Safety and durability of AGT103-T autologous T cell therapy for HIV infection in a Phase 1 trial.

Unlabelled: The cell and gene therapy product AGT103-T was designed to restore the Gag-specific CD4+ T cell response in persons with chronic HIV disease who are receiving antiretroviral therapy. This autologous, genetically engineered cell product is under investigation in a Phase 1 clinical trial (NCT03215004). Trial participants were conditioned with cyclophosphamide approximately 1 week before receiving a one-time low (< 10 genetically modified CD4+ T cells) or high (≥10 genetically modified CD4+ T cells) dose of AGT103-T, delivering between 2 and 21 million genetically modified cells per kilogram (kg) body weight.

Reducing farnesyl diphosphate synthase levels activates Vγ9Vδ2 T cells and improves tumor suppression in murine xenograft cancer models.

Human Vγ9Vδ2 T cells are attractive candidates for cancer immunotherapy due to their potent capacity for tumor recognition and cytolysis of many tumor cell types. However, efforts to deploy clinical strategies for Vγ9Vδ2 T cell cancer therapy are hampered by insufficient potency. We are pursuing an alternate strategy of modifying tumors to increase the capacity for Vγ9Vδ2 T cell activation, as a means for strengthening the anti-tumor response by resident or ex vivo manufactured Vγ9Vδ2 T cells.

FcRn-Targeted Mucosal Vaccination against Influenza Virus Infection.

The respiratory tract is constantly exposed to various airborne pathogens. Most vaccines against respiratory infections are designed for the parenteral routes of administration; consequently, they provide relatively minimal protection in the respiratory tract. A vaccination strategy that aims to induce the protective mucosal immune responses in the airway is urgently needed.

Advances in cell and gene therapy for HIV disease: it is good to be specific.

Purpose Of Review: Tremendous advances in cell and gene therapy may soon realize the goal of treating and possibly curing HIV disease. These advances rely on new technologies for cell engineering and new strategies for product manufacturing that are targeting the most important immune deficits in HIV and promising to reconstitute protective, antiviral immunity and achieve natural suppression of HIV disease.

Recent Findings: We summarize important advances in vectored passive immunity, e.

Preclinical Development and Clinical-Scale Manufacturing of HIV Gag-Specific, LentivirusModified CD4 T Cells for HIV Functional Cure.

Activation, infection, and eventual depletion of human immunodeficiency virus (HIV)-specific cluster of differentiation 4 (CD4) T cells are the crucial pathogenetic events in acquired immunodeficiency syndrome (AIDS). We developed a cell and gene therapy to reconstitute HIV-specific CD4 T cells and prevent their destruction by HIV. Antigen-specific CD4 T cells will provide helper functions to support antiviral cytotoxic T lymphocyte (CTL) function and the production of virus-specific antibodies.

Human cytomegalovirus evades antibody-mediated immunity through endoplasmic reticulum-associated degradation of the FcRn receptor.

Human cytomegalovirus (HCMV) can persistently infect humans, but how HCMV avoids humoral immunity is not clear. The neonatal Fc receptor (FcRn) controls IgG transport from the mother to the fetus and prolongs IgG half-life. Here we show that US11 inhibits the assembly of FcRn with βm and retains FcRn in the endoplasmic reticulum (ER), consequently blocking FcRn trafficking to the endosome.

Persistent gamma delta T-cell dysfunction in chronic HCV infection despite direct-acting antiviral therapy induced cure.

Immune dysfunction is a hallmark of chronic HCV infection and viral clearance with direct antivirals recover some of these immune defects. TCRVγ9Vδ2 T-cell dysfunction in treated HCV patients however is not well studied and was the subject of this investigation. Peripheral blood cells from patients who had achieved sustained virologic response (SVR) or those who had relapsed after interferon-free therapy were phenotyped using flow cytometry.

Gamma Delta T Cell Therapy for Cancer: It Is Good to be Local.

Human gamma delta T cells have extraordinary properties including the capacity for tumor cell killing. The major gamma delta T cell subset in human beings is designated Vγ9Vδ2 and is activated by intermediates of isoprenoid biosynthesis or aminobisphosphonate inhibitors of farnesyldiphosphate synthase. Activated cells are potent for killing a broad range of tumor cells and demonstrated the capacity for tumor reduction in murine xenotransplant tumor models.

Factors associated with high cardiovascular risk in a primarily African American, urban HIV-infected population.

Objective: To determine factors associated with increased risk of developing cardiovascular disease in a high-risk patient population.

Design: Cross-sectional analysis of a retrospective cohort study.

Methods: One-hundred patients at an inner city HIV clinic in 2008 were reviewed.

An HIV Envelope gp120-Fc Fusion Protein Elicits Effector Antibody Responses in Rhesus Macaques.

A goal for HIV prevention programs is to develop safe, effective vaccines that elicit durable and broadly protective antibodies. Many vaccine programs focus on the immune responses to critical epitopes in the gp120 portion of HIV envelope glycoprotein (Env) and seek to improve the quality and quantity of antibodies by altering the sequence, conformation, oligomerization, or glycosylation of gp120 to activate appropriate germ line B cells and mimic the subsequent maturation pathways seen in infected individuals. As a complement to these strategies, we developed dimeric fusion protein immunogens consisting of HIV gp120 monomer attached to a Gly/Ser linker that is, in turn, fused to one half of the dimeric Fc domain from rhesus macaque IgG1 (Env-rFc).

Interleukin-18 activates Vγ9Vδ2 T cells from HIV-positive individuals: recovering the response to phosphoantigen.

The study aimed to identify an immunoregulatory factor that restores the phosphoantigen response of Vγ9Vδ2 T cells from HIV-positive individuals on antiretroviral therapy. It was designed to characterize the effects of interleukin-18 (IL-18) on proliferation and effector function in Vγ9Vδ2 T cells from HIV-negative individuals and test whether exogenous IL-18 reconstitutes the Vγ9Vδ2 T-cell response to phosphoantigen from HIV-positive donors. Vγ9Vδ2 T cells from HIV-negative individuals responded strongly to phosphoantigen or aminobisphosphonate stimulation of peripheral blood mononuclear cells (PBMC), whereas cells with similar T-cell receptor profiles from HIV-positive individuals only responded to aminobisphosphonate.

Prolonged PD1 Expression on Neonatal Vδ2 Lymphocytes Dampens Proinflammatory Responses: Role of Epigenetic Regulation.

A successful pregnancy depends on the maintenance of tolerance at the fetal-maternal interface; strong inflammation in the placental bed is generally associated with adverse fetal outcomes. Among the mechanisms that foster tolerance and limit inflammation, the fetal immune system favors Th2 or regulatory responses over Th1 responses. The unintended consequence of this functional program is high susceptibility to infections.

Evolution and function of the TCR Vgamma9 chain repertoire: It's good to be public.

Lymphocytes expressing a T cell receptor (TCR) composed of Vgamma9 and Vdelta2 chains represent a minor fraction of human thymocytes. Extrathymic selection throughout post-natal life causes the proportion of cells with a Vgamma9-JP rearrangement to increase and elevates the capacity for responding to non-peptidic phosphoantigens. Extrathymic selection is so powerful that phosphoantigen-reactive cells comprise about 1 in 40 circulating memory T cells in healthy adults and the subset expands rapidly upon infection or in response to malignancy.

γδ T Cells in HIV Disease: Past, Present, and Future.

Human immunodeficiency virus (HIV) type 1 dysregulates γδ T cells as part of an immune evasion mechanism. Nearly three decades of research defined the effects of HIV on γδ T cells and how this impacts disease. With highly effective antiretroviral therapy providing virus suppression and longer survival, we expected a return to normal for γδ T cells.

CD25(+) Bcl6(low) T follicular helper cells provide help to maturing B cells in germinal centers of human tonsil.

The majority of CXCR5(+) PD1(+) CD4(+) T follicular helper (Tfh) cells (>90%) are CD25(-) Bcl6(hi) , while a small subpopulation (<10%) are CD25(+) Bcl6(low) but do not express FoxP3 and are not T regulatory cells. We purified T:B-cell conjugates from tonsils and found they were enriched for the CD25(+) Bcl6(low) Tfh-cell subpopulation. In response to IL-2, these CD25(+) Tfh cells increased expression of costimulatory molecules ICOS or OX40, upregulated transcription factor cMaf, produced cytokines IL-21, IL-17, and IL-10, and raised the levels of antiapoptotic protein Bcl2.

Vγ2Vδ2 T cell Costimulation Increases NK cell Killing of Monocyte-derived Dendritic Cells.

Interactions between NK and dendritic cells (DC) affect maturation and function of both cell populations, including NK killing of DC (editing) that is important for controlling the quality of immune responses. We also know that antigen-stimulated Vγ2Vδ2 T cells costimulate NK cells via 4-1BB to enhance killing of tumor cell lines but we do not know what regulates 4-1BB expression or whether other NK effector functions including DC killing, might also be influenced by NK:γδ T cell cross talk. Here we show that antigen-stimulated γδ T cells costimulate NK through ICOS:ICOSL and this signal increases NK killing of autologous DC.

Levels of CD56+TIM-3- effector CD8 T cells distinguish HIV natural virus suppressors from patients receiving antiretroviral therapy.

Prolonged antiretroviral therapy (ART) with effective HIV suppression and reconstitution of CD4 T cells, fails to restore CD8 T cell lytic effector function that is needed to eradicate the viral reservoir. Better understanding of the phenotype and function of circulating CD8 cells in HIV patients will contribute to new targeted therapies directed at increasing CD8 T cell lytic effector function and destruction of the viral reservoir. We show that CD8 T cells from ART treated patients had sharply reduced expression of CD56 (neural cell adhesion molecule-1), a marker associated with cytolytic function whereas elite patients who control HIV in the absence of ART had CD56+ CD8 T cell levels similar to uninfected controls.

Cord blood Vγ2Vδ2 T cells provide a molecular marker for the influence of pregnancy-associated malaria on neonatal immunity.

Background: Plasmodium falciparum placental infection primes the fetal immune system and alters infant immunity. Mechanisms leading to these outcomes are not completely understood. We focused on Vγ2Vδ2 cells, which are part of the immune response against many pathogens, including P.

Critical roles for Akt kinase in controlling HIV envelope-mediated depletion of CD4 T cells.

Background: The cell surface receptors CD4 and CCR5 bind CCR5-tropic HIV Envelope (Env) glycoprotein during virus attachment. These same receptors have signaling activities related to normal immune cell functions. We also know that Env binds to CCR5 present at high levels on CD4-negative γδ T cells where it signals through p38 MAP kinase to activate caspases and Fas-independent cell death.

The γδ T-cell receptor repertoire is reconstituted in HIV patients after prolonged antiretroviral therapy.

Objective: Determine whether reconstitution of Vγ2Vδ2 T cells in patients with HIV is due to new cell synthesis with recovery of the T-cell receptor repertoire or proliferative expansion of residual cells from the time of treatment initiation.

Design: Perform a cross-sectional analysis of the T-cell receptor complexity of Vγ2 chain in patients treated for HIV, natural virus suppressors who control viremia to undetectable levels, patients with chronic low-level viremia in the absence of therapy, and uninfected controls. Apply quantitative methods for repertoire analysis to assess the degree of Vδ2 repertoire loss or reconstitution.

An attenuated Lassa vaccine in SIV-infected rhesus macaques does not persist or cause arenavirus disease but does elicit Lassa virus-specific immunity.

Background: Lassa hemorrhagic fever (LHF) is a rodent-borne viral disease that can be fatal for human beings. In this study, an attenuated Lassa vaccine candidate, ML29, was tested in SIV-infected rhesus macaques for its ability to elicit immune responses without instigating signs pathognomonic for arenavirus disease. ML29 is a reassortant between Lassa and Mopeia viruses that causes a transient infection in non-human primates and confers sterilizing protection from lethal Lassa viral challenge.

High cancer-related mortality in an urban, predominantly African-American, HIV-infected population.

Objective: To determine mortality associated with a new cancer diagnosis in an urban, predominantly African-American, HIV-infected population.

Design: Retrospective cohort study.

Methods: All HIV-infected patients diagnosed with cancer between 1 January 2000 and 30 June 2010 were reviewed.