Targeting Macrophage Dysregulation for Viral Infections: Novel Targets for Immunomodulators

A major barrier to human immunodeficiency virus (HIV-1) cure is the latent viral reservoir, which persists despite antiretroviral therapy (ART), including across the non-dividing myeloid reservoir which is found systemically in sanctuary sites across tissues and the central nervous system (CNS). Unlike activated CD4+ T cells that undergo rapid cell death during initial infection (due to rapid viral replication kinetics), viral replication kinetics are delayed in non-dividing myeloid cells, resulting in long-lived survival of infected macrophages and macrophage-like cells. Simultaneously, persistent inflammation in macrophages confers immune dysregulation that is a key driver of co-morbidities including cardiovascular disease (CVD) and neurological deficits in people living with HIV-1 (PLWH). Macrophage activation and dysregulation is also a key driver of disease progression across other viral infections including SARS-CoV-2, influenza, and chikungunya viruses, underscoring the interplay between macrophages and disease progression, pathogenesis, and comorbidity in the viral infection setting. This review discusses the role of macrophages in persistence and pathogenesis of HIV-1 and related comorbidities, SARS-CoV-2 and other viruses. A special focus is given to novel immunomodulatory targets for key events driving myeloid cell dysregulation and reservoir maintenance across a diverse array of viral infections.

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Transient viral replication during analytical treatment interruptions in SIV infected macaques can alter the rebound-competent viral reservoir

PLoS Pathogens ◽

10.1371/journal.ppat.1009686 ◽

2021 ◽

Vol 17 (6) ◽

pp. e1009686

Author(s):

Taina T. Immonen ◽

Christine M. Fennessey ◽

Leslie Lipkey ◽

Abigail Thorpe ◽

Gregory Q. Del Prete ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Viral Replication ◽

Rhesus Macaques ◽

Treatment Strategies ◽

Viral Reservoir ◽

Virus Population ◽

Analytical Treatment ◽

Treatment Interruptions ◽

The Impact ◽

Hiv 1

Analytical treatment interruptions (ATIs) of antiretroviral therapy (ART) play a central role in evaluating the efficacy of HIV-1 treatment strategies targeting virus that persists despite ART. However, it remains unclear if ATIs alter the rebound-competent viral reservoir (RCVR), the virus population that persists during ART and from which viral recrudescence originates after ART discontinuation. To assess the impact of ATIs on the RCVR, we used a barcode sequence tagged SIV to track individual viral lineages through a series of ATIs in Rhesus macaques. We demonstrate that transient replication of individual rebounding lineages during an ATI can lead to their enrichment in the RCVR, increasing their probability of reactivating again after treatment discontinuation. These data establish that the RCVR can be altered by uncontrolled replication during ATI.

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HIV controllers suppress viral replication and evolution and prevent disease progression following intersubtype HIV-1 superinfection

AIDS ◽

10.1097/qad.0000000000002090 ◽

2019 ◽

Vol 33 (3) ◽

pp. 399-410 ◽

Cited By ~ 2

Author(s):

Suwellen S.D. de Azevedo ◽

Edson Delatorre ◽

Fernanda H. Côrtes ◽

Brenda Hoagland ◽

Beatriz Grinsztejn ◽

...

Keyword(s):

Viral Replication ◽

Disease Progression ◽

Hiv Controllers ◽

Hiv 1

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HIV-Specific Granzyme B-Secreting but Not Gamma Interferon-Secreting T Cells Are Associated with Reduced Viral Reservoirs in Early HIV Infection

Journal of Virology ◽

10.1128/jvi.02233-16 ◽

2017 ◽

Vol 91 (8) ◽

Cited By ~ 14

Author(s):

Feng Yun Yue ◽

Jared C. Cohen ◽

Mu Ho ◽

A. K. M. Nur-ur Rahman ◽

Jun Liu ◽

...

Keyword(s):

T Cells ◽

Hiv Infection ◽

Granzyme B ◽

Viral Reservoir ◽

Major Barrier ◽

Immunodeficiency Virus ◽

Combined Antiretroviral Therapy ◽

Ifn Γ ◽

Hiv 1

ABSTRACT A major barrier to a human immunodeficiency virus type 1 (HIV-1) infection cure is the establishment of a viral reservoir in spite of combined antiretroviral therapy (cART). It is unclear how HIV-specific cytotoxic T lymphocytes (CTLs) influence the size of the reservoir in early HIV infection. Twenty-eight subjects with early HIV infection were recruited to receive cART and followed for 48 weeks. HIV reservoirs in peripheral CD4+ T cells measured by cell-associated proviral DNA and viral outgrowth cultures were determined at baseline and after 48 weeks of cART. At baseline, granzyme B and gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assays were performed with peptides spanning the HIV proteome. All subjects had detectable HIV-specific granzyme B and IFN-γ responses at baseline. The quantity and specificity of granzyme B responses did not correlate with IFN-γ responses. For granzyme B, Tat/Rev was the most dominant whereas for IFN-γ, Gag predominated. HIV-specific granzyme B T cell responses negatively correlated with HIV proviral loads at baseline and at 48 weeks and with replication-competent viral infectious units per million (IUPM) CD4+ T cells at baseline but not significantly at 48 weeks. Tat/Rev-, Env-, Gag-, and Vif-specific granzyme B responses correlated most strongly with reservoir control. There was no correlation of HIV-specific IFN-γ responses with reservoir size at baseline or at 48 weeks. The majority of granzyme B responses were contributed by CD8+ T cells. Thus, our findings suggest that the induction of potent granzyme B-producing CTLs to Tat, Rev, Env, Gag, and Vif during early infection may be able to prevent the establishment of a large viral reservoir, thereby facilitating a reduced HIV burden. IMPORTANCE A major barrier to the cure of human immunodeficiency virus type 1 (HIV-1) infection is the establishment of a viral reservoir that must be significantly reduced or eradicated entirely to enable a cure. Combined antiretroviral therapy (cART) alone is unable to clear this viral reservoir. It has been shown that CD8+ cytotoxic T lymphocytes (CTLs) are important in controlling early HIV infection by reducing plasma viremia. However, it is not known if these HIV-specific CTLs influence the establishment of the viral reservoir in early HIV infection. We show that HIV-specific granzyme B responses targeting HIV Tat/Rev, Env, Gag, and Vif, but not IFN-γ responses, are associated with reduced virus reservoirs at baseline and at 48 weeks of cART. These findings shed light on the nature of the effector CTL response that might limit reservoir size with implications for cure research and HIV vaccines.

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Ongoing Clinical Trials of Human Immunodeficiency Virus Latency-Reversing and Immunomodulatory Agents

Open Forum Infectious Diseases ◽

10.1093/ofid/ofw189 ◽

2016 ◽

Vol 3 (4) ◽

Cited By ~ 50

Author(s):

Héloïse M. Delagrèverie ◽

Constance Delaugerre ◽

Sharon R. Lewin ◽

Steven G. Deeks ◽

Jonathan Z. Li

Keyword(s):

Human Immunodeficiency Virus ◽

Clinical Trials ◽

Virus Production ◽

Viral Reservoir ◽

Virus Eradication ◽

Major Barrier ◽

Reversal Agents ◽

Virus Latency ◽

Immunodeficiency Virus ◽

Hiv 1

Abstract In chronic human immunodeficiency virus (HIV)-1 infection, long-lived latently infected cells are the major barrier to virus eradication and functional cure. Several therapeutic strategies to perturb, eliminate, and/or control this reservoir are now being pursued in the clinic. These strategies include latency reversal agents (LRAs) designed to reactivate HIV-1 ribonucleic acid transcription and virus production and a variety of immune-modifying drugs designed to reverse latency, block homeostatic proliferation, and replenish the viral reservoir, eliminate virus-producing cells, and/or control HIV replication after cessation of antiretroviral therapy. This review provides a summary of ongoing clinical trials of HIV LRAs and immunomodulatory molecules, and it highlights challenges in the comparison and interpretation of the expected trial results.

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Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4+ T cells, and disease progression

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1421607112 ◽

2015 ◽

Vol 112 (12) ◽

pp. E1480-E1489 ◽

Cited By ~ 53

Author(s):

Daniel T. Claiborne ◽

Jessica L. Prince ◽

Eileen Scully ◽

Gladys Macharia ◽

Luca Micci ◽

...

Keyword(s):

T Cell ◽

Disease Progression ◽

T Cell Activation ◽

Immune Activation ◽

Cell Activation ◽

Viral Reservoir ◽

Replicative Fitness ◽

Cell Decline ◽

Protective Genes ◽

Hiv 1

HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1–induced immunopathology and subsequent CD4+ T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8+ T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4+ T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1–related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions.

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Addressing an HIV cure in LMIC

Retrovirology ◽

10.1186/s12977-021-00565-1 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Sherazaan D. Ismail ◽

Joshua Pankrac ◽

Emmanuel Ndashimye ◽

Jessica L. Prodger ◽

Melissa-Rose Abrahams ◽

...

Keyword(s):

Treatment Guidelines ◽

Social Stigma ◽

Post Treatment ◽

Sub Saharan Africa ◽

Viral Reservoir ◽

Latent Reservoir ◽

People Living With Hiv ◽

Geographical Regions ◽

Different Populations ◽

Hiv 1

AbstractHIV-1 persists in infected individuals despite years of antiretroviral therapy (ART), due to the formation of a stable and long-lived latent viral reservoir. Early ART can reduce the latent reservoir and is associated with post-treatment control in people living with HIV (PLWH). However, even in post-treatment controllers, ART cessation after a period of time inevitably results in rebound of plasma viraemia, thus lifelong treatment for viral suppression is indicated. Due to the difficulties of sustained life-long treatment in the millions of PLWH worldwide, a cure is undeniably necessary. This requires an in-depth understanding of reservoir formation and dynamics. Differences exist in treatment guidelines and accessibility to treatment as well as social stigma between low- and-middle income countries (LMICs) and high-income countries. In addition, demographic differences exist in PLWH from different geographical regions such as infecting viral subtype and host genetics, which can contribute to differences in the viral reservoir between different populations. Here, we review topics relevant to HIV-1 cure research in LMICs, with a focus on sub-Saharan Africa, the region of the world bearing the greatest burden of HIV-1. We present a summary of ART in LMICs, highlighting challenges that may be experienced in implementing a HIV-1 cure therapeutic. Furthermore, we discuss current research on the HIV-1 latent reservoir in different populations, highlighting research in LMIC and gaps in the research that may facilitate a global cure. Finally, we discuss current experimental cure strategies in the context of their potential application in LMICs.

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The Impact of Macrophage Nucleotide Pools on HIV-1 Reverse Transcription, Viral Replication, and the Development of Novel Antiviral Agents

Molecular Biology International ◽

10.1155/2012/625983 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 19

Author(s):

Christina Gavegnano ◽

Edward M. Kennedy ◽

Baek Kim ◽

Raymond F. Schinazi

Keyword(s):

Viral Replication ◽

Antiviral Agents ◽

Viral Reservoir ◽

Differentiated Cells ◽

Cellular Environment ◽

Effective Inhibition ◽

Repair Mechanisms ◽

Targeted Inhibition ◽

The Impact ◽

Hiv 1

Macrophages are ubiquitous and represent a significant viral reservoir for HIV-1. Macrophages are nondividing, terminally differentiated cells, which have a unique cellular microenvironment relative to actively dividing T lymphocytes, all of which can impact HIV-1 infection/replication, design of inhibitors targeting viral replication in these cells, emergence of mutations within the HIV-1 genome, and disease progression. Scarce dNTPs drive rNTP incorporation into the proviral DNA in macrophages but not lymphocytes. Furthermore, the efficacy of a ribose-based inhibitor that potently inhibits HIV-1 replication in macrophages, has prompted a reconsideration of the previously accepted dogma that 2′-deoxy-based inhibitors demonstrate effective inhibition of HIV-1 replication. Additionally, higher levels of dUTP and rNTP incorporation in macrophages, and lack of repair mechanisms relative to lymphocytes, provide a further mechanistic understanding required to develop targeted inhibition of viral replication in macrophages. Together, the concentrations of dNTPs and rNTPs within macrophages comprise a distinctive cellular environment that directly impacts HIV-1 replication in macrophages and provides unique insight into novel therapeutic mechanisms that could be exploited to eliminate virus from these cells.

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Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection

Blood ◽

10.1182/blood-2005-03-1100 ◽

2005 ◽

Vol 106 (10) ◽

pp. 3366-3369 ◽

Cited By ~ 221

Author(s):

Galit Alter ◽

Nickolas Teigen ◽

Benjamin T. Davis ◽

Marylyn M. Addo ◽

Todd J. Suscovich ◽

...

Keyword(s):

Viral Replication ◽

Nk Cells ◽

Cell Function ◽

Viral Infections ◽

Nk Cell ◽

Cell Subset ◽

Multiparameter Flow Cytometry ◽

Cell Compartment ◽

Acute Hiv ◽

Hiv 1

AbstractNatural killer (NK) cells are critical in the first-line defense against viral infections. Chronic HIV-1 infection leads to a perturbation in the NK cell compartment, yet the kinetics of this deregulation and the functional consequences are unclear. Here, we characterized changes in the NK cell compartment longitudinally by multiparameter flow cytometry, starting in acute HIV-1 infection. Acute HIV-1 infection was associated with elevated NK cell numbers, with an expansion of CD3negCD56dimCD16pos NK cells and an early depletion of CD3negCD56brightCD16neg NK cells. Ongoing viral replication resulted in a depletion of CD3negCD56dimCD16pos NK cells with a paralleled increase in functionally anergic CD3negCD56negCD16pos NK cells, accompanied by reduced functional activity, as measured by CD107a expression and cytokine secretion. Taken together, these studies demonstrate a sequential impairment of NK cell function with persistent viral replication resulting from a progressive deregulation of NK cell subsets with distinct functional properties.

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Cancer Patients Have a Higher Risk Regarding COVID-19–and Vice Versa?

Pharmaceuticals ◽

10.3390/ph13070143 ◽

2020 ◽

Vol 13 (7) ◽

pp. 143 ◽

Cited By ~ 1

Author(s):

Franz Geisslinger ◽

Angelika M. Vollmar ◽

Karin Bartel

Keyword(s):

Immune Response ◽

Disease Progression ◽

Cancer Patients ◽

Viral Infections ◽

Severe Disease ◽

Special Focus ◽

Long Term Effects ◽

Increased Risk ◽

Inflammatory Immune Response

The world is currently suffering from a pandemic which has claimed the lives of over 230,000 people to date. The responsible virus is called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and causes the coronavirus disease 2019 (COVID-19), which is mainly characterized by fever, cough and shortness of breath. In severe cases, the disease can lead to respiratory distress syndrome and septic shock, which are mostly fatal for the patient. The severity of disease progression was hypothesized to be related to an overshooting immune response and was correlated with age and comorbidities, including cancer. A lot of research has lately been focused on the pathogenesis and acute consequences of COVID-19. However, the possibility of long-term consequences caused by viral infections which has been shown for other viruses are not to be neglected. In this regard, this opinion discusses the interplay of SARS-CoV-2 infection and cancer with special focus on the inflammatory immune response and tissue damage caused by infection. We summarize the available literature on COVID-19 suggesting an increased risk for severe disease progression in cancer patients, and we discuss the possibility that SARS-CoV-2 could contribute to cancer development. We offer lines of thought to provide ideas for urgently needed studies on the potential long-term effects of SARS-CoV-2 infection.

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