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

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.

Virion incorporation of integrin α4β7 facilitates HIV-1 infection and intestinal homing

“…All the clinical isolates were minimally passaged (once or twice) in human PBMC in vitro . SIV isolates smE660.307 (51) and mac251.745 (39) were obtained in our laboratory from the peripheral blood of chronically infected in paientss and expanded in activated human PBMC.…”

Dying to protect: cell death and the control of T‐cell homeostasis

“…IL-7 treatment of both SIV infected and uninfected non-human primates also augmented lymphocyte numbers considerably (361). IL-7 treatment during acute SIV infection was associated with sustained increase in the expression of Bcl-2 on both CD4 + and CD8 + T cells, expansion of CD8 + T-cells and development of antigen-specific responses (362). IL-7 therapy enhanced circulating CD4 + and CD8 + T cell numbers and homeostatic proliferation in HIV infected patients (363) and in patients undergoing ART, recombinant human IL-7 resulted in a dose-dependent, durable CD4 + T cell increase, associated with increased cell cycling and a transient increase in Bcl-2 expression (364).…”

Human Immunodeficiency Virus (HIV) Latency: The Major Hurdle in HIV Eradication

“…In addition, immune responses of HIV-infected patients may be inadequate to eliminate reactivated HIV-infected T cells (232); hence, treatments stimulating CTL response or targeting toxins to infected cells should be added to the therapy regimens. Interestingly, IL-7 was found to boost antiviral CTL response against SIV in rhesus macaques (233).…”