Coverage of some subjectively selected presentations from
the recent CROI meeting in Atlanta, in addition to the prior post on the case report of a potentially
functionally cured infant.
Gene Modification of
Virus-Specific CD4 T Cells
Patrick Younan from the Fred Hutchinson Cancer Research
Center delivered an interesting talk about transplantation of gene-modified
stem cells in pigtailed macaques (abstract, webcast—third in session). The experiment used lentiviral
vectors to deliver the gene for a virus entry inhibitor, C46 (also known as
M87o, it has a similar mechanism of action to the approved antiretroviral
Fuzeon), into stem cells along with a green fluorescent protein (GFP) marker to
make the modified cells identifiable. Four macaques underwent stem cell
transplantation, with two given C46-modified cells and two controls given cells
with only the GFP marker. All were subsequently challenged with the dual-tropic SIV/HIV hybrid virus SHIV89.6P. The two controls displayed typical rapid CD4 T-cell loss, and one was
euthanized at week 32 due to the onset of simian AIDS. In contrast, recipients
of the modified cells recovered CD4 T-cell counts after an initial dip and showed
significantly lower viral loads. Levels of gene-modified CD4 T cells peaked at
around 90% during acute infection, but subsequently declined to pre-challenge levels (around 20% in one animal, 55% in the other) during follow-up. Despite the decline in modified CD4 T cells, levels of unmodified
cells improved over time, suggesting a protective effect of the intervention on
the overall CD4 T-cell pool.
Further studies revealed that superior SHIV-specific CD4 T-cell and antibody responses were associated with the salutary
outcome. SHIV-specific CD4 T cells were not detectable in either of the
controls. Younan found that a striking 85%
of the SHIV-specific CD4 T cells in treated animals were gene-modified,
suggesting that protection of these cells had allowed them to better perform
their role of providing help to B cells and CD8 T cells. One potentially
encouraging implication of this work is that gene therapy approaches might not
have to protect all susceptible cells from HIV infection in order to offer
benefit; if sufficient numbers of HIV-specific CD4 T cells can be
protected, it is possible that these cells will do a better job of coordinating
the immune response against HIV, leading to improved control of viral
replication. This possibility is being investigated in ongoing trials of
Sangamo BioSciences SB-728-T gene therapy, which aims to protect CD4 T cells by
abrogating expression of the CCR5 coreceptor.
Engineering SIV to
Spare the CD4 T-Cell Help
Adrienne Swanstrom from the University of Pennsylvania described
a novel approach to defining the role of infection of CD4 T cells in SIV pathogenesis,
using an engineered version of the highly pathogenic SIVmac239—named iMac-ΔD385—that
does not bind the CD4 molecule (abstract, webcast—seventh in session). In a preliminary experiment involving just two
macaques, Swanstrom found that the modified virus replicated to levels
comparable to the wild-type SIVmac239 during acute infection and targeted a
variety of non-CD4 cell types, but was then robustly controlled by the immune
response. Strong neutralizing antibody responses were detected, which is
unusual in pathogenic SIV infection, and ongoing work is now looking at CD8 T-cell responses. The findings, at least so far, suggest that sparing CD4 T-cell
help led to more effective CD4 T cell–dependent immune responses and superior
control of SIV replication.
CMV Vector
Vaccination Leads to Apparent Clearance of SIV Infection
Louis Picker from the Vaccine and Gene Therapy Institute at Oregon
Health & Science University gave an update on results obtained in macaques
with a CMV-based vaccine against SIV (abstract, webcast—fourth in session). As Picker has shown in published work, the vaccine consistently facilitates strict control of
a pathogenic SIVmac239 challenge in around 50% of immunized macaques. The remarkable
news shared by Picker at CROI is that, over time, these protected animals
appear to clear SIV infection. This claim is based on multiple criteria,
including loss of detectable virus, waning of CD8 T-cell responses to viral
antigens not included in the vaccine, and the failure to
transmit infection to uninfected macaques despite transfer of over 50 million
blood and/or tissue white blood cells (in contrast, similar transfers from elite
controller animals or those on suppressive ART reliably transmitted infection).
Picker noted that the CD8 T-cell responses in the vaccine recipients appear to
“violate all the rules” in that they target very large numbers of different SIV
epitopes and, in many cases, their ability to recognize the virus involves MHC
class II molecules, which normally facilitate antigen recognition by CD4 T
cells rather than CD8 T cells. Picker is now working to shed further light on
these findings, as well as collaborating with the Vaccine and Gene Therapy
Institute of Florida to try and develop a CMV vaccine vector that can safely be
studied in humans.
Results from
Multidose Vorinostat Trial
Sharon Lewin from Monash University in Melbourne debuted
data from the first multidose trial of vorinostat (also known as SAHA) as a
potential anti-HIV latency drug (abstract, webcast—ninth in session). Consistent
with results published by David Margolis from a single-dose trial, expression of HIV
RNA significantly increased among the twenty participants after 14 days of
vorinostat. However, there was no evidence for reduction in the size of the
latent HIV reservoir, suggesting that additional approaches will be needed to
facilitate the elimination of the infected cells. As expected, vorinostat side
effects were more prevalent as a result of the multiple dosing, particularly
fatigue and lethargy.
Curing HIV Removes
the Scars of the Past
One small but encouraging piece of news about the lone adult
considered cured of HIV, Timothy Brown, was to be found in a presentation by
Joyce Sanchez from the University of Minnesota (abstract, webcast—second in session). Sanchez’s
study focused on lymphoid structure abnormalities in people with HIV,
particularly fibrotic (scarring) damage to lymph tissue resulting from
persistent HIV replication and associated immune activation. The extent of
lymph tissue fibrosis can be quantified by measuring collagen
deposition using imaging techniques. Sanchez showed that in gut lymph tissue,
even HIV controllers (individuals with low viral loads in the absence of ART) have
levels of collagen deposition that are higher than those of uninfected individuals
(15.9% compared with 7%). However, samples from Timothy Brown showed levels of
collagen deposition comparable to the uninfected study participants (6.8%), consistent
with studies showing no HIV activity in his body (despite the occasional
detection of viral genetic material that was reported last year).
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