HIV envelope binding by macrophage-expressed gp340 promotes HIV-1 infection

The scavenger receptor cysteine-rich protein gp340 functions as part of the host innate immune defense system at mucosal surfaces. In the genital tract, its expression by cervical and vaginal epithelial cells promotes HIV trans-infection and may play a role in sexual transmission. Gp340 is an alternatively spliced product of the deleted in malignant brain tumors 1 (DMBT1) gene. In addition to its innate immune system activity, DMBT1 demonstrates instability in multiple types of cancer and plays a role in epithelial cell differentiation. We demonstrate that monocyte-derived macrophages express gp340 and that HIV-1 infection is decreased when envelope cannot bind it. Inhibition of infection occurred at the level of fusion of M-, T-, and dual-tropic envelopes. Additional HIV-1 envelope binding molecules, such as dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), mannose-binding lectin, and heparan sulfate, enhance the efficiency of infection of the cells that express them by increasing the local concentration of infectious virus. Our data suggest that gp340, which is expressed by macrophages in vivo, may function to enhance infection in much the same manner. Its expression on tissue macrophages and epithelial cells suggests important new opportunities for HIV-1 pathogenesis investigation and therapy.     

干扰素刺激基因15在人类免疫缺陷病毒感染中作用的研究进展

随着有效的联合抗反转录病毒疗法(combination antiretroviral therapy,cART)的普及,人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染者的生存期逐步延长。这一过程中,HIV感染者自身免疫反应对免疫系统功能的恢复也发挥了至关重要的作用。HIV感染激活干扰素信号通路,诱导干扰素刺激基因(interferon-stimulated gene,ISG)上调表达,从而发挥抗病毒作用。其中,类泛素蛋白ISG15在HIV感染者中显著上调,通过ISG化抑制HIV颗粒的出芽和释放;而HIV的非结构蛋白则通过干扰ISG化过程或结合干扰素信号通路关键分子,逆转ISG15对病毒的抑制作用。本文从ISG15的生物学特性、在不同细胞亚群中的表达、抗病毒功能及病毒逃逸机制等方面进行综述,为进一步解析ISG15在HIV感染中扮演的角色、探索如何获得以抗HIV感染宿主因子为契机的治疗策略提供了思路。     

NK cells in HIV infection: paradigm for protection or targets for ambush

Natural killer cells are a crucial component of the innate immune response to certain tumours and to various viruses, fungi, parasites and bacteria. HIV has infected more than 60 million people worldwide and has led to more than 23 million deaths. At present, there are approximately 40 million people who are living with HIV infection, and there were 5 million new infections in 2004. As part of the innate immune system, natural killer cells might have an important role in host defence against HIV infection, as well as in the control of HIV replication in vivo. In this regard, it is important to understand how natural killer cells and HIV interact. This Review focuses on the role of natural killer cells in controlling HIV infection and on the impact of HIV and HIV-viraemia-induced immune activation on natural-killer-cell function.     

Interplay between hepatitis B virus and the innate immune responses: implications for new therapeutic strategies

Hepatitis B virus (HBV) infection is still a worldwide health problem; however, the current antiviral therapies for chronic hepatitis B are limited in efficacy. The outcome of HBV infection is thought to be the result of complex interactions between the HBV and the host immune system. While the role of the adaptive immune responses in the resolution of HBV infection has been well characterized, the contribution of innate immune mechanisms remains elusive until recent evidence implicates that HBV appears to activate the innate immune response and this response is important for controlling HBV infection. Here, we review our current understanding of innate immune responses to HBV infection and the multifaceted evasion by the virus and discuss the potential strategies to combat chronic HBV infection via induction and restoration of host innate antiviral responses.     

Interplay between hepatitis B virus and the innate immune responses:implications for new therapeutic strategies

Hepatitis B virus(HBV) infection is still a worldwide health problem;however,the current antiviral therapies for chronic hepatitis B are limited in efficacy.The outcome of HBV infection is thought to be the result of complex interactions between the HBV and the host immune system.While the role of the adaptive immune responses in the resolution of HBV infection has been well characterized,the contribution of innate immune mechanisms remains elusive until recent evidence implicates that HBV appears to activate the innate immune response and this response is important for controlling HBV infection.Here,we review our current understanding of innate immune responses to HBV infection and the multifaceted evasion by the virus and discuss the potential strategies to combat chronic HBV infection via induction and restoration of host innate antiviral responses.     

Cross-talk between virus and host innate immunity in pediatric HIV-1 infection and disease progression

Variability in the susceptibility to HIV-1 infection and disease progression depends on both virus and host determinants. Some exposed individuals remain HIV-1-uninfected and HIV-1-infected subjects develop disease at varying intervals with a small percentage remaining long-term non-progressors. As innate immunity is the earliest response to microbial entry and injury, host factors that impact innate immunity may play a role in viral infectivity and pathogenesis. In the pediatric population the interactions between the virus and the host may be of particular relevance due to the still developing adaptive immune system. Data indicate that genetic variants of defensins and Toll-Like Receptors (TLRs), key elements of innate immunity, play a role in mother-to-child transmission (MTCT) of HIV-1, and in the outcome of pediatric HIV-1 disease. Although the mechanisms by which these genetic variants influence HIV-1 interactions with the host are still largely unknown, defensins and TLRs, along with their link with regulatory T cells (Tregs), may play a critical role in the onset and persistence of immune activation, a hallmark of HIV-1 disease.     

Disruption of Type I Interferon Induction by HIV Infection of T Cells

Our main objective of this study was to determine how Human Immunodeficiency Virus (HIV) avoids induction of the antiviral Type I Interferon (IFN) system. To limit viral infection, the innate immune system produces important antiviral cytokines such as the IFN. IFN set up a critical roadblock to virus infection by limiting further replication of a virus. Usually, IFN production is induced by the recognition of viral nucleic acids by innate immune receptors and subsequent downstream signaling. However, the importance of IFN in the defense against viruses has lead most pathogenic viruses to evolve strategies to inhibit host IFN induction or responses allowing for increased pathogenicity and persistence of the virus. While the adaptive immune responses to HIV infection have been extensively studied, less is known about the balance between induction and inhibition of innate immune defenses, including the antiviral IFN response, by HIV infection. Here we show that HIV infection of T cells does not induce significant IFN production even IFN I Interferon production. To explain this paradox, we screened HIV proteins and found that two HIV encoded proteins, Vpu and Nef, strongly antagonize IFN induction, with expression of these proteins leading to loss of expression of the innate immune viral RNA sensing adaptor protein, IPS-1 (IFN-β promoter stimulator-1). We hypothesize that with lower levels of IPS-1 present, infected cells are defective in mounting antiviral responses allowing HIV to replicate without the normal antiviral actions of the host IFN response. Using cell lines as well as primary human derived cells, we show that HIV targeting of IPS-1 is key to limiting IFN induction. These findings describe how HIV infection modulates IFN induction providing insight into the mechanisms by which HIV establishes infection and persistence in a host.     

Genomic HIV RNA induces innate immune responses through RIG-I-dependent sensing of secondary-structured RNA

Background

Innate immune responses have recently been appreciated to play an important role in the pathogenesis of HIV infection. Whereas inadequate innate immune sensing of HIV during acute infection may contribute to failure to control and eradicate infection, persistent inflammatory responses later during infection contribute in driving chronic immune activation and development of immunodeficiency. However, knowledge on specific HIV PAMPs and cellular PRRs responsible for inducing innate immune responses remains sparse.

Methods/Principal Findings

Here we demonstrate a major role for RIG-I and the adaptor protein MAVS in induction of innate immune responses to HIV genomic RNA. We found that secondary structured HIV-derived RNAs induced a response similar to genomic RNA. In primary human peripheral blood mononuclear cells and primary human macrophages, HIV RNA induced expression of IFN-stimulated genes, whereas only low levels of type I IFN and tumor necrosis factor α were produced. Furthermore, secondary structured HIV-derived RNA activated pathways to NF-κB, MAP kinases, and IRF3 and co-localized with peroxisomes, suggesting a role for this organelle in RIG-I-mediated innate immune sensing of HIV RNA.

Conclusions/Significance

These results establish RIG-I as an innate immune sensor of cytosolic HIV genomic RNA with secondary structure, thereby expanding current knowledge on HIV molecules capable of stimulating the innate immune system.     

Vpu mediates depletion of interferon regulatory factor 3 during HIV infection by a lysosome-dependent mechanism

HIV has evolved sophisticated mechanisms to avoid restriction by intracellular innate immune defenses that otherwise serve to control acute viral infection and virus dissemination. Innate defenses are triggered when pattern recognition receptor (PRR) proteins of the host cell engage pathogen-associated molecule patterns (PAMPs) present in viral products. Interferon regulatory factor 3 (IRF3) plays a central role in PRR signaling of innate immunity to drive the expression of type I interferon (IFN) and interferon-stimulated genes (ISGs), including a variety of HIV restriction factors, that serve to limit viral replication directly and/or program adaptive immunity. Productive infection of T cells by HIV is dependent upon the targeted proteolysis of IRF3 that occurs through a virus-directed mechanism that results in suppression of innate immune defenses. However, the mechanisms by which HIV controls innate immune signaling and IRF3 function are not defined. Here, we examined the innate immune response induced by HIV strains identified through their differential control of PRR signaling. We identified viruses that, unlike typical circulating HIV strains, lack the ability to degrade IRF3. Our studies show that IRF3 regulation maps specifically to the HIV accessory protein Vpu. We define a molecular interaction between Vpu and IRF3 that redirects IRF3 to the endolysosome for proteolytic degradation, thus allowing HIV to avoid the innate antiviral immune response. Our studies reveal that Vpu is an important IRF3 regulator that supports acute HIV infection through innate immune suppression. These observations define the Vpu-IRF3 interface as a novel target for therapeutic strategies aimed at enhancing the immune response to HIV.     

Monocyte/Macrophage-Mediated Innate Immunity in HIV-1 Infection:From Early Response to Late Dysregulation and Links to Cardiovascular Diseases Onset

Although monocytes and macrophages are key mediators of the innate immune system, the focus has largely been on the role of the adaptive immune system in the context of human immunodeficiency virus(HIV) infection. Thus more attention and research work regarding the innate immune system—especially the role of monocytes and macrophages during early HIV-1 infection—is required. Blood monocytes and tissue macrophages are both susceptible targets of HIV-1 infection,and the early host response can determine whether the nature of the infection becomes pathogenic or not. For example,monocytes and macrophages can contribute to the HIV reservoir and viral persistence, and influence the initiation/extension of immune activation and chronic inflammation. Here the expansion of monocyte subsets(classical, intermediate and non-classical) provide an increased understanding of the crucial role they play in terms of chronic inflammation and also by increasing the risk of coagulation during HIV-1 infection. This review discusses the role of monocytes and macrophages during HIV-1 pathogenesis, starting from the early response to late dysregulation that occurs as a result of persistent immune activation and chronic inflammation. Such changes are also linked to downstream targets such as increased coagulation and the onset of cardiovascular diseases.     

Characterization of an equine mannose-binding lectin and its roles in disease

The mannose-binding lectin (MBL), a pattern recognition serum protein, participates in the innate immune system of mammals as an opsonin. In humans, MBL plays a key role in first-line host defense against infection during the lag period prior to the development of a specific immune response. MBL also activates complement via the lectin pathway that requires a MBL-associated serine protease-2 (MASP-2). Homologues of human MBL (hMBL) have been identified in a variety of mammals, fish, and primitive animals such as ascidians. In this study, we report that equine MBL (eMBL) has properties that are similar to hMBL. In addition, we found low levels of MBL:MASP activity in sick horses compared to healthy horses. These results suggest that eMBL is involved in the immune response of the horse and that low MBL:MASP activity could be used to monitor immune function and clinical outcome.     

Drugs of abuse and HIV infection/replication: implications for mother-fetus transmission

Human immunodeficiency virus (HIV) infection and progression of acquired immunodeficiency syndrome (AIDS) can be modulated by a number of cofactors, including drugs of abuse. Opioids, cocaine, cannabinoids, methamphetamine (METH), alcohol, and other substances of abuse have been implicated as risk factors for HIV infection, as they all have the potential to compromise host immunity and facilitate viral replication. Although epidemiologic evidence regarding the impact of drugs of abuse on HIV disease progression is mixed, in vitro studies as well as studies using in vivo animal models have indicated that drugs of abuse have the ability to enhance HIV infection/replication. Drugs of abuse may also be a risk factor for perinatal transmission of HIV. Because high levels of viral load in maternal blood are associated with increased risk of HIV vertical transmission, it is likely that drugs of abuse play an important role in promoting mother-fetus transmission. Furthermore, because the neonatal immune system differs qualitatively from the adult system, it is possible that maternal exposure to drugs of abuse would exacerbate neonatal immunity defects, facilitating HIV infection of neonate immune cells and promoting HIV vertical transmission. The availability and use of antiretroviral therapy for women infected with HIV increase, there is an increasing interest in determining the impact of drug abuse on efficacy of AIDS Clinical Trials Group (ACTG)-standardized treatment regimens for woman infected with HIV in the context of HIV vertical transmission.     

抗系统性白念珠菌感染的先天性免疫

白念珠菌是引起浅部、深部真菌感染常见的病原菌.先天免疫反应在宿主抗系统性白念珠菌感染中起主导作用.介导宿主抗念珠菌感染的先天性免疫包括一系列真菌识别受体及免疫效应细胞.宿主对系统性白念珠菌感染的免疫反应是决定患者预后的关键.本文就宿主抗系统性白念珠菌感染的先天性免疫机制进行综述.     

Interferon signaling in the liver during hepatitis C virus infection

Hepatitis C virus is a global health concern, estimated to infect 2-3% of the world's population. Inter-individual differences in the course of infection and response to therapy, highlighted by recent genomewide association studies, point to the crucial role of the host immune system in the efficient control of infection. Ongoing progress in the studies of the role of innate immunity during hepatitis C virus infection has improved our understanding of the intricacies of the host-virus interactions. In this review, we summarize and discuss the current knowledge concerning interferon signaling in the liver during acute and chronic hepatitis C virus infection and its implications for the outcome of interferon-α-based antiviral therapies.     

An Intra-Host Mathematical Model on Interaction Between HIV and Malaria

In this paper a mathematical model is proposed for the interaction of the immune system with HIV viruses and malaria parasites in an individual host. It consists of a system of three coupled ordinary differential equations, which represents the rate of change in the concentration of malaria parasites, HIV viruses and immunity effector within a host, respectively. The theoretical model gives insight into the biological balance between pathogen replication and the immune response to the pathogen: persistence versus elimination of the pathogen, which determines the outcome of infection. Dynamical analysis shows that the outcomes of the interactions between the immune system of the host with either malaria parasites or HIV viruses are dramatic such as malaria infection promoting proliferation of HIV virus, HIV infection increasing the risk from malaria and the immune system of the host failing to keep the diseases under control, etc. The results provide a new perspective for understanding of the complexity mechanisms of the co-infection (or dual infection) with malaria and HIV in a host.     

Who is in control of the stickleback immune system: interactions between Schistocephalus solidus and its specific vertebrate host

The cestode Schistocephalus solidus is a frequent parasite of three-spined sticklebacks and has a large impact on its host's fitness. Selection pressure should therefore be high on stickleback defence mechanisms, like an efficient immune system, and also on parasite strategies to overcome these. Even though there are indications for manipulation of the immune system of its specific second intermediate host by the cestode, nothing is yet known about the chronology of specific interactions of S. solidus with the stickleback immune system. We here expected sticklebacks to first mount an innate immune response directly post-exposure to the parasite to clear the infection at an early stage and after an initial lag phase to upregulate adaptive immunity. Most interestingly, we did not find any upregulation of the specific lymphocyte-mediated immune response. Also, the pattern of activation of the innate immune system did not match our expectations: the proliferation of monocytes followed fluctuating kinetics suggesting that the parasite repeatedly installs a new surface coat not immunogenic to the host. Furthermore, the respiratory burst activity, which has the potential to clear an early S. solidus infection, was upregulated very late during infection, when the parasite was too big to be cleared but ready for transmission to its final host. We here suggest that the late activation of the innate immune system interferes with the neuroendocrine system, which mediates reduced predation avoidance behaviour and so facilitates the transmission to the final host.     

Immunologic basis for revaccination of HIV-infected children receiving HAART

With increasing access to antiretroviral therapy for children infected with HIV, especially in sub-Saharan Africa, better understanding of the development and maintenance of memory T- and B-cell responses to pathogens after immune reconstitution is needed to assess the risk of infection. Knowledge of long-term immune responses after starting HAART is of particular importance for policies on revaccination of HIV-infected children, who may lose protective immunity to prior infections and immunizations. We review normal development of T- and B-cell memory responses to viruses and vaccines against viral pathogens, and contrast the immunological effects of perinatal HIV transmission with HIV infection acquired later in life. We then explore the potential benefits of antiretroviral therapy and revaccination, using measles virus as a model.