Post-Transcriptional HIV-1 Latency: A Promising Target for Therapy?

Human Immunodeficiency Virus type 1 (HIV-1) latency represents a significant hurdle in finding a cure for HIV-1 infections, despite tireless research efforts. This challenge is partly attributed to the intricate nature of HIV-1 latency, wherein various host and viral factors participate in multiple physiological processes. While substantial progress has been made in discovering therapeutic targets for HIV-1 transcription, targets for the post-transcriptional regulation of HIV-1 infections have received less attention.

SARS-CoV-2-Specific Immune Responses in Vaccination and Infection during the Pandemic in 2020-2022.

To gain insight into how immunity develops against SARS-CoV-2 from 2020 to 2022, we analyzed the immune response of a small group of university staff and students who were either infected or vaccinated. We investigated the levels of receptor-binding domain (RBD)-specific and nucleocapsid (N)-specific IgG and IgA antibodies in serum and saliva samples taken early (around 10 days after infection or vaccination) and later (around 1 month later), as well as N-specific T-cell responses. One patient who had been infected in 2020 developed serum RBD and N-specific IgG antibodies, but declined eight months later, then mRNA vaccination in 2021 produced a higher level of anti-RBD IgG than natural infection.

Saliva as a useful tool for evaluating upper mucosal antibody response to influenza.

Mucosal immunity plays a crucial role in controlling upper respiratory infections, including influenza. We established a quantitative ELISA to measure the amount of influenza virus-specific salivery IgA (sIgA) and salivary IgG (sIgG) antibodies using a standard antibody broadly reactive to the influenza A virus. We then analyzed saliva and serum samples from seven individuals infected with the A(H1N1)pdm09 influenza virus during the 2019-2020 flu seasons.

Sustainable Antiviral Efficacy of Rejuvenated HIV-Specific Cytotoxic T Lymphocytes Generated from Induced Pluripotent Stem Cells.

Persistence of HIV latently infected cells is a barrier to HIV cure. The "kick and kill" strategy for a cure includes clearance of the viral reservoir by HIV-specific cytotoxic T lymphocytes (CTLs). However, exhaustion and senescence of T cells accelerates during HIV infection, and does not fully recover, despite complete viral suppression under antiretroviral therapy.

Perspectives on Non-BLT Humanized Mouse Models for Studying HIV Pathogenesis and Therapy.

A variety of humanized mice, which are reconstituted only with human hematopoietic stem cells (HSC) or with fetal thymus and HSCs, have been developed and widely utilized as in vivo animal models of HIV-1 infection. The models represent some aspects of HIV-mediated pathogenesis in humans and are useful for the evaluation of therapeutic regimens. However, there are several limitations in these models, including their incomplete immune responses and poor distribution of human cells to the secondary lymphoid tissues.

Development of an Inflammatory CD14 Dendritic Cell Subset in Humanized Mice.

Humanized mouse models are attractive experimental models for analyzing the development and functions of human dendritic cells (DCs) . Although various types of DC subsets, including DC type 3 (DC3s), have been identified in humans, it remains unclear whether humanized mice can reproduce heterogeneous DC subsets. CD14, classically known as a monocyte/macrophage marker, is reported as an indicator of DC3s.

Substantial induction of non-apoptotic CD4 T-cell death during the early phase of HIV-1 infection in a humanized mouse model.

Several mechanisms underline induction of CD4 T-cell death by human immunodeficiency virus (HIV) infection. For a long time, apoptosis was considered central to cell death involved in the depletion of CD4 T cells during HIV infection. However, which types of cell death are induced during the early phase of HIV infection in vivo remains unclear.

CD4 T Responses Other Than Th1 Type Are Preferentially Induced by Latency-Associated Antigens in the State of Latent Infection.

() produces a diverse range of antigenic proteins in its dormant phase. The cytokine profiles of CD4 T cell responses, especially subsets other than Th1 type (non-Th1 type), against these latency-associated antigens such as α-crystallin (Acr), heparin-binding hemagglutinin (HBHA), and mycobacterial DNA-binding protein 1 (MDP-1) remain elusive in relation to the clinical stage of infection. In the present study, peripheral blood mononuclear cells (PBMCs) collected from different stages of -infected cases and control PBMCs were stimulated with these antigens and ESAT-6/CFP-10.

Correction to: A CCR5 memory subset within HIV-1-infected primary resting CD4 T cells is permissive for replication-competent, latently infected viruses in vitro.

After publication of the original article [1], the authors became aware of a miscalculation in the original Fig. 2d.

A CCR5 memory subset within HIV-1-infected primary resting CD4 T cells is permissive for replication-competent, latently infected viruses in vitro.

Objective: Resting CD4 T cells are major reservoirs of latent HIV-1 infection, and may be formed during the early phase of the infection. Although CCR5-tropic (R5) HIV-1 is highly transmissible during the early phase, newly infected individuals have usually been exposed to a mixture of R5 and CXCR4-tropic (X4) viruses, and X4 viral DNA is also detectable in the host. Our aim was to identify which subsets of resting CD4 T cells contribute to forming the latent reservoir in the presence of both X4 and R5 viruses.

Introduction of Human Flt3-L and GM-CSF into Humanized Mice Enhances the Reconstitution and Maturation of Myeloid Dendritic Cells and the Development of Foxp3CD4 T Cells.

Two cytokines, fms-related tyrosine kinase 3 ligand (Flt3-L) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are considered to be the essential regulators of dendritic cell (DC) development . However, the combined effect of Flt3-L and GM-CSF on human DCs has not been evaluated . In this study, we, therefore, aimed at evaluating this using a humanized mouse model.

HIV LTR-Driven Antisense RNA by Itself Has Regulatory Function and May Curtail Virus Reactivation From Latency.

Latently infected T lymphocytes are an important barrier toward eliminating a persistent HIV infection. Here we describe an HIV-based recombinant fluorescent-lentivirus referred to as "rfl-HIV" that enables to analyze sense and antisense transcription by means of fluorescence reporter genes. This model virus exhibited similar transcriptional and functional properties of the antisense transcript as observed with a wild type HIV, and largely facilitated the generation of latently-infected T cells clones.

Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis.

Regulation of capsid disassembly is crucial for efficient HIV-1 cDNA synthesis after entry, yet host factors involved in this process remain largely unknown. Here, we employ genetic screening of human T-cells to identify maternal embryonic leucine zipper kinase (MELK) as a host factor required for optimal uncoating of the HIV-1 core to promote viral cDNA synthesis. Depletion of MELK inhibited HIV-1 cDNA synthesis with a concomitant delay of capsid disassembly.

HIV-1 susceptibility of transgenic rat-derived primary macrophage/T cells and a T cell line that express human receptors, CyclinT1 and CRM1 genes.

We developed transgenic (Tg) rats that express human CD4, CCR5, CXCR4, CyclinT1, and CRM1 genes. Tg rat macrophages were efficiently infected with HIV-1 and supported production of infectious progeny virus. By contrast, both rat primary CD4 T cells and established T cell lines expressing human CD4, CCR5, CyclinT1, and CRM1 genes were infected inefficiently, but this was ameliorated by inhibition of cyclophilin A.

Homeostatically Maintained Resting Naive CD4 T Cells Resist Latent HIV Reactivation.

Homeostatic proliferation (HSP) is a major mechanism by which long-lived naïve and memory CD4 T cells are maintained and suggested to contribute to the persistence of the latent HIV-1 reservoir. However, while many latency models rely on CD4 T cells that were initially differentiated via T-cell receptor (TCR) stimulation into memory/effector cells, latent infection of naïve resting CD4 T cells maintained under HSP conditions has not been fully addressed. Here, we describe an HSP culture system utilizing the cytokines IL-7 and IL-15 that allows studying latency in naïve resting CD4 T cells.

A novel dual luciferase assay for the simultaneous monitoring of HIV infection and cell viability.

Human immunodeficiency virus type 1 (HIV-1) reporter cell lines are critical tools for drug development. However, one disadvantage of HIV-1 reporter cell lines is that reductions in reporter gene activity need to be normalized to cytotoxicity, i.e.

Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor.

The emergence of multidrug-resistant viruses compromises the efficacy of anti-human immunodeficiency virus type 1 (HIV-1) therapy and limits treatment options. Therefore, new targets that can be used to develop novel antiviral agents need to be identified. We previously identified a potential parent compound, hematoxylin, which suppresses the nuclear import of HIV-1 via the Vpr-importin α interaction and inhibits HIV-1 replication in a Vpr-dependent manner by blocking nuclear import of the pre-integration complex.

MARCH8 inhibits HIV-1 infection by reducing virion incorporation of envelope glycoproteins.

Membrane-associated RING-CH 8 (MARCH8) is one of 11 members of the recently discovered MARCH family of RING (really interesting new gene)-finger E3 ubiquitin ligases. MARCH8 downregulates several host transmembrane proteins, including major histocompatibility complex (MHC)-II, CD86, interleukin (IL)-1 receptor accessory protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 and the transferrin receptor. However, its physiological roles remain largely unknown.

Humanized mice dually challenged with R5 and X4 HIV-1 show preferential R5 viremia and restricted X4 infection of CCR5(+)CD4(+) T cells.

CCR5-tropic (R5) immunodeficiency virus type 1 (HIV-1) strains are highly transmissible during the early stage of infection in humans, whereas CXCR4-tropic (X4) strains are less transmissible. This study aimed to explore the basis for early phase R5 and X4 HIV-1 infection in vivo by using humanized mice dually challenged with R5 HIV-1NLAD8-D harboring DsRed and X4 HIV-1(NL-E) harboring EGFP. Whereas R5 HIV-1 replicated well, X4 HIV-1 caused only transient viremia with variable kinetics; however, this was distinct from the low level but persistent viremia observed in mice challenged with X4 HIV-1 alone.

Vaccine-induced CD107a+ CD4+ T cells are resistant to depletion following AIDS virus infection.

Unlabelled: CD4(+) T-cell responses are crucial for effective antibody and CD8(+) T-cell induction following virus infection. However, virus-specific CD4(+) T cells can be preferential targets for human immunodeficiency virus (HIV) infection. HIV-specific CD4(+) T-cell induction by vaccination may thus result in enhancement of virus replication following infection.

Epitope mapping of the hemagglutinin molecule of A/(H1N1)pdm09 influenza virus by using monoclonal antibody escape mutants.

Unlabelled: We determined the antigenic structure of pandemic influenza A(H1N1)pdm09 virus hemagglutinin (HA) using 599 escape mutants that were selected using 16 anti-HA monoclonal antibodies (MAbs) against A/Narita/1/2009. The sequencing of mutant HA genes revealed 43 amino acid substitutions at 24 positions in three antigenic sites, Sa, Sb, and Ca2, which were previously mapped onto A/Puerto Rico/8/34 (A/PR/8/34) HA (A. J.

Development of a sensitive novel diagnostic kit for the highly pathogenic avian influenza A (H5N1) virus.

Background: Sporadic emergence of the highly pathogenic avian influenza (HPAI) H5N1 virus infection in humans is a serious concern because of the potential for a pandemic. Conventional or quantitative RT-PCR is the standard laboratory test to detect viral influenza infections. However, this technology requires well-equipped laboratories and highly trained personnel.