Homeostatic proliferation of memory T-cells and expansion of the HIV-1 latent reservoir
Presented by Vicente Planelles (United States).
A. Bosque, V. Planelles
University of Utah, Pathology, Salt Lake City, United States
Background: Homeostatic proliferation is the ability of T cells to divide in the
absence of activation, and is triggered by IL-7. It is conceivable that the latent viral
reservoir may be perpetuated or expanded through homeostatic proliferation
of memory T cells.
Methods: We describe a system whereby naive cells from peripheral blood are induced to undergo normal development ex vivo in the
presence of the appropriate cytokine cocktails and antigenic stimulation
through CD3/CD28. These cells are infected while in the activated state, and
return to quiescence as central memory cells (TCM). Infection of
these ex-vivo-generated memory cells leads to latency with a high frequency and
results in the formation of a polyclonal population of integrated viruses.
Using this paradigm, we have explored the influence of homeostatic
proliferation of TCM on HIV-1 latency.
Results: We have examined the influence of cell cycle on viral reactivation entry
and found that memory lymphocytes harboring latent proviruses are
capable of cell division without viral reactivation when incubated in
the presence of IL-2+IL-7. We have also observed that a
combination of IL-2 and IL-7 induces inefficient viral reactivation (20%
of that with antiCD3/antiCD28). While IL-2+IL-7 treatment
induces inefficient reactivation, this cytokine cocktail triggers vigorous
cellular proliferation. Under the above
conditions, the net effect of IL-2+IL-7 treatment is an expansion, not a
contraction, of the latent reservoir. We also examined the signaling pathway
that leads to HIV-1 reactivation upon IL-2+IL-7 incubation and found that it is both NFAT and NFκB
Conclusions: We conclude that IL-7 induces suboptimal viral reactivation but vigorous cell proliferation of TCM. This concept has great
relevance to therapy because of the implicit consequence that the latent
reservoir may be subject to homeostatic expansion. This mechanism could be
contributing to the persistence of HIV-1 latency and should be taken into
account when designing anti-latency treatments.
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