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Activation of HIV-1 expression in latently infected CD4+ T cells by the small molecule PKC412.

BACKGROUND: HIV-1 latency is a major obstacle for HIV-1 eradication. Extensive efforts are being directed toward the reactivation of latent HIV reservoirs with the aim of eliminating latently infected cells via the host immune system and/or virus-mediated cell lysis. RESULTS: We screened over 1,500 small molecules and kinase inhibitors and found that a small molecule, PKC412 (midostaurin, a broad-spectrum kinase inhibitor), can stimulate viral transcription and expression from the HIV-1 latently infected ACH2 cell line and primary resting CD4+ T cells. PKC412 reactivated HIV-1 expression in A

Epstein-Barr virus-recent advances.

Epstein-Barr virus is a tumorigenic herpes virus that is ubiquitous in the adult population. The virus is generally spread to and between young children through salivary contact, and only causes clinical illness where primary infection is delayed until adolescence or beyond, when an intense immunopathological reaction leads to the symptoms of infectious mononucleosis in roughly 50% of cases. More than 90% of the world's population carry Epstein-Barr virus as a life-long, latent infection of B lymphocytes. Recent data show that by mimicking B-cell antigen-activation pathways the virus enters th

Bromodomain proteins regulate human cytomegalovirus latency and reactivation allowing epigenetic therapeutic intervention.

Reactivation of human cytomegalovirus (HCMV) from latency is a major health consideration for recipients of stem-cell and solid organ transplantations. With over 200,000 transplants taking place globally per annum, virus reactivation can occur in more than 50% of cases leading to loss of grafts as well as serious morbidity and even mortality. Here, we present the most extensive screening to date of epigenetic inhibitors on HCMV latently infected cells and find that histone deacetylase inhibitors (HDACis) and bromodomain inhibitors are broadly effective at inducing virus immediate early gene ex

Variation in HIV-1 Tat activity is a key determinant in the establishment of latent infection.

Despite effective treatment, human immunodeficiency virus (HIV) persists in optimally treated people as a transcriptionally silent provirus. Latently infected cells evade the immune system and the harmful effects of the virus, thereby creating a long-lasting reservoir of HIV. To gain a deeper insight into the molecular mechanisms of HIV latency establishment, we constructed a series of HIV-1 fluorescent reporter viruses that distinguish active versus latent infection. We unexpectedly observed that the proportion of active to latent infection depended on a limiting viral factor, which created a

Pathogenesis and virulence of herpes simplex virus.

Two of the most prevalent human viruses worldwide, herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2, respectively), cause a variety of diseases, including cold sores, genital herpes, herpes stromal keratitis, meningitis and encephalitis. The intrinsic, innate and adaptive immune responses are key to control HSV, and the virus has developed mechanisms to evade them. The immune response can also contribute to pathogenesis, as observed in stromal keratitis and encephalitis. The fact that certain individuals are more prone than others to suffer severe disease upon HSV infection can be parti

Control of viral infections by epigenetic-targeted therapy.

Epigenetics is defined as the science that studies the modifications of gene expression that are not owed to mutations or changes in the genetic sequence. Recently, strong evidences are pinpointing toward a solid interplay between such epigenetic alterations and the outcome of human cytomegalovirus (HCMV) infection. Guided by the previous possibly promising experimental trials of human immunodeficiency virus (HIV) epigenetic reprogramming, the latter is paving the road toward two major approaches to control viral gene expression or latency. Reactivating HCMV from the latent phase ("shock and k

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… Herpes simplex virus latency: the DNA repair-centered pathway. Adv Virol. 2017;2017:7028194. 155. Kent JR, Zeng P-Y, Atanasiu D, Gardner J, Fraser NW, Berger SL. … B cell activation and the establishment of Epstein-Barr virus latency. J Exp Med. 1988;168:2059–2075. doi: 10.1084/jem.168.6.2059. 177. Speck SH, Chatila T, Flemington E. Reactivation of Epstein-Barr virus: regulation and function of the BZLF1 gene. …

Differential Expression of Immune Checkpoint Molecules on CD8+ T Cells Specific for Immunodominant and Subdominant Herpes Simplex Virus 1 Epitopes.

Herpes simplex virus 1 (HSV-1) causes a lifelong infection of neurons that innervate barrier sites like the skin and mucosal surfaces like the eye. After primary infection of the cornea, the virus enters latency within the trigeminal ganglion (TG), from which it can reactivate throughout the life of the host. Viral latency is maintained, in part, by virus-specific CD8+ T cells that nonlethally interact with infected neurons. When CD8+ T cell responses are inhibited, HSV-1 can reactivate, and these recurrent reactivation events can lead to blinding scarring of the cornea. In the C57BL/6 mouse,

HIV Tat as a latency reversing agent: turning the tables on viral persistence.

The 'shock and kill' approach to an HIV cure involves the use of latency reversing agents (LRAs) to reactivate latent HIV, with the aim to induce death of infected cells through virus induced cytolysis or immune mediated clearance. Most LRAs tested to date have been unable to overcome the blocks to transcription elongation and splicing that persist in resting CD4+ T cells. Furthermore, most LRAs target host factors and therefore have associated toxicities. Therefore, there remains a high need for HIV-specific LRAs that can also potently upregulate expression of multiply-spliced HIV RNA and vir

Between a shock and a hard place: challenges and developments in HIV latency reversal.

Latently infected cells that persist in HIV-infected individuals on antiretroviral therapy (ART) are a major barrier to cure. One strategy to eliminate latency is by activating viral transcription, commonly called latency reversal. Several small non-randomised clinical trials of latency reversing agents (LRAs) in HIV-infected individuals on ART increased viral production, but disappointingly did not reduce the number of latently infected cells or delay time to viral rebound following cessation of ART. More recent approaches aimed at reversing latency include compounds that both activate virus

Immunobiology of Varicella-Zoster Virus Infection.

Varicella-zoster virus (VZV) causes clinically significant illness during acute and recurrent infection accompanied by robust innate and acquired immune responses. Innate immune cells in skin and ganglion secrete type I interferon (IFN-I) and proinflammatory cytokines to control VZV. Varicella-zoster virus subverts pattern recognition receptor sensing to modulate antigen presentation and IFN-I production. During primary infection, VZV hijacks T cells to disseminate to the skin and establishes latency in ganglia. Durable T- and B-cell memory formed within a few weeks of infection is boosted by

Redefining the Epstein-Barr virus-encoded nuclear antigen EBNA-1 gene promoter and transcription initiation site in group I Burkitt lymphoma cell lines.

The Epstein-Barr virus-encoded nuclear antigen EBNA-1 gene promoter for the restricted Epstein-Barr virus (EBV) latency program operating in group I Burkitt lymphoma (BL) cell lines was previously identified incorrectly. Here we present evidence from RACE (rapid amplification of cDNA ends) cloning, reverse transcription-PCR, and S1 nuclease analyses, which demonstrates that the EBNA-1 gene promoter in group I BL cell lines is located in the viral BamHI Q fragment, immediately upstream of two low-affinity EBNA-1 binding sites. Transcripts initiated from this promoter, referred to as Qp, have th

Latent varicella-zoster viral DNA in human trigeminal and thoracic ganglia.

BACKGROUND: Some human herpesviruses become latent in dorsal-root ganglia. Primary infection with the varicella-zoster virus causes chickenpox, followed by latency, and subsequent reactivation leading to shingles (zoster), but the frequency and distribution of latent virus have not been established. METHODS: Using the polymerase chain reaction, we performed postmortem examinations of trigeminal and thoracic ganglia of 23 subjects 33 to 88 years old who had not recently had chickenpox or shingles to identify the presence of latent varicella-zoster viral DNA. Oligonucleotide primers representin

Latent murine gamma-herpesvirus infection is established in activated B cells, dendritic cells, and macrophages.

Intranasal infection of mice with the murine gamma-herpesvirus MHV-68 results in an acute lytic infection in the lung, followed by the establishment of lifelong latency. Development of an infectious mononucleosis-like syndrome correlates with the establishment of latency and is characterized by splenomegaly and the appearance of activated CD8+ T cells in the peripheral blood. Interestingly, a large population of activated CD8+ T cells in the peripheral blood expresses the V beta 4+ element in their TCR. In this report we show that MHV-68 latency in the spleen after intranasal infection is harb

A Single-Cell Perspective on the Effects of Dopamine in the Regulation of HIV Latency Phenotypes in a Myeloid Cell Model.

Psychostimulants such as methamphetamine (Meth) induce high dopamine (DA) levels in the brain, which can modify immune cells expressing DA receptors. This is relevant in conditions of infection with the human immunodeficiency virus (HIV), overlapping with substance use. However, the effects of DA on HIV latency phenotypes are largely unknown. We used single-cell methods and gene network computational analysis to understand these relationships, using the U1 latent promonocyte model to identify signatures of latency and its reversal in the context of DA exposure. Our findings point to mechanisms

T-cell immunity in human herpesvirus vaccine development: research advances and translational challenges.

Human herpesviruses are widespread, establish lifelong latency, undergo intermittent or context-dependent reactivation, and cause diverse clinical manifestations. These features distinguish herpesvirus vaccine development from that for most acute infections. For indications involving latency, reactivation, or virus-associated disease, assessments based solely on the prevention of primary infection or on neutralizing-antibody responses do not capture all relevant mechanisms of immune control. Depending on the virus and indication, T cells may recognize infected or transformed cells, maintain im

Microtubule-Dependent Trafficking of Alphaherpesviruses in the Nervous System: The Ins and Outs.

The Alphaherpesvirinae include the neurotropic pathogens herpes simplex virus and varicella zoster virus of humans and pseudorabies virus of swine. These viruses establish lifelong latency in the nuclei of peripheral ganglia, but utilize the peripheral tissues those neurons innervate for productive replication, spread, and transmission. Delivery of virions from replicative pools to the sites of latency requires microtubule-directed retrograde axonal transport from the nerve terminus to the cell body of the sensory neuron. As a corollary, during reactivation newly assembled virions must travel

Gammaherpesvirus latency differentially impacts the generation of primary versus secondary memory CD8+ T cells during subsequent infection.

UNLABELLED: Unlike laboratory animals, humans are infected with multiple pathogens, including the highly prevalent herpesviruses. The purpose of these studies was to determine the effect of gammaherpesvirus latency on T cell number and differentiation during subsequent heterologous viral infections. Mice were first infected with murine gammaherpesvirus 68 (MHV68), a model of Epstein-Barr virus (EBV) infection, and then after latency was established, they were challenged with the Armstrong strain of lymphocytic choriomeningitis virus (LCMV). The initial replication of LCMV was lower in latently…

HIV-1 establishes immediate latency in T cells expressing the viral Nef protein.

A variety of dual reporter HIV-1 derivatives have been developed that enable detection of infected cells independently from transcription initiated from the 5' LTR promoter. These reporters enable isolation of cells that are latently infected with HIV-1 provirus. We have previously described several dual reporter derivatives, including Red Green HIV-1 (RGH), which expresses mCherry from a constitutive internal promoter and GFP from the 5' LTR. A limitation of most dual HIV-1 reporter derivatives, including RGH, is that the Nef ORF is often disrupted to accommodate insertion of the internal rep

The link between VLA-4 and JC virus reactivation.

Natalizumab represents an effective biological therapy to treat relapsing-remitting forms of multiple sclerosis and Crohn's disease by block … estions about the pathogenesis of PML but also has provided the opportunity to investigate sites of virus latency and mechanisms of trafficking to the brain.

HIV rebounds from latently infected cells, rather than from continuing low-level replication.

Rapid rebound of plasma viremia in patients after interruption of long-term combination antiretroviral therapy (cART) suggests persistence of low-level replicating cells or rapid reactivation of latently infected cells. To further characterize rebounding virus, we performed extensive longitudinal clonal evolutionary studies of HIV env C2-V3-C3 regions and exploited the temporal relationships of rebounding plasma viruses with regard to pretreatment sequences in 20 chronically HIV-1-infected patients having undergone multiple 2-week structured treatment interruptions (STI). Rebounding virus duri