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. Moreover, our previous work demonstrated that IL-7 is a potent inducer of the main gut-homing integrin, alpha4beta7 (a4b7), which may serve as an additional cellular receptor for HIV-1 and is emerging as a critical molecule in the pathogenesis of HIV-1 disease. Indeed, the gut and its associated lymphoid tissue (GALT) constitute a primary anatomical site for HIV-1 replication, particularly during the early stages of HIV infection, leading to extensive depletion of CD4+ T cells. The role of a4b7 in HIV-1 infection is further corroborated by in vivo studies that documented a protective role of anti-a4b7 antibodies in macaques infected with simian immunodeficiency virus (SIV). Intravenous administration of a primatized anti-a4b7 monoclonal antibody (mAb), ACT-1, was found to prevent or delay SIV infection in macaques challenged by repeated low-dose vaginal inoculation. HIV-1 has the capacity to incorporate a range of host-cell proteins into its external envelope, which may affect its cellular tropism and infectivity. A few years ago, we found that a4b7 was one of the host proteins most efficiently incorporated by HIV-1. The virion-incorporated integrin 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. Over the past year, 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 single molecular clone of SIV mac239 was produced either with or without incorporated a4b7 in a recombinant system and used for macaque transmission studies after extensive infectivity titration in vitro. 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. A detailed characterization of the infection course after transmission in ongoing. With regard to IL-7, we have investigated whether this cytokine can induce the production of CCR5-binding chemokines, i.e., RANTES/CCL5, MIP-1a/CCL3 and MIP-1b/CCL4, which act as natural antagonists of HIV-1 infection. We found that IL-7, at suprahomeostatic concentrations and in the absence of any concomitant stimulation, is a potent inducer of anti-HIV chemokines as well as other cytokines involved in antimicrobial immune responses, and this effect requires an active and contact-dependent cross-talk between T cells and monocytes. An in-depth characterization of the mechanisms that mediate this intercellular cross-talk and the cell-associated and soluble factors involved is under way. We are also investigating the key role of TNF-a in the induction of anti-HIV chemokines by IL-7, as well as a cofactor for IFN activities. Overall, our results demonstrate that IL-7 initiates a program of immunologic defense against intracellular pathogens, like viruses, by 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.