Blocking of α4β7 Gut-Homing Integrin during Acute Infection Leads to Decreased Plasma and Gastrointestinal Tissue Viral Loads in Simian Immunodeficiency Virus-Infected Rhesus Macaques

Ansari, Aftab A.; Reimann, Keith A.; Mayne, Ann E.; Takahashi, Yoshiaki; Stephenson, Susan; Wang, Rijian; Wang, Xinyue; Li, JiChu; Price, Andrew A.; Little, Dawn; Zaidi, Mohammad Y.; Lyles, Robert H.; Villinger, François

doi:10.4049/jimmunol.1003052

Cited by 98 publications

(135 citation statements)

References 57 publications

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“…This balance is key in tissue remodeling, thus making it pertinent that our study showed upregulation of antiproteases in the follicular phase, when the vaginal epithelium is at its thickest, and showed protease upregulation in the luteal phase, when the epithelium is much thinner. Additionally, our genomic analyses showed overexpression in the luteal phase of genes for HIV-1-enhancing proteins: syndecans (48,49), TGF-␤ (50), and a retinoic acid receptor, RARB, which facilitates upregulation of important integrins, including ␣4␤7, and other cell receptors involved in gut homing of T cells, thus enabling enhanced acquisition and dissemination of HIV-1 (51). By showing that MCP-1 was overexpressed in the follicular phase, our study supports the existence of dual roles for proteins like those reported for MIP-3␣, present in the female genital tract (52).…”

Section: Discussionmentioning

confidence: 99%

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

Vishwanathan

Burgener

Bosinger

et al. 2015

J Virol

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Our earlier studies with pig-tailed macaques demonstrated various simian-human immunodeficiency virus (SHIV) susceptibilities during the menstrual cycle, likely caused by cyclic variations in immune responses in the female genital tract. There is concern that high-dose, long-lasting, injectable progestin-based contraception could mimic the high-progesterone luteal phase and predispose women to human immunodeficiency type 1 (HIV-1) acquisition and transmission. In this study, we adopted a systems biology approach employing proteomics (tandem mass spectrometry), transcriptomics (RNA microarray hybridization), and other specific protein assays (enzyme-linked immunosorbent assays and multiplex chemokine and cytokine measurements) to characterize the effects of hormonal changes on the expression of innate factors and secreted proteins in the macaque vagina. Several antiviral factors and pathways (including acute-phase response signaling and complement system) were overexpressed in the follicular phase. Conversely, during the luteal phase there were factors overexpressed (including moesins, syndecans, and integrins, among others) that could play direct or indirect roles in enhancing HIV-1 infection. Thus, our study showed that specific pathways and proteins or genes might work in tandem to regulate innate immunity, thus fostering further investigation and future design of approaches to help counter HIV-1 acquisition in the female genital tract. IMPORTANCEHIV infection in women is poorly understood. High levels of the hormone progesterone may make women more vulnerable to infection. This could be the case during the menstrual cycle, when using hormone-based birth control, or during pregnancy. The biological basis for increased HIV vulnerability is not known. We used an animal model with high risk for infection during periods of high progesterone. Genital secretions and tissues during the menstrual cycle were studied. Our goal was to identify biological factors upregulated at high progesterone levels, and we indeed show an upregulation of genes and proteins which enhance the ability of HIV to infect when progesterone is high. In contrast, during low-progesterone periods, we found more HIV inhibitory factors. This study contributes to our understanding of mechanisms that may regulate HIV infection in females under hormonal influences. Such knowledge is needed for the development of novel prevention strategies. F emale acquisition of human immunodeficiency virus type 1 (HIV-1) is not an efficient process, and transmission events are estimated to occur at frequencies of 1/100 to 1/1,000 exposures (1; reviewed in reference 2). Despite this, the heterosexual route is the predominant mode of HIV-1 transmission worldwide (3), and the development of strategies to reduce male-to-female vaginal transmission rates remains a priority. Animal studies have demonstrated that the time between vaginal exposure and virus detection in draining lymph nodes is as little as 1 to 3 days. There is a small window of early protection whe...

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Section: Discussionmentioning

confidence: 99%

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

Vishwanathan

Burgener

Bosinger

et al. 2015

J Virol

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“…Indeed, ␣4␤7 has been identified as an additional receptor molecule for HIV-1, 35 which might facilitate the initial transmission of the virus and its subsequent spread to lymphoid organs, particularly to the GALT. 36 Thus, it is conceivable that ␣4␤7 activation and proliferation induced by IL-7 could influence the levels of HIV-1 replication in the gut compartment. We are currently investigating the effects of the spontaneous rise in endogenous IL-7 and the consequent up-regulation of ␣4␤7 during the progression toward full-blown AIDS.…”

Section: Discussionmentioning

confidence: 99%

IL-7 induces expression and activation of integrin α4β7 promoting naive T-cell homing to the intestinal mucosa

Cimbro

Vassena

Arthos

et al. 2012

Blood

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Interleukin-7 (IL-7 IntroductionInterleukin-7 (IL-7) is a nonredundant cytokine that plays an essential role in lymphopoiesis and in the homeostasis of the T-lymphoid compartment in adults. 1,2 IL-7 is produced at constitutive levels by stromal cells resident in various organs, as well as by thymic and intestinal epithelial cells. 3 Under physiologic conditions, IL-7 supports long-term survival of naive and memory T cells without inducing proliferation, thereby maintaining the regular size of the T-cell pool. 2 Under conditions of lymphopenia, the concentration of IL-7 rises to suprahomeostatic levels (as reflected by plasma concentrations greater than 10 pg/mL) that induce proliferation of both naive and memory T cells with the aim of reconstituting the physiologic T-cell pool, a process commonly referred to as lymphopenia-induced proliferation. 2 Because of these unique biologic properties and lack of side effects typically associated with other cytokines such as IL-2, IL-7 is currently under clinical evaluation as an immune-reconstitution agent in various forms of immunodeficiencies, including those associated with AIDS and cancer. 4 Short-term courses of IL-7 administration in humans and macaques were shown to result in proliferation of both CD4 ϩ and CD8 ϩ T cells, with preferential expansion of naive T cells associated with increased diversification of the T-cell receptor (TCR) repertoire. [5][6][7][8][9] Remarkably, injection of IL-7 induces a rapid, albeit transient, reduction in circulating lymphocyte counts compatible with redistribution of these cells to peripheral tissues. 6,7 This phenomenon may reflect events that occur naturally when endogenous IL-7 increases to suprahomeostatic levels in response to lymphopenia. Although data obtained in macaques have suggested that lymph nodes, parts of the intestine, and the skin may be homing sites for T cells after IL-7 injection, 10 the anatomical sites where homeostatic processes take place and the molecular mechanisms underlying the IL-7-driven homing and proliferation of T cells in peripheral tissues remain largely undefined.The circulation of T cells from blood to secondary lymphoid organs and other tissues is governed by a complex network of tissue-homing mechanisms, which mainly relies on integrins, chemokine receptors, and their specific ligands. 11 In this study, we show that IL-7 selectively induces expression and functional activation of integrin ␣4␤7, the main intestinal lymphocyte homing receptor, [11][12][13][14] both in vitro and in vivo. This effect occurs predominantly in naive T cells, which indeed showed a marked and selective in vivo homing to the intestinal compartment of humanized mice after treatment with IL-7. The evidence presented in this study provides a mechanism for the rapid reduction of circulating T cells after in vivo IL-7 administration and suggests that ␣4␤7-mediated gut homing of naive T cells may be a fundamental step in the IL-7-driven T-cell reconstitution of lymphopenic hosts. Methods Cells and culture conditionsPeriphe...

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“…[25][26][27] The major population targeted by the virus is CD4 + T lymphocytes. Given the vital role of CD4 + T cells in the host defense against pathogens and cancer, HIVinduced progressive and chronic depletion of such T cells results in the collapse of the immune system, leading to opportunistic infections, malignancies, and ultimately death.…”

Section: The Importance Of Gastrointestinal Mucosa In Hiv Infectionmentioning

confidence: 99%

Induction of Intestinal Immunity by Mucosal Vaccines As a Means of Controlling HIV Infection

Poles

Alvarez²,

Hioe³

2014

AIDS Research and Human Retroviruses

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CD4+ T cells in the mucosa of the gastrointestinal (GI) tract are preferentially targeted and depleted by HIV. As such, the induction of an effective anti-HIV immune response in the mucosa of the GI tract-through vaccination-could protect this vulnerable population of cells. Mucosal vaccination provides a promising means of inducing robust humoral and cellular responses in the GI tract. Here we review data from the literature about the effectiveness of various mucosal vaccination routes-oral (intraintestinal/tonsilar/sublingual), intranasal, and intrarectal-with regard to the induction of immune responses mediated by cytotoxic T cells and antibodies in the GI mucosa, as well as protective efficacy in challenge models. We present data from the literature indicating that mucosal routes have the potential to effectively elicit GI mucosal immunity and protect against challenge. Given their capacity for the induction of anti-HIV immune responses in the GI mucosa, we propose that mucosal routes, including the nonconventional sublingual, tonsilar, and intrarectal routes, be considered for the delivery of the next generation HIV vaccines. However, further studies are necessary to determine the ideal vectors and vaccination regimens for these routes of immunization and to validate their efficacy in controlling HIV infection. HIV Epidemics and Treatment HIV infection has resulted in the death of millions since the early 1980s, and has been responsible for significant morbidity and decline in quality of life for millions more. Each year, an estimated 50,000 people are newly infected with the virus in the United States alone, adding to the 34 million currently living with the virus worldwide.

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Blocking of α4β7 Gut-Homing Integrin during Acute Infection Leads to Decreased Plasma and Gastrointestinal Tissue Viral Loads in Simian Immunodeficiency Virus-Infected Rhesus Macaques

Cited by 98 publications

References 57 publications

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

IL-7 induces expression and activation of integrin α4β7 promoting naive T-cell homing to the intestinal mucosa

Induction of Intestinal Immunity by Mucosal Vaccines As a Means of Controlling HIV Infection

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