re-emerged in two Boston men who underwent
experimental antiretroviral therapy interruption after receiving bone marrow
stem cell transplants for cancer treatment, Timothy Henrich reported yesterday
at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) in Boston. These cases
suggest that a functional cure for HIV will be difficult to achieve if even a
small amount of residual virus remains in the body.
Henrich and Daniel Kuritzkes from Brigham and Women’s
Hospital first described the Boston
patients at the 2012 International AIDS Conference, with more
detailed follow-up presented at the International AIDS Society (IAS) meeting
donor bone marrow containing haematopoietic stem cells, which give rise to all
types of blood cells including the CD4 T-cells that harbour HIV. Both men's
donors had normal or 'wild-type' stem cells susceptible to HIV infection.
These cases therefore differ from the 'Berlin patient', who apparently
remains HIV-free seven years after stem cell transplants from a donor with a
double mutation (CCR5-delta-32) that makes cells resistant to HIV entry.
However, the Boston
patients themselves both carried a single copy of the protective mutation.
Also unlike the Berlin patient, the Boston men received what Henrich called "kinder
and gentler" reduced-intensity chemotherapy conditioning regimens that did
not kill off all their original immune cells. This enabled them to remain on
antiretroviral therapy (ART) throughout the transplant process.
The transplants were successful and the men's own
blood cells were progressively replaced by donor cells. Both men maintained
viral suppression after the procedure, and frequent and extensive testing over
the next few years showed very low levels of HIV. Not only did plasma HIV RNA
remain undetectable, but the virus also could not be found in large volumes of
peripheral blood mononuclear cells (PBMCs), lymph nodes or gut tissue using the
most sensitive assays.
After the men had been apparently HIV-free for 2.6 and
4.3 years, they and their providers agreed to try an analytical ART
interruption to see if the virus would return.
At the 2013 IAS meeting, Henrich reported that the men continued to have undetectable plasma
HIV RNA and undetectable integrated HIV DNA in PBMCs after 7 and 15 weeks
off ART, raising hopes that the stem cell transplant process might contribute
to a functional cure.
But these hopes turned to disappointment when Henrich reported last
December at the International Workshop on
HIV Persistence that the virus had come back in both men.
The first patient experienced HIV re-emergence 12 weeks into his
treatment interruption, while the second man did not show signs of HIV rebound
until he had been off ART for eight months.
Once HIV was detected, both men experienced rapid HIV replication,
reaching viral loads in the millions. Both had detectable HIV in cerebrospinal
fluid. They also developed symptoms of acute retroviral syndrome, similar to
those sometimes seen when people first acquire HIV.
Both men restarted antiretroviral treatment after viral rebound. One
patient had developed a new NNRTI (non-nucleoside reverse transcriptase inhibitor) resistance mutation and switched to a
different fully active ART regimen. Both patients were able to regain viral
suppression, their symptoms rapidly resolved, their CD4 counts recovered and
they are doing well.
"Allogeneic hematopoietic stem cell transplantation can result in
loss of detectable HIV-1 from blood and gut tissue and antiretroviral-free
HIV-1 remission for variable duration," but "viral rebound occurred
despite a reduction in reservoir size...of at least 3 log10,"
the researchers summarised.
They suggested that long-lived tissue reservoirs that are inaccessible
to testing – perhaps including host macrophages which are replaced by donor
cells more slowly than T-cells after a transplant – may have contributed to
Virus detected after rebound was genetically similar, suggesting they
were clones of only one or a few residual remaining viruses. This implies that
even a few remaining HIV-infected cells may be enough to allow full viral
rebound once protective ART is stopped.
Speaking at a community cure workshop preceding the conference, Henrich explained that mathematical models indicate that if only
one HIV-infected cell remains, the chance of cure is high. If 10 cells remain,
viral rebound could take 10 years. If there are 100 residual cells, rebound
could still take up to three years.
While these outcomes are disappointing, they shed further light on HIV
persistence and how it might be overcome to enable a functional cure without
risky stem cells transplants. To date, it remains unclear what factors
contributed to temporary HIV remission in these men, what triggered viral
rebound, or why one patient was able to remain off ART so much longer than the
The researchers saw no increase in the strength of HIV-specific antibody
responses prior to viral rebound. The graft-versus-host reaction – in which
donor cells attack host tissues – may have played a role in continued
surveillance and clearance of residual HIV-infected recipient cells, the
researchers suggested. As reported in a related poster, Henrich said that chemotherapy
may play some role, "but by itself it doesn't seem to be doing too
"Analytic treatment interruption remains the most reliable measure
of viral persistence," the researchers concluded. "Defining the
nature and half-life of HIV-1 reservoirs is essential in order to achieve
durable antiretroviral-free remission."