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Wu L, KewalRamani VN.Dendritic-cell interactions with HIV: infection and viral dissemination. Nat Rev Immunol 6:859-868

Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA.
Nature reviews. Immunology (Impact Factor: 33.84). 12/2006; 6(11):859-68. DOI: 10.1038/nri1960
Source: PubMed

ABSTRACT Dendritic cells (DCs) are crucial for the generation and the regulation of adaptive immunity. Because DCs have a pivotal role in marshalling immune responses, HIV has evolved ways to exploit DCs, thereby facilitating viral dissemination and allowing evasion of antiviral immunity. Defining the mechanisms that underlie cell-cell transmission of HIV and understanding the role of DCs in this process should help us in the fight against HIV infection. This Review highlights the latest advances in our understanding of the interactions between DCs and HIV, focusing on the mechanisms of DC-mediated viral dissemination.

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    • "epithelium can support productive HIV-1 infection in vivo is controversial. It is known that these myeloid cells can sample antigens in the mucosa, capture the virus and transfer virus to susceptible CD4 þ T cells (Ballweber et al., 2011; Hu et al., 2004; Wu and KewalRamani, 2006). Furthermore, macrophages in the mucosa express the HIV-1 receptor CD4 and co-receptor CCR5, but their role in the initial events of HIV-1 infection is yet to be defined (Shen et al., 2009; Wira et al., 2005). "
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    ABSTRACT: Exosomes are membranous extracellular nanovesicles secreted by diverse cell types. Exosomes from healthy human semen have been shown to inhibit HIV-1 replication and to impair progeny virus infectivity. In this study, we examined the ability of healthy human semen exosomes to restrict HIV-1 and LP-BM5 murine AIDS virus transmission in three different model systems. We show that vaginal cells internalize exosomes with concomitant transfer of functional mRNA. Semen exosomes blocked the spread of HIV-1 from vaginal epithelial cells to target cells in our cell-to-cell infection model and suppressed transmission of HIV-1 across the vaginal epithelial barrier in our trans-well model. Our in vivo model shows that human semen exosomes restrict intravaginal transmission and propagation of murine AIDS virus. Our study highlights an antiretroviral role for semen exosomes that may be harnessed for the development of novel therapeutic strategies to combat HIV-1 transmission. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 08/2015; 482. DOI:10.1016/j.virol.2015.03.040 · 3.28 Impact Factor
    • "Dysregulation of DCs occurs during the course of HIV-1 disease (Sabado et al., 2010). Moreover, the early events in HIV-1–host interactions are likely to make critical contributions to disease progression (Neil and Bieniasz, 2009; Wu and KewalRamani, 2006). Vpr protein, which is enclosed within HIV-1 virions and is capable of causing cell cycle arrest in CD4 + T cells (Poon et al., 1998), is one of the HIV-1 proteins encountered by host cells during the early stage of infection (Cohen et al., 1990; Poon et al., 1998). "
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    ABSTRACT: Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that directly link the innate and adaptive immune responses. HIV-1 infection of DCs leads to a diverse array of changes in gene expression and play a major role in dissemination of the virus into T-cells. Although HIV-1 Vpr is a pleiotropic protein involved in HIV-1 replication and pathogenesis, its exact role in APCs such as DCs remains elusive. In this study, utilizing a microarray-based systemic biology approach, we found that HIV-1 Vpr differentially regulates (fold change > 2.0) more than 200 genes, primarily those involved in the immune response and innate immune response including type I interferon signaling pathway. The differential expression profiles of select genes involved in innate immune responses (interferon-stimulated genes [ISGs]), including MX1, MX2, ISG15, ISG20, IFIT1, IFIT2, IFIT3, IFI27, IFI44L, and TNFSF10, were validated by real-time quantitative PCR; the results were consistent with the microarray data. Taken together, our findings are the first to demonstrate that HIV-1 Vpr induces ISGs and activates the type I IFN signaling pathway in human DCs, and provide insights into the role of Vpr in HIV-1 pathogenesis. Copyright © 2015. Published by Elsevier B.V.
    Virus Research 06/2015; 208. DOI:10.1016/j.virusres.2015.06.017 · 2.83 Impact Factor
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    • "In fact, during the initial steps of viral infection the virus needs to overcome the mucosal barrier and to find proper target cells such as DCs, macrophages, activated CD4 T cells, to rapidly replicate and spread (87, 88). The presence of intraepithelial DCs, capable of sampling the “outside” and to rapidly bring and transfer the virus to neighbor CD4 T cells and activate them seems to be pivotal to infection establishment (87, 88). Accordingly, inflammation, immune activation and mucosal lesions (mostly due to other sexually transmitted infection, STI) enormously enhance sexual transmission (89, 90). "
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    ABSTRACT: Many attempts have been made or are ongoing for HIV prevention and HIV cure. Many successes are in the list, particularly for HIV drugs, recently proposed also for prevention. However, no eradication of infection has been achieved so far with any drug. Further, a residual immune dysregulation associated to chronic immune activation and incomplete restoration of B and T cell subsets, together with HIV DNA persistence in reservoirs, are still unmet needs of the highly active antiretroviral therapy, causing novel "non-AIDS related" diseases that account for a higher risk of death even in virologically suppressed patients. These "ART unmet needs" represent a problem, which is expected to increase by ART roll out. Further, in countries such as South Africa, where six millions of individuals are infected, ART appears unable to contain the epidemics. Regretfully, all the attempts at developing a preventative vaccine have been largely disappointing. However, recent therapeutic immunization strategies have opened new avenues for HIV treatment, which might be exploitable also for preventative vaccine approaches. For example, immunization strategies aimed at targeting key viral products responsible of virus transmission, activation, and maintenance of virus reservoirs may intensify drug efficacy and lead to a functional cure providing new perspectives also for prevention and future virus eradication strategies. However, this approach imposes new challenges to the scientific community, vaccine developers, and regulatory bodies, such as the identification of novel immunological and virological biomarkers to assess efficacy end-points, taking advantage from the natural history of infection and exploiting lessons from former trials. This review will focus first on recent advancement of therapeutic strategies, then on the progresses made in preventative approaches, discussing concepts, and problems for the way ahead for the development of vaccines for HIV treatment and prevention.
    Frontiers in Immunology 09/2014; 5:417. DOI:10.3389/fimmu.2014.00417
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