Serological responses and clinical outcomes following a three-dose primary COVID-19 vaccine schedule in kidney transplant recipients and people on dialysis.

Objectives: Despite vaccination strategies, people with chronic kidney disease, particularly kidney transplant recipients (KTRs), remained at high risk of poor COVID-19 outcomes. We assessed serological responses to the three-dose COVID-19 vaccine schedule in KTRs and people on dialysis, as well as seroresponse predictors and the relationship between responses and breakthrough infection.

Methods: Plasma from 30 KTRs and 17 people receiving dialysis was tested for anti-Spike receptor binding domain (RBD) IgG and neutralising antibodies (NAb) to the ancestral and Omicron BA.

CXCR4-Using HIV Strains Predominate in Naive and Central Memory CD4 T Cells in People Living with HIV on Antiretroviral Therapy: Implications for How Latency Is Established and Maintained.

HIV can persist in people living with HIV (PLWH) on antiretroviral therapy (ART) in multiple CD4 T cell subsets, including naive cells, central memory (CM) cells, transitional (TM) cells, and effector memory (EM) cells. Since these cells express different levels of the viral coreceptors CXCR4 and CCR5 on their surface, we sought to determine whether the HIV envelope protein (Env) was genotypically and phenotypically different between CD4 T cell subsets isolated from PLWH on suppressive ART ( = 8). Single genome amplification for the HIV gene was performed on genomic DNA extracts from different CD4 T cell subsets.

Human Immunodeficiency Virus (HIV)-Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy.

Background: Identifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN; n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy.

Methods: Cell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction.

Human Immunodeficiency Virus Persistence and T-Cell Activation in Blood, Rectal, and Lymph Node Tissue in Human Immunodeficiency Virus-Infected Individuals Receiving Suppressive Antiretroviral Therapy.

Background: Immune activation and inflammation remain elevated in human immunodeficiency virus (HIV)-infected individuals receiving antiretroviral therapy (ART) and may contribute to HIV persistence.

Methods: Using flow cytometry expression of CD38, HLA-DR and PD-1 were measured in blood (n = 48), lymph node (LN; n = 9), and rectal tissue (n = 17) from virally suppressed individuals. Total and integrated HIV DNA, 2-LTR circles, and cell-associated unspliced HIV RNA were quantified.

CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART.

HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4+ T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART.

The antiviral compound BIT225 inhibits HIV-1 replication in myeloid dendritic cells.

Background: Previous studies with BIT225 (N-carbamimidoyl-5-(1-methyl-1H-pyrazol-4-yl)-2-naphthamide) have demonstrated a unique antiviral activity that blocks the release of HIV-1 from monocyte-derived macrophages (MDM). Antagonising the ion channel formed by HIV-1 Vpu, BIT225 preferentially targets de novo intracellular virus produced in 'virus-containing compartments' of MDM. In primary infections, dendritic cells (DC) are one of the first cells infected by HIV-1 and can transfer virus to more permissive CD4(+) T cells, making these cells an important target for novel antiviral therapies.

Persistence of integrated HIV DNA in CXCR3 + CCR6 + memory CD4+ T cells in HIV-infected individuals on antiretroviral therapy.

Background: HIV latent infection can be established in vitro by treating resting CD4 T cells with chemokines that bind to chemokine receptors (CKR), CCR7, CXCR3, and CCR6, highly expressed on T cells.

Objective: To determine if CKR identify CD4 T cells enriched for HIV in HIV-infected individuals receiving suppressive antiretroviral therapy (ART).

Design: A cross-sectional study of CKR expression and HIV persistence in blood from HIV-infected individuals on suppressive ART for more than 3 years (n = 48).

Ex vivo response to histone deacetylase (HDAC) inhibitors of the HIV long terminal repeat (LTR) derived from HIV-infected patients on antiretroviral therapy.

Histone deacetylase inhibitors (HDACi) can induce human immunodeficiency virus (HIV) transcription from the HIV long terminal repeat (LTR). However, ex vivo and in vivo responses to HDACi are variable and the activity of HDACi in cells other than T-cells have not been well characterised. Here, we developed a novel assay to determine the activity of HDACi on patient-derived HIV LTRs in different cell types.

Targeting antigen to bone marrow stromal cell-2 expressed by conventional and plasmacytoid dendritic cells elicits efficient antigen presentation.

Bone marrow stromal cell-2 (BST-2) has major roles in viral tethering and modulation of interferon production. Here we investigate BST-2 as a receptor for the delivery of antigen to dendritic cells (DCs). We show that BST-2 is expressed by a panel of mouse and human DC subsets, particularly under inflammatory conditions.

HIV persistence: chemokines and their signalling pathways.

Latently infected resting CD4+ T cells are the major barrier to curing HIV. We have recently demonstrated that chemokines, which bind to the chemokine receptors CCR7, CXCR3 and CCR6, facilitate efficient HIV nuclear localisation and integration in resting CD4+ T cells, leading to latency. As latently infected cells are enriched in lymphoid tissues, where chemokines are highly concentrated, this may provide a mechanism for the generation of latently infected cells in vivo.

The role of naïve T-cells in HIV-1 pathogenesis: an emerging key player.

Functional naïve T-cells are critical for an effective immune response to multiple pathogens. HIV leads to a significant reduction in CD4+ naïve T-cell number and impaired function and there is incomplete recovery following combination antiretroviral therapy (cART). Here we review the basic homeostatic mechanisms that maintain naïve CD4+ T-cells and discuss recent developments in understanding the impact of HIV infection on naïve CD4+ T-cells.

Expression and reactivation of HIV in a chemokine induced model of HIV latency in primary resting CD4+ T cells.

Background: We recently described that HIV latent infection can be established in vitro following incubation of resting CD4+ T-cells with chemokines that bind to CCR7. The main aim of this study was to fully define the post-integration blocks to virus replication in this model of CCL19-induced HIV latency.

Results: High levels of integrated HIV DNA but low production of reverse transcriptase (RT) was found in CCL19-treated CD4+ T-cells infected with either wild type (WT) NL4.

Both CD31(+) and CD31⁻ naive CD4(+) T cells are persistent HIV type 1-infected reservoirs in individuals receiving antiretroviral therapy.

Background: Naive T cell recovery is critical for successful immune reconstitution after antiretroviral therapy (ART), but the relative contribution of CD31(+) and CD31⁻ naive T cells to immune reconstitution and viral persistence is unknown.

Methods: In a cross-sectional (n = 94) and longitudinal (n = 10) study of human immunodeficiency virus (HIV)-infected patients before and after ART, we examined the ratio of CD31(+) to CD31⁻ naive CD4(+) T cells. In the longitudinal cohort we then quantified the concentration of HIV-1 DNA in each cell subset and performed single-genome amplification of virus from memory and naive T cells.

Antiviral efficacy of the novel compound BIT225 against HIV-1 release from human macrophages.

Building on previous findings that amiloride analogues inhibit HIV-1 replication in monocyte-derived macrophages (MDM), Biotron Limited has generated a library of over 300 small-molecule compounds with significant improvements in anti-HIV-1 activity. Our lead compound, BIT225, blocks Vpu ion channel activity and also shows anti-HIV-1 activity, with a 50% effective concentration of 2.25+/-0.