Mucosal immunity in human and simian immunodeficiency lentivirus infections

Brenchley, Jason M.

doi:10.1038/mi.2013.15

Cited by 64 publications

(68 citation statements)

References 111 publications

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“…The LPL compartment, which is the effector arm of the GI immune system, is enriched for viral target cells and consequently is a major site of viral replication, CD4 ϩ T-cell depletion, and dissemination. Additionally, active viral replication in this compartment stimulates increased proinflammatory cytokine/ chemokine production, which, in addition to amplifying the inflammatory reaction, also disrupts the intestinal epithelial barrier, facilitating microbial translocation and chronic local and systemic immune activation/inflammation (1,2). Consequently, the numerous effector cells that traffic into this compartment directly interact with cytokines and translocated microbial products, resulting in their persistent hyperactivation, thus setting up a vicious cycle involving viral replication, immune activation/inflammation, epithelial barrier disruption, and microbial translocation that eventually leads to AIDS progression.…”

Section: Discussionmentioning

confidence: 99%

“…Further, miR-223, previously associated with NK-cell activation, also showed decreased expression at 90 dpi (36,37). Furthermore, the expression of the Th17-enriched miR-301a (38) was significantly decreased at both time points, possibly be due to the virus-induced depletion of these cells (1,2). Figure S2 in the supplemental material shows the expression of 12 differentially expressed miRNAs in five animals compared longitudinally to their preinfection levels.…”

Section: Fig 3 Changes In Mirna Expression In Intestinal Lpls Of Rhesmentioning

confidence: 99%

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Longitudinal Examination of the Intestinal Lamina Propria Cellular Compartment of Simian Immunodeficiency Virus-Infected Rhesus Macaques Provides Broader and Deeper Insights into the Link between Aberrant MicroRNA Expression and Persistent Immune Activation

Kumar

Torben

Kenway

et al. 2016

J Virol

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Chronic immune activation/inflammation driven by factors like microbial translocation is a key determinant of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) disease progression. Although extensive research on inflammation has focused on studying protein regulators, increasing evidence suggests a critical role for microRNAs (miRNAs) in regulating several aspects of the immune/inflammatory response and immune cell proliferation, differentiation, and activation. To understand their immunoregulatory role, we profiled miRNA expression sequentially in intestinal lamina propria leukocytes (LPLs) of eight macaques before and at 21, 90, and 180 days postinfection (dpi). At 21 dpi, ϳ20 and 9 miRNAs were up-and downregulated, respectively. However, at 90 dpi (n ‫؍‬ 60) and 180 dpi (n ‫؍‬ 44), >75% of miRNAs showed decreased expression. Notably, the T-cell activation-associated miR-15b, miR-142-3p, miR-142-5p, and miR-150 expression was significantly downregulated at 90 and 180 dpi. Out of ϳ10 downregulated miRNAs predicted to regulate CD69, we confirmed miR-92a to directly target CD69. Interestingly, the SIV-induced miR-190b expression was elevated at all time points. Additionally, elevated lipopolysaccharide (LPS)-responsive miR-146b-5p expression at 180 dpi was confirmed in primary intestinal macrophages following LPS treatment in vitro. A major hallmark of untreated human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infection is chronic generalized immune activation and inflammation that is linked to viral replication, loss of CD4 ϩ T cells, immunological dysfunction, and disease progression (1-3). Further, chronic immune activation has been reported to persist even in HIV-infected individuals successfully treated with combination antiretroviral therapy (cART), suggesting that proinflammatory signaling does not completely subside in treated individuals (4). While the exact mechanisms driving chronic immune activation in HIV/SIV infection remain to be determined, several independent studies have implicated HIV persistence, coinfections with hepatitis C virus/ hepatitis B virus/cytomegalovirus (HCV/HBV/CMV), compensatory homeostatic mechanisms, and chronic stimulation by translocated intestinal microbial products to drive this phenomenon. Among these, microbial translocation from a structurally and functionally damaged gastrointestinal (GI) tract has received considerable attention and is considered to significantly contribute to

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Section: Discussionmentioning

confidence: 99%

Section: Fig 3 Changes In Mirna Expression In Intestinal Lpls Of Rhesmentioning

confidence: 99%

Longitudinal Examination of the Intestinal Lamina Propria Cellular Compartment of Simian Immunodeficiency Virus-Infected Rhesus Macaques Provides Broader and Deeper Insights into the Link between Aberrant MicroRNA Expression and Persistent Immune Activation

Kumar

Torben

Kenway

et al. 2016

J Virol

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“…ϩ T cells that express CCR5 and reside in mucosal tissues are selectively and rapidly depleted (116,120,121), associated with a disruption in the epithelial barrier that contributes to microbial translocation and systemic immune activation (20,27,28,122,123). In addition, by focusing infection onto T cell subsets that provide help for adaptive immune responses, including Th1, Th17, and Tfh cells, it is likely that CD4 tropism has profound effects on antiviral immune responses, which ultimately are inadequate to contain viral replication and disease progression.…”

Section: Discussionmentioning

confidence: 99%

Derivation and Characterization of a CD4-Independent, Non-CD4-Tropic Simian Immunodeficiency Virus

Swanstrom

Haggarty

Jordan

et al. 2016

J Virol

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CD4 tropism is conserved among all primate lentiviruses and likely contributes to viral pathogenesis by targeting cells that are critical for adaptive antiviral immune responses. Although CD4-independent variants of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) have been described that can utilize the coreceptor CCR5 or CXCR4 in the absence of CD4, these viruses typically retain their CD4 binding sites and still can interact with CD4. We describe the derivation of a novel CD4-independent variant of pathogenic SIVmac239, termed iMac239, that was used to derive an infectious R5-tropic SIV lacking a CD4 binding site. Of the seven mutations that differentiate iMac239 from wild-type SIVmac239, a single change (D178G) in the V1/V2 region was sufficient to confer CD4 independence in cell-cell fusion assays, although other mutations were required for replication competence. Like other CD4-independent viruses, iMac239 was highly neutralization sensitive, although mutations were identified that could confer CD4-independent infection without increasing its neutralization sensitivity. Strikingly, iMac239 retained the ability to replicate in cell lines and primary cells even when its CD4 binding site had been ablated by deletion of a highly conserved aspartic acid at position 385, which, for HIV-1, plays a critical role in CD4 binding. iMac239, with and without the D385 deletion, exhibited an expanded host range in primary rhesus peripheral blood mononuclear cells that included CCR5 ؉ CD8 ؉ T cells. As the first non-CD4-tropic SIV, iMac239-⌬D385 will afford the opportunity to directly assess the in vivo role of CD4 targeting on pathogenesis and host immune responses. IMPORTANCECD4 tropism is an invariant feature of primate lentiviruses and likely plays a key role in pathogenesis by focusing viral infection onto cells that mediate adaptive immune responses and in protecting virions attached to cells from neutralizing antibodies. Although CD4-independent viruses are well described for HIV and SIV, these viruses characteristically retain their CD4 binding site and can engage CD4 if available. We derived a novel CD4-independent, CCR5-tropic variant of the pathogenic molecular clone SIVmac239, termed iMac239. The genetic determinants of iMac239's CD4 independence provide new insights into mechanisms that underlie this phenotype. This virus remained replication competent even after its CD4 binding site had been ablated by mutagenesis. As the first truly non-CD4-tropic SIV, lacking the capacity to interact with CD4, iMac239 will provide the unique opportunity to evaluate SIV pathogenesis and host immune responses in the absence of the immunomodulatory effects of CD4 ؉ T cell targeting and infection.T he primate lentiviruses human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV) share a mechanism of target cell entry by interacting with CD4 and a member of the chemokine receptor family (1-3). CD4 binding to the envelope glycoprotein (Env) trimer initiates a ca...

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“…Action potential height was determined by measuring the threshold to the peak of the action potential. Voltage dependence of steady-state inactivation and activation was determined and fit via Boltzmann's distribution as described previously (Akbarali and Giles, 1993).…”

Section: Methodsmentioning

confidence: 99%

Effects of HIV-1 Tat on Enteric Neuropathogenesis

Ngwainmbi

Smith

et al. 2014

J. Neurosci.

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The gastrointestinal (GI) tract presents a major site of immune modulation by HIV, resulting in significant morbidity. Most GI processes affected during HIV infection are regulated by the enteric nervous system. HIV has been identified in GI histologic specimens in up to 40% of patients, and the presence of viral proteins, including the trans-activator of transcription (Tat), has been reported in the gut indicating that HIV itself may be an indirect gut pathogen. Little is known of how Tat affects the enteric nervous system. Here we investigated the effects of the Tat protein on enteric neuronal excitability, proinflammatory cytokine release, and its overall effect on GI motility. Direct application of Tat (100 nM) increased the number of action potentials and reduced the threshold for action potential initiation in isolated myenteric neurons. This effect persisted in neurons pretreated with Tat for 3 d (19 of 20) and in neurons isolated from Tat ϩ (Tatexpressing) transgenic mice. Tat increased sodium channel isoforms Na v 1.7 and Na v 1.8 levels. This increase was accompanied by an increase in sodium current density and a leftward shift in the sodium channel activation voltage. RANTES, IL-6, and IL-1␤, but not TNF-␣, were enhanced by Tat. Intestinal transit and cecal water content were also significantly higher in Tat ϩ transgenic mice than Tat Ϫ littermates (controls). Together, these findings show that Tat has a direct and persistent effect on enteric neuronal excitability, and together with its effect on proinflammatory cytokines, regulates gut motility, thereby contributing to GI dysmotilities reported in HIV patients.

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Mucosal immunity in human and simian immunodeficiency lentivirus infections

Cited by 64 publications

References 111 publications

Longitudinal Examination of the Intestinal Lamina Propria Cellular Compartment of Simian Immunodeficiency Virus-Infected Rhesus Macaques Provides Broader and Deeper Insights into the Link between Aberrant MicroRNA Expression and Persistent Immune Activation

Longitudinal Examination of the Intestinal Lamina Propria Cellular Compartment of Simian Immunodeficiency Virus-Infected Rhesus Macaques Provides Broader and Deeper Insights into the Link between Aberrant MicroRNA Expression and Persistent Immune Activation

Derivation and Characterization of a CD4-Independent, Non-CD4-Tropic Simian Immunodeficiency Virus

Effects of HIV-1 Tat on Enteric Neuropathogenesis

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