IL-7 Unable to Wake up HIV Sleepers ?
A recently published study shows that HIV viruses detected during episodic blips following interleukin-7 administration are similar to the viruses present before and after IL-7 therapy. This is bad news for eradication trials planning to use IL-7 to ‘purge’ HIV reservoirs.
Since the work of Roger Pomerantz group in 2005 (1), IL-7 is considered as a cytokine able to reactivate HIV in silent HIV reservoirs. Trials are ongoing or planned, which combine potent anti-retroviral combinations and IL-7 to ‘flush out’ the HIV reservoir (2).
An informative study published in AIDS (3) shows that the low level viremia induced by IL-7 likely reflects predominantly transient induction or release of virus from a preexisting pool rather than activation of silent quasispecies.
The study participants were HIV-1-infected adults who had plasma HIV-RNA levels less than 50 copies/ml and CD4 T-cell counts at least 100 cells/ml at screening and had received HAART for a minimum of 12 months. Participants received a single dose of subcutaneous recombinant human IL-7 on day 0. Plasma and PBMCs (5 x 106) samples were obtained at baseline (day 0 of recombinant human IL-7 therapy), during the episode of viral blips (day 4), and at a time when levels of plasma HIV-RNA had returned to less than 50 copies/ml
Transient ‘blips’ in plasma viremia were detected during the days of observed peak T-cell proliferation (day 4) and increased T-cell counts (day 14) in seven of 15 recombinant human IL-7 recipients with HIV-RNA less than 50 copies/ml at study entry. The magnitude of the blips was low (median: 79 copies/ml, range: 56–154 copies/ml).
Levels of proviral DNA remained stable during the 28-day sampling period. Baseline level of provirus did not appear to predict the likelihood of blipping during IL-7 therapy.
No increase in genetic diversity was observed. Overall, the plasma virus detected on day 4 was indistinguishable from the viral quasispecies present at day 0 and 28 within an individual patient. The episodic blips did not have any substantial impact on the distribution pattern of PBMCs proviral DNA. Instead, the diverse provirus population present at baseline persisted throughout the sampling period.
The low level viremia induced by IL-7 likely reflects predominantly
transient induction or release of virus from a preexisting pool rather than activation of silent quasispecies.
In conclusion, the viruses detected at the times of episodic HIV viremia were derived from the same sources giving rise to viruses in plasma before and after recombinant human IL-7 therapy, and it is likely that recombinant human IL-7 is inducing a transient viral burst primarily by amplifying virus present before IL-7 therapy, rather than inducing production from previously silent reservoirs.
1- Wang FX, Xu Y, Sullivan J, et al. IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART. J Clin Invest. 2005 Jan; 115(1):128-37.
2- Mok HP, Lever A. Waking up the sleepers: HIV latency and reactivation. J Formos Med Assoc. 2008 Dec; 107(12): 909-14.
3- Imamichi H, Degray G, Asmuth DM, Fischl MA, Landay AL, Lederman MM, Sereti I. HIV-1 viruses detected during episodic blips following interleukin-7 administration are similar to the viruses present before and after interleukin-7 therapy. AIDS. 2010 Nov 30. [Epub ahead of print]
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