Treatment with IL-7 Prevents the Decline of Circulating CD4+ T Cells during the Acute Phase of SIV Infection in Rhesus Macaques

Lia Vassena,Giulia Cassina,Michel Morre,Paolo Lusso,Mauro S Malnati,Bernard A Lafont,Vanessa M Hirsch,Huiyi Miao,Anthony S Fauci,Raffaello Cimbro,Michael A Proschan,Guido Silvestri

doi:10.1371/journal.ppat.1002636

Abstract

Although treatment with interleukin-7 (IL-7) was shown to transiently expand the naïve and memory T-cell pools in patients with chronic HIV-1 infection receiving antiretroviral therapy (ART), it is uncertain whether a full immunologic reconstitution can be achieved. Moreover, the effects of IL-7 have never been evaluated during acute HIV-1 (or SIV) infection, a critical phase of the disease in which the most dramatic depletion of CD4+ T cells is believed to occur. In the present study, recombinant, fully glycosylated simian IL-7 (50 µg/kg, s.c., once weekly for 7 weeks) was administered to 6 rhesus macaques throughout the acute phase of infection with a pathogenic SIV strain (mac251); 6 animals were infected at the same time and served as untreated controls. Treatment with IL-7 did not cause clinically detectable side effects and, despite the absence of concomitant ART, did not induce significant increases in the levels of SIV replication except at the earliest time point tested (day 4 post-infection). Strikingly, animals treated with IL-7 were protected from the dramatic decline of circulating naïve and memory CD4+ T cells that occurred in untreated animals. Treatment with IL-7 induced only transient T-cell proliferation, but it was associated with sustained increase in the expression of the anti-apoptotic protein Bcl-2 on both CD4+ and CD8+ T cells, persistent expansion of all circulating CD8+ T-cell subsets, and development of earlier and stronger SIV Tat-specific T-cell responses. However, the beneficial effects of IL-7 were not sustained after treatment interruption. These data demonstrate that IL-7 administration is effective in protecting the CD4+ T-cell pool during the acute phase of SIV infection in macaques, providing a rationale for the clinical evaluation of this cytokine in patients with acute HIV-1 infection.

Highlights

HIV-1 establishes a chronic active infection that evolves toward clinical immunodeficiency over a span of several years, accumulating evidence indicates that critical pathogenic events take place during the acute phase of infection, leading to a massive and seemingly irreversible depletion of CD4+ T cells, predominantly of the memory phenotype [1,2]
We previously demonstrated that interleukin-7 (IL-7), a nonredundant cytokine that plays a critical role in the development and homeostasis of the T-lymphoid compartment
IL-7 has been tested exclusively in patients with chronic HIV-1 infection, while it appears that the immune system is irreparably damaged during acute primary infection, within the first few weeks after encountering the virus

Summary

Introduction

HIV-1 establishes a chronic active infection that evolves toward clinical immunodeficiency over a span of several years, accumulating evidence indicates that critical pathogenic events take place during the acute phase of infection, leading to a massive and seemingly irreversible depletion of CD4+ T cells, predominantly of the memory phenotype [1,2]. A large fraction of the T-cell pool in the body is harbored in the gut-associated lymphoid tissue (GALT) [3], which has been identified as a primary anatomical site for CD4+ T-cell depletion in both HIV-1-infected patients [4,5,6] and SIV-infected nonhuman primates [1,2,7,8]; yet, the loss of CD4+ T cells within the early phase of infection appears to be a systemic phenomenon that involves all secondary lymphoid organs [1,9,10] Taken together, these observations suggest that interventions aimed at preventing or reducing the immunologic damage caused by HIV-1 would be most effective if implemented during the earliest stages of infection, before the pool of memory CD4+ T cells becomes irreversibly compromised. We previously demonstrated that interleukin-7 (IL-7), a nonredundant cytokine that plays a critical role in the development and homeostasis of the T-lymphoid compartment

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Conclusion