It has been known for decades that the development of a
pathogen-specific immune response involves the activation (or “priming”) of
naïve CD4 T cells. These cells subsequently divide extensively and, over a
matter of weeks, generate memory CD4 T cells that coordinate ongoing
surveillance against the pathogen (in many cases protecting against
re-infection or, for some persistent infections such as CMV, keeping the
pathogen in check for life). Based on this knowledge, it would be logical to
surmise that many studies must have been conducted to investigate how this
process plays out in HIV infection and the impact of the virus on HIV-specific
memory CD4 T cell generation. Surprisingly, this is not the case. A new study in PLoS One represents the first published attempt to evaluate the effect of HIV on
T cell priming in an in vitro model. This paper compliments the one detailed in
vivo study conducted to date, which was published by Zohn Zaunders and
colleagues in 2006.
The researchers, led by Rachel Lubon Sabado from NYU,
established an in vitro system in which highly purified naïve CD4 T cells and
antigen-presenting dendritic cells (both sampled from uninfected individuals) were
exposed to live or inactivated HIV. The inactivated virus was created by
chemical treatment with AT-2, a process developed by Larry Arthur and Jeff
Lifson at NCI. After prolonged culture, both HIV-specific CD4 and, to a lesser
extent, CD8 T cells could be generated. The magnitude of the
response was lower when infectious virus was used, suggesting that viral
replication impacts the memory T cell differentiation process. In terms of the
HIV epitopes targeted, there was considerable overlap with the epitope-specific
responses that have previously been described in vivo. The researchers
identified some novel CD4 T cell responses against Env and Pol proteins, which
led them to evaluate whether these responses might be seen in a cohort of
acutely infected individuals. They found that almost all of the novel responses
could be seen transiently during acute infection, but declined rapidly and became
undetectable in chronic infection.
In discussing the findings, the study authors suggest that
understanding why certain HIV-specific CD4 and CD8 T cell responses are rapidly
lost in acute infection is an important goal for future research, particularly
as long-term non-progressors tend to maintain responses better than individuals
with progressive disease. They also note that AT-2-inactivated HIV may be a
useful immunogen due to its ability to prime broad memory T cell responses from
naïve cells.
One other statement in the discussion is worth highlighting.
The researchers write: “The
continuous presence of viral antigens gives rise to new memory T cells from the
existing naïve population as long as the immune system remains functionally
intact and/or the existing naïve T cells can respond to HIV-antigens, thus
explaining the highly heterogeneous population of HIV-specific T cells that
exist in HIV-infected individuals.” Although this phenomenon has been alluded
to in prior studies, the implications for HIV pathogenesis may deserve more
careful consideration. In particular, ongoing activation of HIV-specific naïve T cells could
contribute to the elevated levels of immune activation that are observed in HIV
infection (these activated cells express very high levels of CD38). This would
be consistent with the correlation between immune activation and naïve T cell
depletion that has been reported in HIV infection. A recent basic immunology study also suggests that depletion of naïve T cells could contribute to microbial translocation, which
in turn can further exacerbate immune activation and naïve T cell depletion by broadening the array of antigens being presented to include those from gut bacteria.
PLoS ONE 4(1): e4256 doi:10.1371/journal.pone.0004256
Rachel Lubong Sabado1, Daniel G. Kavanagh2, Daniel E.
Kaufmann2, Karlhans Fru4, Ethan Babcock1, Eric Rosenberg2, Bruce Walker2,
Jeffrey Lifson3, Nina Bhardwaj1, Marie Larsson4*
1 New York University School of Medicine, New York, New
York, United States of America, 2 Partners AIDS Research Center (PARC),
Massachusetts General Hospital, Harvard Medical School, Charlestown,
Massachusetts, United States of America, 3 SAIC Fredrick, Inc., National Cancer
Institute, Fredrick, Frederick, Maryland, United States of America, 4 Molecular
Virology, Department of Clinical and Experimental Medicine, Linköping
University, Linköping, Sweden
Abstract
Background
The requirements for priming of HIV-specific T cell
responses initially seen in infected individuals remain to be defined.
Activation of T cell responses in lymph nodes requires cell-cell contact
between T cells and DCs, which can give concurrent activation of T cells and
HIV transmission.
Methodology
The study aim was to establish whether DCs pulsed with HIV-1
could prime HIV-specific T cell responses and to characterize these responses.
Both infectious and aldrithiol-2 inactivated noninfectious HIV-1 were compared
to establish efficiencies in priming and the type of responses elicited.
Findings
Our findings show that both infectious and inactivated HIV-1
pulsed DCs can prime HIV-specific responses from naïve T cells. Responses
included several CD4+ and CD8+ T cell epitopes shown to be recognized in vivo
by acutely and chronically infected individuals and some CD4+ T cell epitopes
not identified previously. Follow up studies of acute and recent HIV infected
samples revealed that these latter epitopes are among the earliest recognized
in vivo, but the responses are lost rapidly, presumably through
activation-induced general CD4+ T cell depletion which renders the newly
activated HIV-specific CD4+ T cells prime targets for elimination.
Conclusion
Our studies highlight the ability of DCs to efficiently
prime naïve T cells and induce a broad repertoire of HIV-specific responses and
also provide valuable insights to the pathogenesis of HIV-1 infection in vivo.
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