HIV Latency-Reversing Agents Have Diverse Effects on Natural Killer Cell Function

In an effort to clear persistent HIV infection and achieve a durable therapy-free remission of HIV disease, extensive pre-clinical studies and early pilot clinical trials are underway to develop and test agents that can reverse latent HIV infection and present viral antigen to the immune system for clearance. It is, therefore, critical to understand the impact of latency-reversing agents (LRAs) on the function of immune effectors needed to clear infected cells. We assessed the impact of LRAs on the function of natural killer (NK) cells, the main effector cells of the innate immune system. We studied the effects of three histone deacetylase inhibitors [SAHA or vorinostat (VOR), romidepsin, and panobinostat (PNB)] and two protein kinase C agonists [prostratin (PROST) and ingenol] on the antiviral activity, cytotoxicity, cytokine secretion, phenotype, and viability of primary NK cells. We found that ex vivo exposure to VOR had minimal impact on all parameters assessed, while PNB caused a decrease in NK cell viability, antiviral activity, and cytotoxicity. PROST caused non-specific NK cell activation and, interestingly, improved antiviral activity. Overall, we found that LRAs can alter the function and fate of NK cells, and these effects must be carefully considered as strategies are developed to clear persistent HIV infection

Eradicating HIV-1 infection: seeking to clear a persistent pathogen

Effective antiretroviral therapy (ART) blunts viraemia, which enables HIV-1-infected individuals to control infection and live long, productive lives. However, HIV-1 infection remains incurable owing to the persistence of a viral reservoir that harbours integrated provirus within host cellular DNA. This latent infection is unaffected by ART and hidden from the immune system. Recent studies have focused on the development of therapies to disrupt latency. These efforts unmasked residual viral genomes and highlighted the need to enable the clearance of latently infected cells, perhaps via old and new strategies that improve the HIV-1-specific immune response. In this Review, we explore new approaches to eradicate established HIV-1 infection and avoid the burden of lifelong ART

Deep characterization of human γδ T cell subsets defines shared and lineage-specific traits

Under non-pathological conditions, human γδ T cells represent a small fraction of CD3+ T cells in peripheral blood (1-10%). They constitute a unique subset of T lymphocytes that recognize stress ligands or non-peptide antigens through MHC-independent presentation. Major human γδ T cell subsets, Vδ1 and Vδ2, expand in response to microbial infection or malignancy, but possess distinct tissue localization, antigen recognition, and effector responses. We hypothesized that differences at the gene, phenotypic, and functional level would provide evidence that γδ T cell subpopulations belong to distinct lineages. Comparisons between each subset and the identification of the molecular determinants that underpin their differences has been hampered by experimental challenges in obtaining sufficient numbers of purified cells. By utilizing a stringent FACS-based isolation method, we compared highly purified human Vδ1 and Vδ2 cells in terms of phenotype, gene expression profile, and functional responses. We found distinct genetic and phenotypic signatures that define functional differences in γδ T cell populations. Differences in TCR components, repertoire, and responses to calcium-dependent pathways suggest that Vδ1 and Vδ2 T cells are different lineages. These findings will facilitate further investigation into the ligand specificity and unique role of Vδ1 and Vδ2 cells in early immune responses

Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1

Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include “shock and kill” strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination

Platelet-Released Factors: Their Role in Viral Disease and Applications for Extracellular Vesicle (EV) Therapy

Platelets, which are small anuclear cell fragments, play important roles in thrombosis and hemostasis, but also actively release factors that can both suppress and induce viral infections. Platelet-released factors include sCD40L, microvesicles (MVs), and alpha granules that have the capacity to exert either pro-inflammatory or anti-inflammatory effects depending on the virus. These factors are prime targets for use in extracellular vesicle (EV)-based therapy due to their ability to reduce viral infections and exert anti-inflammatory effects. While there are some studies regarding platelet microvesicle-based (PMV-based) therapy, there is still much to learn about PMVs before such therapy can be used. This review provides the background necessary to understand the roles of platelet-released factors, how these factors might be useful in PMV-based therapy, and a critical discussion of current knowledge of platelets and their role in viral diseases

HIV Latency in Myeloid Cells: Challenges for a Cure

The use of antiretroviral therapy (ART) for Human Immunodeficiency Virus (HIV) treatment has been highly successful in controlling plasma viremia to undetectable levels. However, a complete cure for HIV is hindered by the presence of replication-competent HIV, integrated in the host genome, that can persist long term in a resting state called viral latency. Resting memory CD4+ T cells are considered the biggest reservoir of persistent HIV infection and are often studied exclusively as the main target for an HIV cure. However, other cell types, such as circulating monocytes and tissue-resident macrophages, can harbor integrated, replication-competent HIV. To develop a cure for HIV, focus is needed not only on the T cell compartment, but also on these myeloid reservoirs of persistent HIV infection. In this review, we summarize their importance when designing HIV cure strategies and challenges associated to their identification and specific targeting by the “shock and kill” approach

Human Vδ2 T Cells and Their Versatility for Immunotherapeutic Approaches

Gamma/delta (γδ) T cells are innate-like immune effectors that are a critical component linking innate and adaptive immune responses. They are recognized for their contribution to tumor surveillance and fight against infectious diseases. γδ T cells are excellent candidates for cellular immunotherapy due to their unique properties to recognize and destroy tumors or infected cells. They do not depend on the recognition of a single antigen but rather a broad-spectrum of diverse ligands through expression of various cytotoxic receptors. In this manuscript, we review major characteristics of the most abundant circulating γδ subpopulation, Vδ2 T cells, their immunotherapeutic potential, recent advances in expansion protocols, their preclinical and clinical applications for several infectious diseases and malignancies, and how additional modulation could enhance their therapeutic potential

Defying convention in the time of COVID-19: Insights into the role of γδ T cells

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is a complex disease which immune response can be more or less potent. In severe cases, patients might experience a cytokine storm that compromises their vital functions and impedes clearance of the infection. Gamma delta (γδ) T lymphocytes have a critical role initiating innate immunity and shaping adaptive immune responses, and they are recognized for their contribution to tumor surveillance, fighting infectious diseases, and autoimmunity. γδ T cells exist as both circulating T lymphocytes and as resident cells in different mucosal tissues, including the lungs and their critical role in other respiratory viral infections has been demonstrated. In the context of SARS-CoV-2 infection, γδ T cell responses are understudied. This review summarizes the findings on the antiviral role of γδ T cells in COVID-19, providing insight into how they may contribute to the control of infection in the mild/moderate clinical outcome

Boosting the Immune System for HIV Cure: A γδ T Cell Perspective

The major barrier to HIV cure is a population of long-lived cells that harbor latent but replication-competent virus, are not eliminated by antiretroviral therapy (ART), and remain indistinguishable from uninfected cells. However, ART does not cure HIV infection, side effects to treatment still occur, and the steady global rate of new infections makes finding a sustained ART-free HIV remission or cure for HIV-seropositive individuals urgently needed. Approaches aimed to cure HIV are mostly based on the “shock and kill” method that entails the use of a drug compound to reactivate latent virus paired together with strategies to boost or supplement the existing immune system to clear reactivated latently infected cells. Traditionally, these strategies have utilized CD8+ cytotoxic lymphocytes (CTL) but have been met with a number of challenges. Enhancing innate immune cell populations, such as γδ T cells, may provide an alternative route to HIV cure. γδ T cells possess anti-viral and cytotoxic capabilities that have been shown to directly inhibit HIV infection and specifically eliminate reactivated, latently infected cells in vitro. Most notably, their access to immune privileged anatomical sites and MHC-independent antigen recognition may circumvent many of the challenges facing CTL-based strategies. In this review, we discuss the role of γδ T cells in normal immunity and HIV infection as well as their current use in strategies to treat cancer. We present this information as means to speculate about the utilization of γδ T cells for HIV cure strategies and highlight some of the fundamental gaps in knowledge that require investigation

HIV Latency Reversing Agents have diverse effects on Natural Killer Cell Function

In an effort to clear persistent HIV infection, and achieve a durable therapy-free remission of HIV disease, extensive pre-clinical studies and early pilot clinical trials are underway to develop and test agents that can reverse latent HIV infection and present viral antigen to the immune system for clearance. It is therefore critical to understand the impact of latency reversing agents (LRAs) on the function of immune effectors needed to clear infected cells. We assessed the impact of LRAs on the function of natural killer (NK) cells, the main effector cells of the innate immune system. We studied the effects of three histone deacetylase inhibitors (SAHA or vorinostat, romidepsin and panobinostat) and two protein kinase C (PKC) agonists (prostratin and ingenol) on the antiviral activity, cytotoxicity, cytokine secretion, phenotype and viability of primary NK cells. We found that ex vivo exposure to vorinostat had minimal impact on all parameters assessed, while panobinostat caused a decrease in NK cell viability, antiviral activity and cytotoxicity. Prostratin caused NK cell activation and interestingly, improved antiviral activity. Overall, we found that LRAs can alter the function and fate of NK cells, and these effects must be carefully considered as strategies are developed to clear persistent HIV infection