Abstract

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 (T_CM). 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 T_CM 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 independent.
Conclusions: We conclude that IL-7 induces suboptimal viral reactivation but vigorous cell proliferation of T_CM. 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.