Evaluating the psychosocial experiences of participants in HIV cure research before, during, and after analytical treatment interruptions: A longitudinal qualitative study in the United States.

The lack of socio-behavioral research on stress and psychosocial experiences among research participants who undergo analytical treatment interruption (ATI) in HIV cure studies underscores a critical gap in cure science. Existing literature acknowledges mixed and potentially adverse mental health impacts of ATIs among trial participants, but empirical insights before, during, and after clinical studies are scarce. We used longitudinal in-depth interviews with 11 participants in HIV cure-related research to explore their experiences with stress, coping, and psychological well-being before, during, and after an ATI.

Impact of misclassified defective proviruses on HIV reservoir measurements.

Most proviruses persisting in people living with HIV (PWH) on antiretroviral therapy (ART) are defective. However, rarer intact proviruses almost always reinitiate viral rebound if ART stops. Therefore, assessing therapies to prevent viral rebound hinges on specifically quantifying intact proviruses.

Distinct gene expression by expanded clones of quiescent memory CD4 T cells harboring intact latent HIV-1 proviruses.

Antiretroviral therapy controls, but does not cure, HIV-1 infection due to a reservoir of rare CD4 T cells harboring latent proviruses. Little is known about the transcriptional program of latent cells. Here, we report a strategy to enrich clones of latent cells carrying intact, replication-competent HIV-1 proviruses from blood based on their expression of unique T cell receptors.

Integration features of intact latent HIV-1 in CD4+ T cell clones contribute to viral persistence.

Latent intact HIV-1 proviruses persist in a small subset of long-lived CD4+ T cells that can undergo clonal expansion in vivo. Expanded clones of CD4+ T cells dominate latent reservoirs in individuals on long-term antiretroviral therapy (ART) and represent a major barrier to HIV-1 cure. To determine how integration landscape might contribute to latency, we analyzed integration sites of near full length HIV-1 genomes from individuals on long-term ART, focusing on individuals whose reservoirs are highly clonal.

The immune response fails to control HIV early in initial virus spread.

Discontinued antiretroviral therapy (ART) results in uncontrolled HIV replication in most cases. How the virus population that persists during ART escapes immune control remains unknown. In this issue of the JCI, Mitchell and authors investigated plasmacytoid dendritic cells (pDCs) from the blood of individuals living with HIV.

Antigen-responsive CD4+ T cell clones contribute to the HIV-1 latent reservoir.

Antiretroviral therapy suppresses but does not cure HIV-1 infection due to the existence of a long-lived reservoir of latently infected cells. The reservoir has an estimated half-life of 44 mo and is largely composed of clones of infected CD4+ T cells. The long half-life appears to result in part from expansion and contraction of infected CD4+ T cell clones.

The Biology of the HIV-1 Latent Reservoir and Implications for Cure Strategies.

Antiretroviral therapy (ART) inhibits HIV replication but is not curative. During ART, the integrated HIV genome persists indefinitely within CD4 T cells and perhaps other cells. Here, we describe the mechanisms thought to contribute to its persistence during treatment and highlight findings from numerous recent studies describing the importance of cell proliferation in that process.

HIV-1 reservoir dynamics in CD4+ T cells.

Purpose Of Review: To provide a summary of the recent data examining infected CD4+ T cell dynamics during ART and implications for cure strategies.

Recent Findings: HIV-1 cure is a worldwide unmet medical need. Although combination antiretroviral therapies effectively suppress HIV-1 replication in vivo, viral rebound occurs shortly after therapy cessation.

Relationship between intact HIV-1 proviruses in circulating CD4 T cells and rebound viruses emerging during treatment interruption.

Combination antiretroviral therapy controls but does not cure HIV-1 infection because a small fraction of cells harbor latent viruses that can produce rebound viremia when therapy is interrupted. The circulating latent virus reservoir has been documented by a variety of methods, most prominently by viral outgrowth assays (VOAs) in which CD4 T cells are activated to produce virus in vitro, or more recently by amplifying proviral near full-length (NFL) sequences from DNA. Analysis of samples obtained in clinical studies in which individuals underwent analytical treatment interruption (ATI), showed little if any overlap between circulating latent viruses obtained from outgrowth cultures and rebound viruses from plasma.

Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4 T cells.

Human immunodeficiency virus (HIV) infection is currently incurable, due to the persistence of latently infected cells. The 'shock and kill' approach to a cure proposes to eliminate this reservoir via transcriptional activation of latent proviruses, enabling direct or indirect killing of infected cells. Currently available latency-reversing agents (LRAs) have however proven ineffective.

Clonal CD4 T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation.

Despite suppressive combination antiretroviral therapy (ART), latent HIV-1 proviruses persist in patients. This latent reservoir is established within 48-72 h after infection, has a long half-life, enables viral rebound when ART is interrupted, and is the major barrier to a cure for HIV-1 . Latent cells are exceedingly rare in blood (∼1 per 1 × 10 CD4 T cells) and are typically enumerated by indirect means, such as viral outgrowth assays.

HIV: Persistence through division.

A long-lived latent reservoir for HIV-1 persists in CD4 T cells despite antiretroviral therapy and is the major barrier to cure. In this issue of JEM, Hosmane et al. show that T cell proliferation could explain the long-term persistence of this reservoir.

Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA.

HIV-1-infected individuals harbor a latent reservoir of infected CD4 T cells that is not eradicated by antiretroviral therapy (ART). This reservoir presents the greatest barrier to an HIV-1 cure and has remained difficult to characterize, in part, because the vast majority of integrated sequences are defective and incapable of reactivation. To characterize the replication-competent reservoir, we have combined two techniques, quantitative viral outgrowth and qualitative sequence analysis of clonal outgrowth viruses.

Leptin receptor signaling in T cells is required for Th17 differentiation.

The hormone leptin plays a key role in energy homeostasis, and the absence of either leptin or its receptor (LepR) leads to severe obesity and metabolic disorders. To avoid indirect effects and to address the cell-intrinsic role of leptin signaling in the immune system, we conditionally targeted LepR in T cells. In contrast with pleiotropic immune disorders reported in obese mice with leptin or LepR deficiency, we found that LepR deficiency in CD4(+) T cells resulted in a selective defect in both autoimmune and protective Th17 responses.

HIV-1 integration landscape during latent and active infection.

The barrier to curing HIV-1 is thought to reside primarily in CD4(+) T cells containing silent proviruses. To characterize these latently infected cells, we studied the integration profile of HIV-1 in viremic progressors, individuals receiving antiretroviral therapy, and viremic controllers. Clonally expanded T cells represented the majority of all integrations and increased during therapy.

Dendritic cell-targeted vaccines.

Despite significant effort, the development of effective vaccines inducing strong and durable T-cell responses against intracellular pathogens and cancer cells has remained a challenge. The initiation of effector CD8(+) T-cell responses requires the presentation of peptides derived from internalized antigen on class I major histocompatibility complex molecules by dendritic cells (DCs) in a process called cross-presentation. A current strategy to enhance the effectiveness of vaccination is to deliver antigens directly to DCs.

Antigen delivery to early endosomes eliminates the superiority of human blood BDCA3+ dendritic cells at cross presentation.

Human BDCA3(+) dendritic cells (DCs), the proposed equivalent to mouse CD8α(+) DCs, are widely thought to cross present antigens on MHC class I (MHCI) molecules more efficiently than other DC populations. If true, it is unclear whether this reflects specialization for cross presentation or a generally enhanced ability to present antigens on MHCI. We compared presentation by BDCA3(+) DCs with BDCA1(+) DCs using a quantitative approach whereby antigens were targeted to distinct intracellular compartments by receptor-mediated internalization.

Internalization and endosomal degradation of receptor-bound antigens regulate the efficiency of cross presentation by human dendritic cells.

Dendritic cells (DCs) can capture extracellular antigens and load resultant peptides on to MHC class I molecules, a process termed cross presentation. The mechanisms of cross presentation remain incompletely understood, particularly in primary human DCs. One unknown is the extent to which antigen delivery to distinct endocytic compartments determines cross presentation efficiency, possibly by influencing antigen egress to the cytosol.

Influenza A virus infection of human primary dendritic cells impairs their ability to cross-present antigen to CD8 T cells.

Influenza A virus (IAV) infection is normally controlled by adaptive immune responses initiated by dendritic cells (DCs). We investigated the consequences of IAV infection of human primary DCs on their ability to function as antigen-presenting cells. IAV was internalized by both myeloid DCs (mDCs) and plasmacytoid DCs but only mDCs supported viral replication.

siRNA knockdown of PD-L1 and PD-L2 in monocyte-derived dendritic cells only modestly improves proliferative responses to Gag by CD8(+) T cells from HIV-1-infected individuals.

Introduction: Due to their capacity to elicit and regulate immunity, dendritic cells (DCs) are important targets to improve vaccination. Knowing that programmed death-1 (PD-1) high virus-specific T cells become functionally exhausted during chronic exposure to human immunodeficiency virus-1 (HIV-1), the development of a therapeutic DC-based HIV-1 vaccine might include strategies that downregulate PD-L1 and PD-L2 counter-receptors.

Methods: After showing that monocyte-derived DCs rapidly upregulated PD-L1 and PD-L2 expression upon maturation with a variety of stimuli, e.