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HIV Pathogenesis, Vaccine and Eradication Strategies

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A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "HIV Vaccines".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 34660

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Special Issue Editor

Dr. Mudit Tyagi

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Guest Editor

Thomas Jefferson University, Philadelphia, USA
Interests: HIV latency; HIV pathogenesis; HIV eradication; transcription; epigentics; drugs of abuse

Special Issue Information

Dear Colleagues,

Human Immunodeficiency Virus (HIV) is still a very big problem for humanity. Fortunately, current anti-HIV drug regimens are highly effective in controlling HIV transmission and replication. However, it is well established that current anti-HIV therapy will not be able to eradicate or cure HIV. Numerous strategies have been applied unsuccessfully to flush out the latent HIV reservoirs, the main hurdle in HIV eradication. However, due to the mutadaptability of HIV, both preventive and therapeutic vaccines have been proven to be ineffective. In addition, several other prophylactic approaches, including microbicides, are struggling to make an impact.

We are interested in a broad area of research, focusing primarily on the mechanisms of HIV pathogenesis, life cycle, latency and therapeutics. In addition, we are calling for manuscripts dealing with vaccine trials (pre-clinical and clinical) and strategies to develop a more effective HIV vaccine. We aim to present a combination of manuscripts dealing with different vital aspects of HIV, which can be exploited to develop a more effective anti-HIV therapy.

Dr. Mudit Tyagi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Vaccines
Human Immunodeficiency Virus (HIV)
Microbicides
Latency
Virus–host interaction
Infection and immunity
Vaccinology
Animal models

Published Papers (10 papers)

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Research

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22 pages, 5082 KiB

Open AccessArticle

Cytokine Adjuvants IL-7 and IL-15 Improve Humoral Responses of a SHIV LentiDNA Vaccine in Animal Models

by Laury-Anne Leroy, Alice Mac Donald, Aditi Kandlur, Deepanwita Bose, Peng Xiao, Jean Gagnon, François Villinger and Yahia Chebloune

Vaccines 2022, 10(3), 461; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines10030461 - 17 Mar 2022

Cited by 3 | Viewed by 2513

Abstract

HIV-1 remains a major public health issue worldwide in spite of efficacious antiviral therapies, but with no cure or preventive vaccine. The latter has been very challenging, as virus infection is associated with numerous escape mechanisms from host specific immunity and the correlates of protection remain incompletely understood. We have developed an innovative vaccine strategy, inspired by the efficacy of live-attenuated virus, but with the safety of a DNA vaccine, to confer both cellular and humoral responses. The CAL-SHIV-IN⁻ lentiDNA vaccine comprises the backbone of the pathogenic SHIV_KU2 genome, able to mimic the early phase of viral infection, but with a deleted integrase gene to ensure safety precluding integration within the host genome. This vaccine prototype, constitutively expressing viral antigen under the CAEV LTR promoter, elicited a variety of vaccine-specific, persistent CD4 and CD8 T cells against SIV-Gag and Nef up to 80 weeks post-immunization in cynomolgus macaques. Furthermore, these specific responses led to antiviral control of the pathogenic SIV_mac251. To further improve the efficacy of this vaccine, we incorporated the IL-7 or IL-15 genes into the CAL-SHIV-IN⁻ plasmid DNA in efforts to increase the pool of vaccine-specific memory T cells. In this study, we examined the immunogenicity of the two co-injected lentiDNA vaccines CAL-SHIV-IN⁻ IRES IL-7 and CAL-SHIV-IN⁻ IRES IL-15 in BALB/cJ mice and rhesus macaques and compared the immune responses with those generated by the parental vaccine CAL-SHIV-IN⁻. This co-immunization elicited potent vaccine-specific CD4 and CD8 T cells both in mice and rhesus macaques. Antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies were detected up to 40 weeks post-immunization in both plasma and mucosal compartments of rhesus macaques and were enhanced by the cytokines. Full article

(This article belongs to the Special Issue HIV Pathogenesis, Vaccine and Eradication Strategies)

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17 pages, 3203 KiB

Open AccessArticle

Enhancement of the HIV-1-Specific Immune Response Induced by an mRNA Vaccine through Boosting with a Poxvirus MVA Vector Expressing the Same Antigen

by Carmen Elena Gómez, Beatriz Perdiguero, Lorena Usero, Laura Marcos-Villar, Laia Miralles, Lorna Leal, Carlos Óscar S. Sorzano, Cristina Sánchez-Corzo, Montserrat Plana, Felipe García and Mariano Esteban

Vaccines 2021, 9(9), 959; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9090959 - 27 Aug 2021

Cited by 11 | Viewed by 2413

Abstract

Development of a vaccine against HIV remains a major target goal in the field. The recent success of mRNA vaccines against the coronavirus SARS-CoV-2 is pointing out a new era of vaccine designs against pathogens. Here, we have generated two types of mRNA vaccine candidates against HIV-1; one based on unmodified vectors and the other on 1-methyl-3′-pseudouridylyl modified vectors expressing a T cell multiepitopic construct including protective conserved epitopes from HIV-1 Gag, Pol and Nef proteins (referred to as RNA-TMEP and RNA-TMEPmod, respectively) and defined their biological and immunological properties in cultured cells and in mice. In cultured cells, both mRNA vectors expressed the corresponding protein, with higher levels observed in the unmodified mRNA, leading to activated macrophages with differential induction of innate immune molecules. In mice, intranodal administration of the mRNAs induced the activation of specific T cell (CD4 and CD8) responses, and the levels were markedly enhanced after a booster immunization with the poxvirus vector MVA-TMEP expressing the same antigen. This immune activation was maintained even three months later. These findings revealed a potent combined immunization regimen able to enhance the HIV-1-specific immune responses induced by an mRNA vaccine that might be applicable to human vaccination programs with mRNA and MVA vectors. Full article

(This article belongs to the Special Issue HIV Pathogenesis, Vaccine and Eradication Strategies)

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17 pages, 3299 KiB

Open AccessArticle

Telomere Length Shortening in Microglia: Implication for Accelerated Senescence and Neurocognitive Deficits in HIV

by Chiu-Bin Hsiao, Harneet Bedi, Raquel Gomez, Ayesha Khan, Taylor Meciszewski, Ravikumar Aalinkeel, Ting Chean Khoo, Anna V. Sharikova, Alexander Khmaladze and Supriya D. Mahajan

Vaccines 2021, 9(7), 721; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9070721 - 01 Jul 2021

Cited by 6 | Viewed by 3221

Abstract

The widespread use of combination antiretroviral therapy (cART) has led to the accelerated aging of the HIV-infected population, and these patients continue to have a range of mild to moderate HIV-associated neurocognitive disorders (HAND). Infection results in altered mitochondrial function. The HIV-1 viral protein Tat significantly alters mtDNA content and enhances oxidative stress in immune cells. Microglia are the immune cells of the central nervous system (CNS) that exhibit a significant mitotic potential and are thus susceptible to telomere shortening. HIV disrupts the normal interplay between microglia and neurons, thereby inducing neurodegeneration. HIV cART contributes to the inhibition of telomerase activity and premature telomere shortening in activated peripheral blood mononuclear cells (PBMC). However, limited information is available on the effect of cART on telomere length (TL) in microglia. Although it is well established that telomere shortening induces cell senescence and contributes to the development of age-related neuro-pathologies, the effect of HIV-Tat on telomere length in human microglial cells and its potential contribution to HAND are not well understood. It is speculated that in HAND intrinsic molecular mechanisms that control energy production underlie microglia-mediated neuronal injury. TL, telomerase and mtDNA expression were quantified in microglial cells using real time PCR. Cellular energetics were measured using the Seahorse assay. The changes in mitochondrial function were examined by Raman Spectroscopy. We have also examined TL in the PBMC obtained from HIV-1 infected rapid progressors (RP) on cART and those who were cART naïve, and observed a significant decrease in telomere length in RP on cART as compared to RP’s who were cART naïve. We observed a significant decrease in telomerase activity, telomere length and mitochondrial function, and an increase in oxidative stress in human microglial cells treated with HIV Tat. Neurocognitive impairment in HIV disease may in part be due to accelerated neuro-pathogenesis in microglial cells, which is attributable to increased oxidative stress and mitochondrial dysfunction. Full article

(This article belongs to the Special Issue HIV Pathogenesis, Vaccine and Eradication Strategies)

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Review

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30 pages, 1075 KiB

Open AccessReview

Crossroads of Drug Abuse and HIV Infection: Neurotoxicity and CNS Reservoir

by Shilpa Sonti, Kratika Tyagi, Amit Pande, Rene Daniel, Adhikarimayum Lakhikumar Sharma and Mudit Tyagi

Vaccines 2022, 10(2), 202; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines10020202 - 27 Jan 2022

Cited by 5 | Viewed by 3905

Abstract

Drug abuse is a common comorbidity in people infected with HIV. HIV-infected individuals who abuse drugs are a key population who frequently experience suboptimal outcomes along the HIV continuum of care. A modest proportion of HIV-infected individuals develop HIV-associated neurocognitive issues, the severity of which further increases with drug abuse. Moreover, the tendency of the virus to go into latency in certain cellular reservoirs again complicates the elimination of HIV and HIV-associated illnesses. Antiretroviral therapy (ART) successfully decreased the overall viral load in infected people, yet it does not effectively eliminate the virus from all latent reservoirs. Although ART increased the life expectancy of infected individuals, it showed inconsistent improvement in CNS functioning, thus decreasing the quality of life. Research efforts have been dedicated to identifying common mechanisms through which HIV and drug abuse lead to neurotoxicity and CNS dysfunction. Therefore, in order to develop an effective treatment regimen to treat neurocognitive and related symptoms in HIV-infected patients, it is crucial to understand the involved mechanisms of neurotoxicity. Eventually, those mechanisms could lead the way to design and develop novel therapeutic strategies addressing both CNS HIV reservoir and illicit drug use by HIV patients. Full article

(This article belongs to the Special Issue HIV Pathogenesis, Vaccine and Eradication Strategies)

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12 pages, 601 KiB

Open AccessReview

Human Immunodeficiency Virus Type-1 (HIV-1) Transcriptional Regulation, Latency and Therapy in the Central Nervous System

by Joseph Hokello, Adhikarimayum Lakhikumar Sharma, Priya Tyagi, Alok Bhushan and Mudit Tyagi

Vaccines 2021, 9(11), 1272; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9111272 - 03 Nov 2021

Cited by 7 | Viewed by 1787

Abstract

The central nervous system (CNS) is highly compartmentalized and serves as a specific site of human immunodeficiency virus (HIV) infection. Therefore, an understanding of the cellular populations that are infected by HIV or that harbor latent HIV proviruses is imperative in the attempts to address cure strategies, taking into account that HIV infection and latency in the CNS may differ considerably from those in the periphery. HIV replication in the CNS is reported to persist despite prolonged combination antiretroviral therapy due to the inability of the current antiretroviral drugs to penetrate and cross the blood–brain barrier. Consequently, as a result of sustained HIV replication in the CNS even in the face of combination antiretroviral therapy, there is a high incidence of HIV-associated neurocognitive disorders (HAND). This article, therefore, provides a comprehensive review of HIV transcriptional regulation, latency, and therapy in the CNS. Full article

(This article belongs to the Special Issue HIV Pathogenesis, Vaccine and Eradication Strategies)

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26 pages, 15176 KiB

Open AccessReview

Alzheimer’s-Like Pathology at the Crossroads of HIV-Associated Neurological Disorders

by Divya T. Chemparthy, Muthukumar Kannan, Lila Gordon, Shilpa Buch and Susmita Sil

Vaccines 2021, 9(8), 930; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9080930 - 21 Aug 2021

Cited by 10 | Viewed by 3593

Abstract

Despite the widespread success of combined antiretroviral therapy (cART) in suppressing viremia, the prevalence of human immunodeficiency virus (HIV)-associated neurological disorders (HAND) and associated comorbidities such as Alzheimer’s disease (AD)-like symptomatology is higher among people living with HIV. The pathophysiology of observed deficits in HAND is well understood. However, it has been suggested that it is exacerbated by aging. Epidemiological studies have suggested comparable concentrations of the toxic amyloid protein, amyloid-β42 (Aβ42), in the cerebrospinal fluid (CSF) of HAND patients and in the brains of patients with dementia of the Alzheimer’s type. Apart from abnormal amyloid-β (Aβ) metabolism in AD, a better understanding of the role of similar pathophysiologic processes in HAND could be of substantial value. The pathogenesis of HAND involves either the direct effects of the virus or the effect of viral proteins, such as Tat, Gp120, or Nef, as well as the effects of antiretrovirals on amyloid metabolism and tauopathy, leading, in turn, to synaptodendritic alterations and neuroinflammatory milieu in the brain. Additionally, there is a lack of knowledge regarding the causative or bystander role of Alzheimer’s-like pathology in HAND, which is a barrier to the development of therapeutics for HAND. This review attempts to highlight the cause–effect relationship of Alzheimer’s-like pathology with HAND, attempting to dissect the role of HIV-1, HIV viral proteins, and antiretrovirals in patient samples, animal models, and cell culture model systems. Biomarkers associated with Alzheimer’s-like pathology can serve as a tool to assess the neuronal injury in the brain and the associated cognitive deficits. Understanding the factors contributing to the AD-like pathology associated with HAND could set the stage for the future development of therapeutics aimed at abrogating the disease process. Full article

(This article belongs to the Special Issue HIV Pathogenesis, Vaccine and Eradication Strategies)

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11 pages, 1138 KiB

Open AccessReview

HIV in the Brain: Identifying Viral Reservoirs and Addressing the Challenges of an HIV Cure

by Michelle K. Ash, Lena Al-Harthi and Jeffrey R. Schneider

Vaccines 2021, 9(8), 867; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9080867 - 05 Aug 2021

Cited by 29 | Viewed by 4087

Abstract

Advances in antiretroviral therapy have prolonged the life of people living with HIV and diminished the level of virus in these individuals. Yet, HIV quickly rebounds after disruption and/or cessation of treatment due to significant cellular and anatomical reservoirs for HIV, which underscores the challenge for HIV cure strategies. The central nervous system (CNS), in particular, is seeded with HIV within 1–2 weeks of infection and is a reservoir for HIV. In this review, we address the paradigm of HIV reservoirs in the CNS and the relevant cell types, including astrocytes and microglia, that have been shown to harbor viral infection even with antiretroviral treatment. In particular, we focus on developmental aspects of astrocytes and microglia that lead to their susceptibility to infection, and how HIV infection propagates among these cells. We also address challenges of measuring the HIV latent reservoir, advances in viral detection assays, and how curative strategies have evolved in regard to the CNS reservoir. Current curative strategies still require optimization to reduce or eliminate the HIV CNS reservoir, and may also contribute to levels of neuroinflammation that lead to cognitive decline. With this in mind, the latent HIV reservoir in the brain should remain a prominent focus when assessing treatment options and overall viral burden in the clinic, especially in the context of HIV-associated neurocognitive disorders (HAND). Full article

(This article belongs to the Special Issue HIV Pathogenesis, Vaccine and Eradication Strategies)

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13 pages, 284 KiB

Open AccessReview

An Update on the HIV DNA Vaccine Strategy

by Joseph Hokello, Adhikarimayum Lakhikumar Sharma and Mudit Tyagi

Vaccines 2021, 9(6), 605; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9060605 - 05 Jun 2021

Cited by 17 | Viewed by 5140

Abstract

In 2020, the global prevalence of human immunodeficiency virus (HIV) infection was estimated to be 38 million, and a total of 690,000 people died from acquired immunodeficiency syndrome (AIDS)–related complications. Notably, around 12.6 million people living with HIIV/AIDS did not have access to life-saving treatment. The advent of the highly active antiretroviral therapy (HAART) in the mid-1990s remarkably enhanced the life expectancy of people living with HIV/AIDS as a result of improved immune functions. However, HAART has several drawbacks, especially when it is not used properly, including a high risk for the development of drug resistance, as well as undesirable side effects such as lipodystrophy and endocrine dysfunctions, which result in HAART intolerability. HAART is also not curative. Furthermore, new HIV infections continue to occur globally at a high rate, with an estimated 1.7 million new infections occurring in 2018 alone. Therefore, there is still an urgent need for an affordable, effective, and readily available preventive vaccine against HIV/AIDS. Despite this urgent need, however, progress toward an effective HIV vaccine has been modest over the last four decades. Reasons for this slow progress are mainly associated with the unique aspects of HIV itself and its ability to rapidly mutate, targeting immune cells and escape host immune responses. Several approaches to an HIV vaccine have been undertaken. However, this review will mainly discuss progress made, including the pre-clinical and clinical trials involving vector-based HIV DNA vaccines and the use of integrating lentiviral vectors in HIV vaccine development. We concluded by recommending particularly the use of integrase-defective lentiviral vectors, owing to their safety profiles, as one of the promising vectors in HIV DNA vaccine strategies both for prophylactic and therapeutic HIV vaccines. Full article

(This article belongs to the Special Issue HIV Pathogenesis, Vaccine and Eradication Strategies)

23 pages, 1372 KiB

Open AccessReview

Epigenetic Mechanisms of HIV-1 Persistence

by Roxane Verdikt, Olivier Hernalsteens and Carine Van Lint

Vaccines 2021, 9(5), 514; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9050514 - 17 May 2021

Cited by 13 | Viewed by 3841

Abstract

Eradicating HIV-1 in infected individuals will not be possible without addressing the persistence of the virus in its multiple reservoirs. In this context, the molecular characterization of HIV-1 persistence is key for the development of rationalized therapeutic interventions. HIV-1 gene expression relies on the redundant and cooperative recruitment of cellular epigenetic machineries to cis-regulatory proviral regions. Furthermore, the complex repertoire of HIV-1 repression mechanisms varies depending on the nature of the viral reservoir, although, so far, few studies have addressed the specific regulatory mechanisms of HIV-1 persistence in other reservoirs than the well-studied latently infected CD4⁺ T cells. Here, we present an exhaustive and updated picture of the heterochromatinization of the HIV-1 promoter in its different reservoirs. We highlight the complexity, heterogeneity and dynamics of the epigenetic mechanisms of HIV-1 persistence, while discussing the importance of further understanding HIV-1 gene regulation for the rational design of novel HIV-1 cure strategies. Full article

(This article belongs to the Special Issue HIV Pathogenesis, Vaccine and Eradication Strategies)

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15 pages, 1700 KiB

Open AccessReview

The HIV-1 Antisense Gene ASP: The New Kid on the Block

by Zahra Gholizadeh, Mohd. Shameel Iqbal, Rui Li and Fabio Romerio

Vaccines 2021, 9(5), 513; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9050513 - 17 May 2021

Cited by 8 | Viewed by 2817

Abstract

Viruses have developed incredibly creative ways of making a virtue out of necessity, including taking full advantage of their small genomes. Indeed, viruses often encode multiple proteins within the same genomic region by using two or more reading frames in both orientations through a process called overprinting. Complex retroviruses provide compelling examples of that. The human immunodeficiency virus type 1 (HIV-1) genome expresses sixteen proteins from nine genes that are encoded in the three positive-sense reading frames. In addition, the genome of some HIV-1 strains contains a tenth gene in one of the negative-sense reading frames. The so-called Antisense Protein (ASP) gene overlaps the HIV-1 Rev Response Element (RRE) and the envelope glycoprotein gene, and encodes a highly hydrophobic protein of ~190 amino acids. Despite being identified over thirty years ago, relatively few studies have investigated the role that ASP may play in the virus lifecycle, and its expression in vivo is still questioned. Here we review the current knowledge about ASP, and we discuss some of the many unanswered questions. Full article

(This article belongs to the Special Issue HIV Pathogenesis, Vaccine and Eradication Strategies)

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