Franco Lori

[This corrects the article DOI: 10.1371/journal.pone.0276751.].

The COVID‐19 pandemic profoundly changes the perception of the impact of viral diseases on society and the consequent need to develop new and more effective technologies in vaccines and antivirals. Thus, research in the field of antivirals has received a new and strong impetus by considering new approaches and innovative methodologies. One example...

Background Selective Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) have revolutionized the treatment of breast cancer and have potential in other cancers, being manageable drugs yet with some bone marrow toxicity. Selective CDK9 inhibitors (CDK9i) never advanced into clinical use, partly due to side effects, including gastrointestinal toxicity,...

The scientific community is actively engaged in the development of innovative nanomaterials with broad‐spectrum virucidal properties, particularly those capable of producing reactive oxygen species (ROS), to combat upcoming pandemics effectively. The generation of ROS capable of inhibiting viral activity on high‐touch surfaces can prove an effectiv...

The emergence of SARS-CoV-2 variants requires close monitoring to prevent the reoc-currence of a new pandemic in the near future. The Omicron variant, in particular, is one of the fastest-spreading viruses, showing a high ability to infect people and evade neutralization by anti-bodies elicited upon infection or vaccination. Therefore, the search f...

Background: The COVID-19 pandemic has necessitated the development of efficient diagnostic tools to predict T-cell responses, which are crucial for viral clearance and protection against reinfection. Current diagnostic tests lack the ability to predict the epitope repertoire of an individual that induces T-cell responses. Methods: We developed VERD...

Background. Airborne transmission of endemic respiratory viruses, such as SARS-CoV-2 and influenza viruses, poses significant public health challenges. Aims. This manuscript investigates the efficacy of electromagnetic waves as a novel approach for airborne viruses inactivation in bioaerosol suspension, that is their natural route of transmission....

SARS-CoV-2 is inactivated in aerosol (its primary mode of transmission) by means of radiated microwaves at frequencies that have been experimentally determined. Such frequencies are best predicted by the mathematical model suggested by Taylor, Margueritat and Saviot. The alignment between such mathematical prediction and the outcomes of our experim...

Coronaviruses are a family of viruses that cause disease in mammals and birds. In humans, coronaviruses cause infections on the respiratory tract that can be fatal. These viruses can cause both mild illnesses such as the common cold and lethal illnesses such as SARS, MERS, and COVID-19. Air transmission represents the principal mode by which people...

Despite new antivirals are being approved against SARS-CoV-2 they suffer from significant constraints and are not indicated for hospitalized patients, who are left with few antiviral options. Repurposed drugs have previously shown controversial clinical results and it remains difficult to understand why certain trials delivered positive results and...

The coronavirus pandemic (COVID-19) had spread rapidly since December 2019, when it was first identified in Wuhan, China. As of April 2021, more than 130 million cases have been confirmed, with more than 3 million deaths, making it one of the deadliest pandemics in history. Different approaches must be put in place to confront a new pandemic: commu...

ViroStatics is a privately held small pharmaceutical company dedicated to discovering and developing novel compounds for a multifaceted treatment of cancers and viral diseases and focuses on novel, selective, host cell kinase targeted inhibitors in its state-of-the-art Biological Safety Level 3 Laboratory. The company has strong expertise in testin...

Ozone is a powerful anti-bacterial, anti-fungal and anti-viral agent, yet exposure to high levels of ozone can pose risks to human/animal health and, in the long term, corrode certain objects. In order to overcome these risks, we evaluated the potential of using a relatively short exposure of a low concentration of ozone to disinfect an indoor envi...

img src=” https://s3.amazonaws.com/production.scholastica/article/12561/medium/prnano_412020_figure_1.jpg?1586516744”> Although disease enhancement by antibodies has been described for corona and other viruses, nobody can predict whether such antibodies induced by the vaccine will not be harmful, especially after reinfection with a different strain...

e14298 Background: Cancer vaccines activate T-cells with peptides presented by HLA alleles. We hypothesized that peptides binding to multiple HLA alleles of a patient are more likely to induce T-cell responses than epitopes presented by a single HLA. To prove this hypothesis we predicted the outcome of vaccine clinical trials in a Model Population...

3557 Background: The goal of this study was to evaluate the safety, tolerability and immunogenicity of a single dose of PolyPEPI1018 as an add-on to maintenance therapy in subjects with metastatic colorectal cancer (mCRC). PolyPEPI1018 is a peptide vaccine containing 12 unique epitopes derived from 7 conserved cancer testis antigens (CTAs) frequent...

e13132 Background: Association between certain HLA types and cancer is well known. We hypothesized that the number of epitopes of tumor antigens presented by autologous HLAs characterizes a patient’s capacity to kill tumor cells. These CD8+ T cell epitopes are presented by 6 out of >13,000 known HLA class I alleles and induce extremely variable tum...

e14295 Background: Neoantigen vaccines can activate T-cells that specifically kill tumor cells. However, most vaccine peptides, selected either as HLA-binders or as HLA-presented epitopes, do not induce T-cell responses in HLA allele-matched individuals. We hypothesized that personal-epitopes (PEPIs) binding to multiple autologous HLA-alleles induc...

HIV/AIDS is still one of the leading causes of death worldwide. Current drugs that target the canonical steps of the HIV-1 life cycle are efficient in blocking viral replication but are unable to eradicate HIV-1 from infected patients. Moreover, drug resistance (DR) is often associated with the clinical use of these molecules, thus raising the need...

There is no clinically available cancer immunotherapy that exploits Langerhans cells (LCs), the epidermal precursors of dendritic cells (DCs) that are the natural agent of antigen delivery. We developed a DNA formulation with a polymer and obtained synthetic 'pathogen-like' nanoparticles that preferentially targeted LCs in epidermal cultures. These...

HIV-specific cellular immune responses are associated with control of viremia and delayed disease progression. An effective therapeutic vaccine could mimic these effects and reduce the need for continued antiretroviral therapy. DermaVir, a topically administered plasmid DNA-nanomedicine expressing HIV (CladeB) virus-like particles consisting of 15...

Background: A new class of antiretrovirals, AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs), has been proposed as a disease-modifying therapy to both reduce Human Immunodeficiency Virus Type 1 (HIV-1) RNA levels and the excessive immune activation now recognized as the major driver of not only the continual loss of CD4(+) T cells and pr...

CONSORT Checklist. (DOC)

Sub-Study Demographics Table. (DOCX)

Trial Protocol (PDF)

The GIHU004 study was designed to evaluate the safety and immunogenicity of three doses of DermaVir immunization in HIV-infected subjects on fully suppressive combination antiretroviral therapy (cART). This first-in-human dose escalation study was conducted with three topical DermaVir doses targeted to epidermal Langerhans cells to express fifteen...

Trial protocol. (PDF)

CONSORT checklist. (DOCX)

CONSORT flowchart. (DOCX)

The HIV global pandemic continues to rage with over 33 million people living with the disease. Although multidrug therapy has improved the prognosis for those infected by the virus, it has not eradicated the infection. Immunological therapies, including therapeutic vaccines, are needed to supplement drug therapy in the search for a 'functional cure...

Immunotherapy in patients with HIV-1 infection aims to restore and broaden immunological competence, reduce viral load and thereby permit longer periods without combined antiretroviral treatment (cART). Twelve HIV-1-infected patients on cART were immunized on the skin with DNA plasmids containing genes of several HIV-1 subtypes with or without the...

We describe here a single plasmid DNA immunogen representing the broadest antigen repertoire among HIV vaccine candidates. This pDNA was "ANTIGENeered" for the regulated expression of thirteen complete and two non-functional HIV protein antigens. These proteins self assemble into complex virus-like particles (VLP(+)). Multiple irreversible safety f...

Antiviral hyper-activation-limiting therapeutic agents (AV-HALTs) are a novel experimental drug class designed to both decrease viral replication and down-regulate excessive immune system activation for the treatment of chronic infections, including human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. VS411, a first-in-class AV-HA...

Awarding the Nobel prize in physiology or medicine to Francoise Barre-Sinoussi and Luc Montagnier for the discovery of HIV-1, the causative agent of AIDS ([1][1]), is timely given the harm that the virus continues to inflict on the people of the world. While these awardees fully deserve the award

In the context of HIV-driven, prolonged overactivation of the immune system, ultimately leading to AIDS, Rethi and colleagues have identified key components able to support both life and death of immune-competent T cells. Rethi and colleagues have shown that Fas, increasingly expressed during T-

Evidences have recently suggested that the preservation of vaccine-induced memory rather than effector T cells is essential for better outcome and survival following pathogenic SIV challenge in macaques. However, an equivalent demonstration in humans is missing, and the immune correlates of HIV-1 control have been only partially characterized. We f...

IL-7 and IL-15 are key cytokines involved in the generation and maintenance of memory CD8+ T-cells. We evaluated these cytokines as molecular adjuvants for topical HIV-1 DermaVir vaccine. We found that mice receiving DermaVir formulated with HIV-1 Gag plasmid in the presence of IL-7- or IL-15-encoding plasmid significantly enhanced Gag-specific cen...

To collect published evidence in support of a novel immune therapeutic approach to reduce the excess of immune activation that ultimately turns into immune deficiency in HIV/AIDS. A large body of evidence has been collected in support of the pathogenetic interpretation that prolonged immune overactivation induced by HIV during the course of chronic...

During uncontrolled HIV disease, both TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptor expression are increased. Enhanced TRAIL sensitivity is due to TRAIL receptor up-regulation induced by gp120. As a result of successful antiretroviral therapy TRAIL is down-regulated, and there are fewer TRAIL-sensitive cells. In this setting, we...

To improve the efficacy of DNA immunization epidermal Langerhans cells are attractive targets to deliver antigen-encoding plasmid DNA. Topical vaccination with naked plasmid DNA has been shown to induce immune responses, and their potency might be improved by chemical and physical methods aimed to enhance the efficiency of plasmid DNA delivery into...

Topical DNA vaccination (DermaVir) facilitates antigen presentation to naive T cells. DermaVir immunization in mice, using HIV-1 Env and Gag, elicited cellular immune responses. Boosting with HIV-1 gp120 Env and p41 Gag augmented Th1 cytokine levels. Intramuscular DNA administration was less efficient in priming antigen-specific cytokine production...

Structured treatment interruptions may have beneficial effects on metabolic parameters, while data on anthropometric parameters and on the quality of life are scanty. This study was designed to evaluate the effects of structured treatment interruptions on plasma cholesterol, triglycerides, anthropometric, immunologic, virologic changes and quality...

In vivo antigen expression by plasmid DNA could provide a potent and cost-effective vaccine platform if its immunogenicity were improved to induce antigen-specific memory T-cell responses. To study these immune responses, we compared naked DNA vaccine with topical DermaVir formulated with the same HIV-1 (Gag) DNA in the mouse model. Topical DermaVi...

To examine the literature in search of data supporting (stopping highly active antiretroviral therapy (HAART) temporarily in the absence of virus rebound) to expand HIV treatment options. We proposed investigating HAART interruptions after the 'Berlin patient' had discontinued HAART while keeping HIV suppressed. The idea of inducing immune control...

Highly active antiretroviral treatment (HAART), i.e. the combination of three or more drugs against human immunodeficiency virus type 1 (HIV-1), has greatly improved the clinical outcome of HIV-1-infected individuals. However, HAART is unable to reconstitute HIV-specific immunity and eradicate the virus. Several observations in primate models and i...

In this review we discuss the features of a new class of antiretroviral combinations, namely "Virostatics". Virostatics are characterized by the combination of a drug directly inhibiting virus production (viro), and another drug indirectly inhibiting the virus by reducing cellular proliferation (static). In particular, we will focus on the combinat...

This review highlights some of the most common cytokines currently being tested as adjuvants in HIV-1-DNA vaccine regimens. We discuss their use in both the prophylactic and therapeutic setting. Finally, we describe a novel dendritic cell-targeted vaccine candidate for HIV-1 treatment and prevention called DermaVir and explore the combination of th...

The mechanism of chronic immune activation and impairment of HIV-specific immune responses during chronic infection is not fully understood. However, it is known that high immune activation leads to more rapid progression to AIDS. We hypothesize that CD4(+) T cell-mediated viral antigen presentation contributes to this pathologic immune activation...

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DermaVir employs a topical, non-invasive method for vaccine delivery to dendritic cells. The vaccine product contains plasmid DNA as the active ingredient, encoding authentically expressed retroviral genes with appropriate safety modifications. The non-viral delivery system packages the DNA within pathogen-like nanoparticles and studies indicate th...

The hydroxyurea-didanosine combination has been shown to limit immune activation (a major pathogenic component of HIV/AIDS) and suppress viral load by both antiviral and cytostatic ('virostatic') activities. Virostatics action represent a novel approach to attack HIV/AIDS from multiple directions; however, the use of these drugs is limited by the l...

The goal of this study was to optimize the hydroxyurea dosage in HIV-infected patients, and to minimize the toxicity and maximize the antiviral efficacy of the hydroxyurea-didanosine combination. In a randomized, open-label study (RIGHT 702, a multicenter trial performed in private and institutional practices), three daily doses (600 microg, 800-90...

DermaVir is a novel topical immunisation designed to target Langerhans cells (LC), the epidermal precursors of dendritic cells. LC serve as a vehicle to process and transfer antigens from the skin to T cell areas in the lymphoid organs. The HIV DNA delivered by DermaVir to LC expresses most viral regulatory and structural genes and induces T cell-m...

To demonstrate that, despite a dose-dependent cytostatic effect, hydroxyurea (HU) does not have immunosuppressive effects. The effects of HU on T lymphocyte proliferation parameters, activation phenotype and cytokine production were examined in vitro after exposure to clinically relevant concentrations of HU (10, 50, and 100 micromol/l). The effect...

Human immunodeficiency virus (HIV) vaccines have the potential to improve antiretroviral drug treatment by inducing cytotoxic killing of HIV-infected cells. Prophylactic vaccines utilize new antigens to initiate immunity; however, in HIV-infected individuals the load of viral antigen is not the limiting factor for the restoration of immune response...

To reconstitute immune responses capable of eliminating infected cells and suppressing viral load during chronic retroviral infection. : A topical, DNA-based therapeutic immunization (DermaVir) was designed to express most of the regulatory and structural viral genes in dendritic cells. DermaVir alone and in combination with antiretroviral drugs wa...

Therapeutic immunization may be thought of as an adjunct to highly active antiretroviral therapy to prime the immune system and possibly correct for immunological defects. Most therapeutic vaccine strategies currently under investigation aim to increase HIV-specific cellular responses. This may be most successfully accomplished by utilizing profess...

Lifelong adherence to very complex anti-HIV therapy presents drawbacks such as drug resistance and chronic drug-related toxicity, underscoring the need for innovative therapeutic options. As it is becoming increasingly evident that immune activation may be responsible for immune pathology, novel approaches to limit immune activation are under inves...

Data from the first phase III HIV vaccine trial does not indicate efficacy regarding the production of neutralizing antibodies and prevention of HIV infection. The induction of a potent HIV-specific cellular response through therapeutic vaccination is now thought to be a more attainable goal through HIV DNA vaccines. This review will summarize the...

The combination of three or more antiretroviral drugs is referred to as highly active antiretroviral therapy (HAART) and constitutes the standard of care for HIV-1 patients in industrialized nations. Although HAART is usually effective in reducing viral load and re-constituting CD4 counts, latent virus reservoirs persist, and as many as 60 years th...

T-cell receptor excision circles (TREC) may be a useful surrogate marker in HIV-1 infection for evaluating the likelihood of continued clinical stability and/or the response to therapeutics, including vaccines. Analysis of TREC in SHIV and SIV models of HIV-1 infection may provide additional information concerning the utility of TREC as a marker. W...

Toxicity and other drug adherence-related factors have contributed to decreased compliance to antiretroviral regimens amongst HIV-infected patients. Irregular therapy disruption causes loss of CD4 T cells, onset of drug resistance and rapid rebound of plasma viral load (VL). However, an appropriate choice of drugs and properly scheduled structured...

The 2nd International Symposium on Molecular Diagnostics and Skin Gene Therapy was held on a beautiful spring weekend at one of the youngest universities in the world, the Heinrich-Heine University, founded 1965. The conference attracted more than 340 participants from 24 different countries, including ethicists, basic researchers, virologists, imm...

The induction of a Th-1 polarized immune response is believed to be advantageous when designing immunologic approaches for HIV therapy. DNA vaccines represent one of the best immunologic strategies capable of inducing such a response. From conception to clinical application it is now possible to rationally design DNA vaccines based on reliable expe...

Human immunodeficiency virus (HIV)-specific T cells play a critical role in anti-virus immunity. Therefore, during the clinical development of immune-based therapies, it is important to perform a diagnostic test that rapidly quantifies and characterizes cellular immune responses. For detection of functional HIV-specific CD8(+) cytotoxic T cells (CT...

The investigation of novel and innovative treatment approaches for long-term management of HIV-infection has intensified due to the growing number of infected individuals worldwide and the constraints of resistance, toxicity and inconvenience associated with lifelong therapy. Current treatment relies entirely on antiretroviral drugs targeting vario...

Data from basic science and clinical studies suggest that hydroxyurea (hydroxycarbamide)-based regimens are effective treatment options for patients with HIV at various stages of disease. In vitro studies of HIV-infected lymphocytes have shown that hydroxyurea: (i) inhibits viral DNA synthesis; (ii) synergistically interacts with nucleoside reverse...

To study the effect of highly active antiretroviral therapy (HAART) with and without hydroxyurea (HU) on changes in plasma viral load (VL) set-point, and on HIV-1-specific responses, after five cycles of structured treatment interruptions (STI). A group of 20 patients taking HAART for chronic HIV infection with VL < 20 copies/ml were randomized to...

Protection from exogenous invaders and elimination of endogenous aberrations are the main contributions of T cells to homeostasis. T cells with Vγ9Vδ2-encoded T-cell receptors (TCRs) have a unique ability to interact with a plethora of phosphoantigens in a major histocompatibility complex (MHC)-unrestricted manner. The biological function of this r...

HIV-specific CD8 T cells play a central role in the immune control of virus replication. To further understand the role of CD8 T cells in clinical settings, there is a need for a diagnostic assay that quantifies HIV-specific CD8 T cells in all HIV-infected individuals. and methods: The CD8VIR (CD8 T cell-mediated virus-specific immune response) ass...

Highly active antiretroviral therapy (HAART) allows for substantial control of HIV replication in vivo, and has caused a significant decline in morbidity and mortality rates among patients. However, eradication of the virus from the body is not possible. Therefore, HAART necessarily becomes a life-long treatment and this is associated with several...

Highly active antiretroviral therapy (HAART) allows for substantial control of HIV replication in vivo, and has caused a significant decline in morbidity and mortality rates among patients. However, eradication of the virus from the body is not possible. Therefore, HAART necessarily becomes a lifelong treatment and this is associated with several p...

Interleukin 2 (IL-2) in combination with highly active antiretroviral therapy (HAART) can significantly increase CD4+ T cell counts but does not improve HIV-specific T cell-mediated immune responses that are associated with the control of viral replication. To characterize the immunomodulatory activity of IL-2 in HIV-infected individuals we studied...

To study whether and under what circumstances HIV can be controlled in chronically infected patients. Nine patients treated with hydroxyurea and didanosine (PANDAs) were compared with 7 patients on highly active antiretroviral therapy (HAART) during an 8-week treatment interruption. Both groups had similar baseline viral load, CD4 count, and length...

Background: Gene therapy has recently been advanced by the development of HIV-based vectors that are able to transduce some non-dividing cells. The manipulation of most non-dividing cells remains, however, scarcely efficient. One of the biological mechanisms postulated to prevent powerful transduction of quiescent cells by lentiviral vectors is th...

Structured treatment interruption (STI) has been investigated for three distinct clinical scenarios: during acute infection with the goal of immune reconstitution and auto immunization; during chronic infection, to decrease the amount and toxicity of antiretroviral drugs; and during virologic failure to restore response to subsequent antiretroviral...

Dendritic cells are susceptible to human immunodeficiency virus (HIV) infection and may transmit the virus to T cells in vivo. Scarce information is available about drug efficacy in dendritic cells because preclinical testing of antiretroviral drugs has been limited predominantly to T cells and macrophages. We compared the antiviral activities of h...

The HIV pandemic represents a new challenge to biomedical research. What began as a handful of recognized cases among homosexual men in the US has become a global pandemic of such proportions that it clearly ranks as one of the most destructive viral scourges in history. In the past few years new treatments and drugs have been developed and tested,...

Highly active antiretroviral therapies (HAART) represent a major advance in the treatment of HIV infection. Although with HAART a substantial suppression of viral replication can be obtained, eradication of the virus from the body cannot be achieved. Therefore, HIV-infected subjects have to be treated for the rest of their lives. Long term treatmen...

Antiretroviral drugs constitute a milestone in the treatment of human immunodeficiency virus (HIV) infection; however, emerging problems limit their long-term use, and an increasing number of patients interrupt the prescribed continuous drug therapy for short or long periods. Some patients appear to benefit from structured treatment interruptions (...

The HIV/AIDS epidemic continues to be an enormous problem despite years of intense research work. Currently, an estimated 36 million people in the world are living with HIV and about 20 million people have already died. Drug therapies have greatly improved the quality of life of many infected persons, however millions of people cannot have access t...

Mitochondrial toxicity is a serious side-effect of antiretroviral drugs, especially nucleoside reverse transcriptase inhibitors (NRTI). An in vitro assay to predict mitochondrial toxicity of in-use and developmental NRTI would be invaluable. To test the ability of a cytofluorimetric technique to predict the mitochondrial-dependent pancreatic and he...

A novel technology combining replication- and integration-defective human immunodeficiency virus type 1 (HIV-1) vectors with genetically modified dendritic cells was developed in order to induce T-cell immunity. We introduced the vector into dendritic cells as a plasmid DNA using polyethylenimine as the gene delivery system, thereby circumventing t...

In a randomized controlled trial with acute simian immunodeficiency virus (SIV)-infected macaques, both highly active antiretroviral therapy (HAART) and HAART with fixed-schedule structured treatment interruption (STI-HAART; alternating 3 weeks on and 3 weeks off therapy) suppressed viral load. In the STI-HAART group, T cell virus-specific immune r...

Hydroxyurea has been extensively used in medical practice, mainly for treating chronic myelogenous leukemia, sickle cell anemia, and other diseases. In light of its ability to inhibit DNA synthesis and to induce cell cycle arrest through inhibition of ribonucleotide reductase, the effects of hydroxyurea on replication of human immunodeficiency viru...

Current drug combinations can achieve long-term suppression of HIV replication in infected individuals. Unfortunately, complicated dosing schedules and high toxicity make long-term compliance with drug regimens difficult for most patients. Gene therapy may provide a permanent solution for HIV disease by generating cells genetically resistant to vir...

Structured treatment interruptions progressively lowered the rate of viral rebound in some HIV-1 infected patients. This approach should be explored as an alternative to continuous antiretroviral therapies.