Cell-Cell Interaction-Mediated Signaling in the Testis Induces Reproductive Dysfunction-Lesson from the Toxicant/Pharmaceutical Models.

Emerging evidence has shown that cell-cell interactions between testicular cells, in particular at the Sertoli cell-cell and Sertoli-germ cell interface, are crucial to support spermatogenesis. The unique ultrastructures that support cell-cell interactions in the testis are the basal ES (ectoplasmic specialization) and the apical ES. The basal ES is found between adjacent Sertoli cells near the basement membrane that also constitute the blood-testis barrier (BTB).

Impaired differentiation of small airway basal stem/progenitor cells in people living with HIV.

With highly active anti-retroviral therapy (HAART), higher incidence of airway abnormalities is common in the HIV population consistent with the concept of accelerated lung "aging". Our previous findings demonstrated that HIV induces human airway basal cells (BC) into destructive and inflammatory phenotypes. Since BC function as stem/progenitor cells of the small airway epithelium (SAE), responsible for self-renewal and differentiation of SAE, we hypothesized that BC from people living with HIV (PLWH) may have altered differentiation capacity that contribute to premature aging.

HIV induces airway basal progenitor cells to adopt an inflammatory phenotype.

Despite the introduction of anti-retroviral therapy, chronic HIV infection is associated with an increased incidence of other comorbidities such as COPD. Based on the knowledge that binding of HIV to human airway basal stem/progenitor cells (BC) induces a destructive phenotype by increased MMP-9 expression through MAPK signaling pathways, we hypothesized that HIV induces the BC to express inflammatory mediators that contribute to the pathogenesis of emphysema. Our data demonstrate that airway BC isolated from HAART-treated HIV nonsmokers spontaneously release inflammatory mediators IL-8, IL-1β, ICAM-1 and GM-CSF.

HIV Reprograms Human Airway Basal Stem/Progenitor Cells to Acquire a Tissue-Destructive Phenotype.

While highly active anti-retroviral therapy has dramatically improved the survival of HIV-infected individuals, there is an increased risk for other co-morbidities, such as COPD, manifesting as emphysema. Given that emphysema originates around the airways and that human airway basal cells (BCs) are adult airway stem/progenitor cells, we hypothesized that HIV reprograms BCs to a distinct phenotype that contributes to the development of emphysema. Our data indicate that HIV binds to but does not replicate in BCs.

Stable 293 T and CHO cell lines expressing cleaved, stable HIV-1 envelope glycoprotein trimers for structural and vaccine studies.

Background: Recombinant soluble, cleaved HIV-1 envelope glycoprotein SOSIP.664 gp140 trimers based on the subtype A BG505 sequence are being studied structurally and tested as immunogens in animals. For these trimers to become a vaccine candidate for human trials, they would need to be made in appropriate amounts at an acceptable quality.

Autoantibodies induced by chimeric cytokine-HIV envelope glycoprotein immunogens.

Cytokines are often used as adjuvants to increase the immunogenicity of vaccines because they can improve the immune response and/or direct it into a desired direction. As an alternative to codelivering Ags and cytokines separately, they can be fused into a composite protein, with the advantage that both moieties act on the same immune cells. The HIV-1 envelope glycoprotein (Env) spike, located on the outside of virus particles and the only relevant protein for the induction of neutralizing Abs, is poorly immunogenic.

An HIV-1 envelope glycoprotein trimer with an embedded IL-21 domain activates human B cells.

Broadly neutralizing antibodies (bNAbs) that target the HIV-1 envelope glycoproteins (Env) can prevent virus acquisition, but several Env properties limit its ability to induce an antibody response that is of sufficient quantity and quality. The immunogenicity of Env can be increased by fusion to co-stimulatory molecules and here we describe novel soluble Env trimers with embedded interleukin-4 (IL-4) or interleukin-21 (IL-21) domains, designed to activate B cells that recognize Env. In particular, the chimeric Env(IL-21) molecule activated B cells efficiently and induced the differentiation of antibody secreting plasmablast-like cells.

Clinical adjuvant combinations stimulate potent B-cell responses in vitro by activating dermal dendritic cells.

CD14(+) dermal DCs (CD14(+) DDCs) have a natural capacity to activate naïve B-cells. Targeting CD14(+) DDCs is therefore a rational approach for vaccination strategies aimed at improving humoral responses towards poorly immunogenic antigens, for example, HIV-1 envelope glycoproteins (Env). Here, we show that two clinically relevant TLR ligand combinations, Hiltonol plus Resiquimod and Glucopyranosyl lipid A plus Resiquimod, potently activate CD14(+) DDCs, as shown by enhanced expression of multiple cytokines (IL-6, IL-10, IL-12p40 and TNF-α).

Binding of HIV-1 gp120 to DC-SIGN promotes ASK-1-dependent activation-induced apoptosis of human dendritic cells.

During disease progression to AIDS, HIV-1 infected individuals become increasingly immunosuppressed and susceptible to opportunistic infections. It has also been demonstrated that multiple subsets of dendritic cells (DC), including DC-SIGN⁺ cells, become significantly depleted in the blood and lymphoid tissues of AIDS patients, which may contribute to the failure in initiating effective host immune responses. The mechanism for DC depletion, however, is unclear.

Potent induction of antibody-secreting B cells by human dermal-derived CD14+ dendritic cells triggered by dual TLR ligation.

Targeting CD14(+) dermal-derived dendritic cells (DDCs) is a rational approach for vaccination strategies aimed at improving humoral immune responses, because of their natural ability to stimulate naive B cells. In this study, we show that CD14(+) DDCs express mRNA for TLRs 1-9, but respond differentially to single or paired TLR ligands. Compared to single ligands, some combinations were particularly effective at activating CD14(+) DDCs, as shown by enhanced expression of B cell stimulatory cytokines (IL-6, IL-10, and TNF-α) and more pronounced phenotypic maturation.

HIV-1 gp120 impairs the induction of B cell responses by TLR9-activated plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) play a central role in innate and adaptive immune responses to viral infections, including HIV type 1 (HIV-1). pDCs produce substantial quantities of type I IFN and proinflammatory cytokines upon stimulation via TLRs, specifically TLR7 or TLR9. The HIV-1 envelope glycoproteins, exemplified by the gp120 monomer, are the focus of vaccines aimed at inducing B cell responses.

Glycan-dependent immunogenicity of recombinant soluble trimeric hemagglutinin.

Recombinant soluble trimeric influenza A virus (IAV) hemagglutinin (sHA(3)) has proven an effective vaccine antigen against IAV. Here, we investigate to what extent the glycosylation status of the sHA(3) glycoprotein affects its immunogenicity. Different glycosylation forms of subtype H5 trimeric HA protein (sH5(3)) were produced by expression in insect cells and different mammalian cells in the absence and presence of inhibitors of N-glycan-modifying enzymes or by enzymatic removal of the oligosaccharides.

Targeting HIV-1 envelope glycoprotein trimers to B cells by using APRIL improves antibody responses.

An HIV-1 vaccine remains elusive, in part because various factors limit the quantity and quality of the antibodies raised against the viral envelope glycoprotein complex (Env). We hypothesized that targeting Env vaccines directly to B cells, by fusing them to molecules that bind and activate these cells, would improve Env-specific antibody responses. Therefore, we fused trimeric Env gp140 to A PRoliferation-Inducing Ligand (APRIL), B-cell Activating Factor (BAFF), and CD40 Ligand (CD40L).

HIV-1 transmission by dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is regulated by determinants in the carbohydrate recognition domain that are absent in liver/lymph node-SIGN (L-SIGN).

In this study, we identify determinants in dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) necessary for human immunodeficiency virus, type 1 (HIV-1), transmission. Although human B cell lines expressing DC-SIGN efficiently capture and transmit HIV-1 to susceptible target cells, cells expressing the related molecule liver/lymph node-specific ICAM-3-grabbing nonintegrin (L-SIGN) do not. To understand the differences between DC-SIGN and L-SIGN that affect HIV-1 interactions, we developed Raji B cell lines expressing different DC-SIGN/L-SIGN chimeras.

A macaque model of HIV-1 infection.

The lack of a primate model that utilizes HIV-1 as the challenge virus is an impediment to AIDS research; existing models generally employ simian viruses that are divergent from HIV-1, reducing their usefulness in preclinical investigations. Based on an understanding of species-specific variation in primate TRIM5 and APOBEC3 antiretroviral genes, we constructed simian-tropic (st)HIV-1 strains that differ from HIV-1 only in the vif gene. We demonstrate that such minimally modified stHIV-1 strains are capable of high levels of replication in vitro in pig-tailed macaque (Macaca nemestrina) lymphocytes.

A mixed-valent ruthenium-oxo oxalato cluster Na7[Ru4(mu3-O)4(C2O4)6] with potent anti-HIV activities.

A structurally characterized mixed-valent tetranuclear ruthenium-oxo oxalato cluster exhibits anti-viral activities toward R5- and X4-tropic HIV-1, and possesses cytoprotective activity toward HIV-1 infected cells.

Silver nanoparticles fabricated in Hepes buffer exhibit cytoprotective activities toward HIV-1 infected cells.

Silver nanoparticles fabricated in Hepes buffer exhibit potent cytoprotective and post-infected anti-HIV-1 activities toward Hut/CCR5 cells.

Physiologically stable vanadium(IV) porphyrins as a new class of anti-HIV agents.

The water soluble oxovanadium(IV) tetraarylporphyrin has demonstrated excellent solution stability against glutathione reduction and high potency (5 microM, 97% inhibition) in inhibiting HIV-1 replication in Hut/CCR5 cells.