Abstract
HIV infection elicits defects in CD4 T-cell homeostasis in both a quantitative and qualitative manner. Interleukin-7 (IL-7) is essential to T-cell homeostasis and several groups have shown reduced levels of the IL-7 receptor alpha-chain (CD127) on both CD4 and CD8 T-cells in viremic HIV+ patients. We have shown previously that soluble HIV Tat protein specifically down regulates cell surface expression of CD127 on human CD8 T-cells in a paracrine fashion. The effects of Tat on CD127 expression in CD4 T-cells has yet to be described. To explore this effect, CD4 T-cells were isolated from healthy individuals and expression levels of CD127 were examined on cells incubated in media alone or treated with Tat protein. We show here that, similar to CD8 T-cells, the HIV-1 Tat protein specifically down regulates CD127 on primary human CD4 T-cells and directs the receptor to the proteasome for degradation. Down regulation of CD127 in response to Tat was seen on both memory and naive CD4 T-cell subsets and was blocked using either heparin or anti-Tat antibodies. Tat did not induce apoptosis in cultured primary CD4 T-cells over 72 hours as determined by Annexin V and PI staining. Pre-incubation of CD4 T-cells with HIV-1 Tat protein did however reduce the ability of IL-7 to up regulate Bcl-2 expression. Similar to exogenous Tat, endogenously expressed HIV Tat protein also suppressed CD127 expression on primary CD4 T-cells. In view of the important role IL-7 plays in lymphocyte proliferation, homeostasis and survival, down regulation of CD127 by Tat likely plays a central role in immune dysregulation and CD4 T-cell decline. Understanding this effect could lead to new approaches to mitigate the CD4 T-cell loss evident in HIV infection.
Highlights
CD4 T-cell depletion is a hallmark of HIV disease progression
Given the effect of soluble HIV-1 Tat protein on CD127 expression on CD8 T-cells, we wanted to determine if this HIV regulatory protein had the same effect on CD4 T-cells
While CD127 surface expression varied little on cells cultured in medium alone over at least 72 hours, cells incubated in medium containing soluble Tat protein demonstrated a significant reduction in surface CD127 expression both in terms of percent positive cells and in mean channel fluorescence (Figures 1A and 1B)
Summary
The exact mechanisms by which HIV causes CD4 T-cell loss, have yet to be fully elucidated. While direct cytopathic effects of HIV and activation of HIV-specific natural killer cells and cytotoxic T-cells are two important means by which HIVinfected CD4 T-cells may be eliminated, these mechanisms likely explain only a portion of the loss given less than 0.2% of the peripheral CD4 T-cell population is productively infected [1,2,3]. Interleukin (IL)-7 is pivotal to T-cell survival and homeostasis and plays an important role in maintaining constant numbers of naıve and memory CD4 and CD8 T-lymphocytes in the peripheral circulation [9]. In the absence of IL-7 signaling there is a substantial depletion of T-cells from the peripheral circulation [18]
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