Boston patients."
But it's not clear exactly what.
Near the end of the annual Conference on Retroviruses and Opportunistic Infections, Tim Henrich, MD, of Brigham and Women's Hospital in Boston presented the fullest description yet of what happened with the Boston patients.
The bottom line appears to be this: an allogeneic stem cell transplant can make HIV almost undetectable and lead to remission -- without antiretroviral therapy -- "of variable duration."
In this experiment, that variable duration was 12 weeks for Patient A and 8 months for Patient B.
Both patients needed an allogeneic transplant for other reasons -- Hodgkin lymphoma for Patient A and myelodysplastic syndrome for Patient B.
In both cases, the donor cells did not have the CCR5 delta32 mutation that renders T cells immune to HIV, but both men were heterozygous for the mutation.
The men were given what Henrich called a "kinder, gentler" conditioning regimen to prepare for the transplants, which did not include whole-body irradiation or anti-thymocyte immune globulin.
They remained on their effective antiretroviral regimens throughout the process and for several months afterward.
Note the contrasts with the case of Timothy Brown, the so-called Berlin patient. Brown had full myeloablative conditioning before his transplant along with chemotherapy. The donor cells were homozygous for delta32 and he went off his anti-HIV medication.
One similarity -- all three men suffered graft-versus-host disease, a common consequence of transplants.
In the wake of the Berlin patient reports, researchers asked what had led to the unexpected outcome. Most attention centered on the HIV-resistant donor cells, but there were other possibilities -- the transplant process itself and the graft-versus host disease were two.
Henrich and colleagues noticed that starting several months after the transplants, they could no longer detect HIV DNA in peripheral blood mononuclear cells or in CD4 cells, or on other sensitive assays.
This apparent absence of HIV lasted for almost 4 years in one case and 2 years in the other. So Henrich and colleagues, along with the patients, decided to see what would happen if the men stopped therapy.
First, Henrich reported, the researchers flow-sorted 100 million or more peripheral blood mononuclear cells from apheresis samples taken before therapy was stopped.
They quantified the amount of HIV DNA in several subsets of CD4 -- naïve, stem cell memory, central memory, effector memory, and terminally differentiated -- and came up all but empty.
In Patient A, they found a low-level signal in the short-lived terminally differentiated CD4 cells, but nothing in the other types, while Patient B had no detectable HIV DNA, period.
HIV, it still seemed, had vanished. The reservoir was empty.
Now, it's important to note that this was all done very carefully and by the book. Before the treatment interruption, the investigators monitored HIV closely. During the treatment interruption, they frequently checked clinical viral load and HIV DNA in blood, as well as conducting large-volume blood sampling after the first few weeks and again every 3 months.
And they had a clear rule for restarting therapy -- if the plasma viral load spiked once to 1,000 copies/ml or there were at least two readings of 200 copies.
When that eventually happened, both men had what looked like an acute infection -- understandable since their new immune system was naïve to HIV.
And interestingly, analysis showed that the recrudescent HIV in Patient A is monophyletic -- derived from a single ancestor -- rather than genetically diverse, as it was before (Henrich did not present evidence from Patient B at the meeting.)
Henrich said that probably means that one, or a handful of cells at most, reactivated and began the infection process anew. Many more infected cells might still be present but undetected and quiescent.
The implication is that just reducing the size of the HIV reservoir is not going to be enough to cause lasting remission, he said, adding that "it's going to be a multitiered approach."
But most people in the field that I've talked to were never very hopeful that just knocking down the reservoir would be all it took. Difficult as that appears to be, it would still be the first time HIV has yielded to a single intervention.
What's still not clear is exactly what happened in Boston. Something happened, that's for sure -- HIV usually rebounds in days after therapy is stopped, not months.
The problem is that the experiment had too many variables. It now seems less likely that the simple fact of transplant turned the trick. But what if Henrich and colleagues had used HIV-resistant donor cells? Would the remission have lasted longer? What if they had used wild-type cells, but the full-bore myeloablation? Or added chemotherapy?
It's even possible that allogeneic transplants cannot cure no matter what you do, but only lead -- as Henrich and colleagues put it -- to remission of "variable duration," with Timothy Brown just the longest so far.
I'm not sure the Boston experiment helped very much to winnow down the possibilities.
This study was funded by The Foundation for AIDS Research (AmfAR), NIH, the National Institute of Allergy and Infectious Diseases, and the Bill and Melinda Gates Foundation.
The authors reported no conflicts of interest.