Role of IL-7 and Integrin alpha4beta7 in Human Immunodeficiency Virus Infection

National Institute Of Allergy And Infectious Diseases

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Abstract

Interleukin-7 (IL-7) is the principal T-cell homeostatic factor in the body and is critical to reconstitute the normal T-lymphocyte pool when lymphopenia (loss of lymphocytes) occurs. Our previous work demonstrated that IL-7 is a potent inducer of the main gut-homing integrin, alpha4beta7 (a4b7), and thereby redirects nave T cells to the intestine, which is a primary anatomical site for HIV-1 replication. Furthermore, we found that a4b7 is incorporated into the HIV-1 virion during its egress from infected cells. Virion-incorporated a4b7 is functionally active as it is able to bind to its natural ligand, MAdCAM-1, and promote gut homing of HIV-1 viral particles in a mouse model. Importantly, a4b7 incorporation also occurs in vivo in HIV-infected patients and SIV-infected macaques, suggesting that it may be a critical virulence factor that promotes and sustains HIV-1 infection of the gut compartment, particularly during the early phases of HIV-1 infection. We have also demonstrated that another host receptor, P-selectin glycoprotein ligand-1 (PSGL-1/CD162), is incorporated into HIV-1 virions both in vitro and in vivo. We have started to investigate whether SIV virions containing incorporated a4b7 have an increased capacity to mediate viral transmission in a macaque model. Thus, a homogeneous molecular clone of SIVmac239 was produced either with or without incorporated a4b7 and used for transmission studies by the vaginal route in female macaques. Preliminary results suggest that the presence of incorporated a4b7 may facilitate infection, even though transmission was highly variable in different macaques, as expected in studies with outbred animals. Further studies are ongoing to evaluate if the advantage conferred by a4b7 incorporation may be more significant upon SIV transmission by the intrarectal route. With regard to IL-7, we have discovered a new function of this cytokine, by showing that, at suprahomeostatic concentrations, IL-7 is a potent inducer of anti-HIV chemokines (i.e., RANTES/CCL5, MIP-1a/CCL3 and MIP-1b/CCL4) and other cytokines involved in antimicrobial immune responses. This effect occurs in the absence of any other concomitant stimulation but requires an active and contact-dependent cross-talk between T cells and monocytes. An in-depth characterization of the mechanisms that mediate this IL-7 effect has demonstrated a key role of TNF-alpha. We have also characterized the signal transduction that mediates the IL-7 effects and performed RNAseq analysis, which has unraveled a complex program of gene expression aimed at antimicrobial defense readiness. We have re-evaluated the microarray results from a study of in vivo IL-7 treatment that we had performed in macaques 10 years ago (Vassena et al., PLoS Path 2012) and found that many of the genes activated in vitro by IL-7 are also induced in vivo in the macaque model. Finally, we have started to study the effect of interferon-alpha as a potential antagonist of the IL-7 effects. Overall, our results demonstrate that IL-7 initiates a program of immunologic defense against invading microbes through the concerted recruitment of multiple cytokines and chemokines. These results illustrate a novel potential mechanism of antimicrobial control that does not require the triggering of a full T-cell activation program and that the body may implement under conditions of lymphopenia in an attempt to reconstitute the lost immune function as well as to facilitate non-cytolytic immune-mediated suppression of HIV-1.