Editorial

2 pages, 186 KiB

Open AccessEditorial

by Daria Trabattoni and Mara Biasin

Cells 2021, 10(12), 3549; https://doi.org/10.3390/cells10123549 - 16 Dec 2021

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Effective antiviral immune responses rely on the host’s genetic background and its interaction with the surrounding environment [...] Full article

(This article belongs to the Special Issue HIV and Host Interactions)

Research

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21 pages, 3797 KiB

Open AccessArticle

Spatial and Genomic Correlates of HIV-1 Integration Site Targeting

by Parmit Kumar Singh, Gregory J. Bedwell and Alan N. Engelman

Cells 2022, 11(4), 655; https://doi.org/10.3390/cells11040655 - 14 Feb 2022

Cited by 11 | Viewed by 3258

Abstract

HIV-1 integrase and capsid proteins interact with host proteins to direct preintegration complexes to active transcription units within gene-dense regions of chromosomes for viral DNA integration. Analyses of spatially-derived genomic DNA coordinates, such as nuclear speckle-associated domains, lamina-associated domains, super enhancers, and Spatial [...] Read more.

HIV-1 integrase and capsid proteins interact with host proteins to direct preintegration complexes to active transcription units within gene-dense regions of chromosomes for viral DNA integration. Analyses of spatially-derived genomic DNA coordinates, such as nuclear speckle-associated domains, lamina-associated domains, super enhancers, and Spatial Position Inference of the Nuclear (SPIN) genome states, have further informed the mechanisms of HIV-1 integration targeting. Critically, however, these different types of genomic coordinates have not been systematically analyzed to synthesize a concise description of the regions of chromatin that HIV-1 prefers for integration. To address this informational gap, we have extensively correlated genomic DNA coordinates of HIV-1 integration targeting preferences. We demonstrate that nuclear speckle-associated and speckle-proximal chromatin are highly predictive markers of integration and that these regions account for known HIV biases for gene-dense regions, highly transcribed genes, as well as the mid-regions of gene bodies. In contrast to a prior report that intronless genes were poorly targeted for integration, we find that intronless genes in proximity to nuclear speckles are more highly targeted than are spatially-matched intron-containing genes. Our results additionally highlight the contributions of capsid and integrase interactions with respective CPSF6 and LEDGF/p75 host factors in these HIV-1 integration targeting preferences. Full article

(This article belongs to the Special Issue HIV and Host Interactions)

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13 pages, 1943 KiB

Open AccessCommunication

Immunological Characterization of HIV and SARS-CoV-2 Coinfected Young Individuals

by Claudia Vanetti, Daria Trabattoni, Marta Stracuzzi, Antonella Amendola, Clara Fappani, Valeria Rubinacci, Claudio Fenizia, Laura Gianolio, Mara Biasin, Anna Dighera, Irma Saulle, Elisabetta Tanzi, Gianvincenzo Zuccotti, Mario Clerici and Vania Giacomet

Cells 2021, 10(11), 3187; https://doi.org/10.3390/cells10113187 - 16 Nov 2021

Cited by 9 | Viewed by 2458

Abstract

While the risk of SARS-CoV-2 infection and/or COVID-19 disease progression in the general population has been largely assessed, its impact on HIV-positive individuals remains unclear. We present clinical and immunological data collected in a cohort of HIV-infected young individuals during the first wave [...] Read more.

While the risk of SARS-CoV-2 infection and/or COVID-19 disease progression in the general population has been largely assessed, its impact on HIV-positive individuals remains unclear. We present clinical and immunological data collected in a cohort of HIV-infected young individuals during the first wave of COVID-19 pandemic. SARS-CoV-2 RNA, virus-specific antibodies, as well as the expression of factors involved in the anti-viral immune response were analyzed. Moreover, we set up an in vitro coinfection assay to study the mechanisms correlated to the coinfection process. Our results did not show any increased risk of severe COVID-19 in HIV-positive young individuals. In those subjects who contracted SARS-CoV-2 infection, an increase in IL-10 expression and production was observed. Furthermore, in the in vitro coinfection assay, we revealed a reduction in SARS-CoV-2 replication associated to an upregulation of IL-10. We speculate that IL-10 could play a crucial role in the course of SARS-CoV-2 infection in HIV-positive individuals. These results might help defining clinical management of HIV/SARS-CoV-2 co-infected young individuals, or putative indications for vaccination schedules in this population. Full article

(This article belongs to the Special Issue HIV and Host Interactions)

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11 pages, 1939 KiB

Open AccessArticle

CD46 Genetic Variability and HIV-1 Infection Susceptibility

by Carmen Serrano-Rísquez, Mohamed Omar, María Amparo Gómez-Vidal, Luis Miguel Real, Juan Antonio Pineda, Antonio Rivero, Antonio Rivero-Juárez, Donald Forthal, Francisco J. Márquez, Sergio Lo Caputo, Mario Clerici, Mara Biasin and Antonio Caruz

Cells 2021, 10(11), 3094; https://doi.org/10.3390/cells10113094 - 09 Nov 2021

Cited by 3 | Viewed by 2136

Abstract

CD46 is the main receptor for complement protein C3 and plays an important role in adaptive immune responses. CD46 genetic variants are associated with susceptibility to several infectious and autoimmune diseases. Additionally, CD46 function can be subverted by HIV-1 to evade attack by [...] Read more.

CD46 is the main receptor for complement protein C3 and plays an important role in adaptive immune responses. CD46 genetic variants are associated with susceptibility to several infectious and autoimmune diseases. Additionally, CD46 function can be subverted by HIV-1 to evade attack by complement, a strategy shared by viruses of other families. We sought to determine the association between CD46 gene variants and HIV-1 acquired through intravenous drug use (IDU) and sexual routes (n = 823). Study subjects were of European ancestry and were HIV-1 infected (n = 438) or exposed but seronegative (n = 387). Genotyping of the rs2796265 SNP located in the CD46 gene region was done by allele-specific real-time PCR. A meta-analysis merging IDU and sexual cohorts indicates that the minor genotype (CC) was associated with increased resistance to HIV-1 infection OR = 0.2, 95% CI (0.07–0.61), p = 0.004. The HIV-1-protective genotype is correlated with reduced CD46 expression and alterations in the ratio of CD46 mRNA splicing isoforms. Full article

(This article belongs to the Special Issue HIV and Host Interactions)

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12 pages, 884 KiB

Open AccessArticle

NanoHIV: A Bioinformatics Pipeline for Producing Accurate, Near Full-Length HIV Proviral Genomes Sequenced Using the Oxford Nanopore Technology

by Imogen A. Wright, Kayla E. Delaney, Mary Grace K. Katusiime, Johannes C. Botha, Susan Engelbrecht, Mary F. Kearney and Gert U. van Zyl

Cells 2021, 10(10), 2577; https://doi.org/10.3390/cells10102577 - 28 Sep 2021

Cited by 5 | Viewed by 4263

Abstract

HIV-1 proviral single-genome sequencing by limiting-dilution polymerase chain reaction (PCR) amplification is important for differentiating the sequence-intact from defective proviruses that persist during antiretroviral therapy (ART). Intact proviruses may rebound if ART is interrupted and are the barrier to an HIV cure. Oxford [...] Read more.

HIV-1 proviral single-genome sequencing by limiting-dilution polymerase chain reaction (PCR) amplification is important for differentiating the sequence-intact from defective proviruses that persist during antiretroviral therapy (ART). Intact proviruses may rebound if ART is interrupted and are the barrier to an HIV cure. Oxford Nanopore Technologies (ONT) sequencing offers a promising, cost-effective approach to the sequencing of long amplicons such as near full-length HIV-1 proviruses, but the high diversity of HIV-1 and the ONT sequencing error render analysis of the generated data difficult. NanoHIV is a new tool that uses an iterative consensus generation approach to construct accurate, near full-length HIV-1 proviral single-genome sequences from ONT data. To validate the approach, single-genome sequences generated using NanoHIV consensus building were compared to Illumina^® consensus building of the same nine single-genome near full-length amplicons and an average agreement of 99.4% was found between the two sequencing approaches. Full article

(This article belongs to the Special Issue HIV and Host Interactions)

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11 pages, 1039 KiB

Open AccessArticle

The TLR9 2848C/T Polymorphism Is Associated with the CMV DNAemia among HIV/CMV Co-Infected Patients

by Agnieszka Jabłońska, Elżbieta Jabłonowska, Mirosława Studzińska, Juliusz Kamerys and Edyta Paradowska

Cells 2021, 10(9), 2360; https://doi.org/10.3390/cells10092360 - 08 Sep 2021

Cited by 3 | Viewed by 1966

Abstract

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns and are essential components of the host’s innate immune response. The aim of this study was to determine the TLR9 genotype frequency and investigate the association between TLR9 polymorphisms and cytomegalovirus (CMV) DNAemia in human immunodeficiency [...] Read more.

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns and are essential components of the host’s innate immune response. The aim of this study was to determine the TLR9 genotype frequency and investigate the association between TLR9 polymorphisms and cytomegalovirus (CMV) DNAemia in human immunodeficiency virus (HIV)/CMV co-infected patients. A total of 205 HIV/CMV co-infected adults were screened for the presence of the four TLR9 polymorphisms (−1237T/C, −1486T/C, 1174G/A, and 2848C/T) by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Mutation presented in at least one allele of the TLR9 2848C/T single nucleotide polymorphism (SNP) was associated with the occurrence of CMV DNAemia among HIV-infected patients with CMV co-infection (p = 0.004). The level of CMV DNA was higher in patients who were homozygous recessive or heterozygous for the 2848C/T polymorphism compared with those who had a wild-type genotype for this polymorphism (p = 0.005). Mutation detected in at least one allele of this SNP was also associated with a lower interferon type β (IFN-β) concentration (p = 0.048), while no relationships between TLR9 −1237T/C, −1486T/C, and 1174G/A SNPs and CMV DNAemia were observed. Our findings suggest that the mutation present in at least one allele of the TLR9 2848C/T SNP may be associated with the active CMV infection in HIV/CMV co-infected subjects. Full article

(This article belongs to the Special Issue HIV and Host Interactions)

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10 pages, 950 KiB

Open AccessArticle

Synonymous Codon Pair Recoding of the HIV-1 env Gene Affects Virus Replication Capacity

by Ana Jordan-Paiz, Sandra Franco and Miguel Angel Martinez

Cells 2021, 10(7), 1636; https://doi.org/10.3390/cells10071636 - 29 Jun 2021

Cited by 9 | Viewed by 2027

Abstract

Synonymous codon pair deoptimization is an efficient strategy for virus attenuation; however, the underlying mechanism remains controversial. Here, we optimized and deoptimized the codon pair bias (CPB) of the human immunodeficiency virus type 1 (HIV-1) envelope (env) gene to investigate the [...] Read more.

Synonymous codon pair deoptimization is an efficient strategy for virus attenuation; however, the underlying mechanism remains controversial. Here, we optimized and deoptimized the codon pair bias (CPB) of the human immunodeficiency virus type 1 (HIV-1) envelope (env) gene to investigate the influence of env synonymous CPB recoding on virus replication capacity, as well as the potential mechanism. We found that env CPB deoptimization did not always generate attenuation, whereas CPB optimization attenuated virus replication in MT-4 cells. Furthermore, virus attenuation correlated with reduced Env protein production but not with decreased viral RNA synthesis. Remarkably, in our model, increasing the number of CpG dinucleotides in the 5′ end of env did not reduce the replication capacity of HIV-1. These results indicate that factors other than CPB or CpG content may have impacted the viral fitness of the synonymously recoded study variants. Our findings provide evidence that CPB recoding-associated attenuation can affect translation efficiency. Moreover, we demonstrated that an increased number of CpGs in the 5′ end of HIV-1 env is not always associated with reduced virus replication capacity. Full article

(This article belongs to the Special Issue HIV and Host Interactions)

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19 pages, 6132 KiB

Open AccessArticle

Enhanced Intestinal TGF-β/SMAD-Dependent Signaling in Simian Immunodeficiency Virus Infected Rhesus Macaques

by Nongthombam Boby, Alyssa Ransom, Barcley T. Pace, Kelsey M. Williams, Christopher Mabee, Arpita Das, Sudesh K. Srivastav, Edith Porter and Bapi Pahar

Cells 2021, 10(4), 806; https://doi.org/10.3390/cells10040806 - 04 Apr 2021

Cited by 11 | Viewed by 3631

Abstract

Transforming growth factor-β signaling (TGF-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-β promotes immunosuppression in Human [...] Read more.

Transforming growth factor-β signaling (TGF-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-β promotes immunosuppression in Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection. However, the cellular source and downstream events of increased TGF-β production that attributes to its pathological manifestations remain unknown. Here, we have shown increased production of TGF-β in a majority of intestinal CD3⁻CD20⁻CD68⁺ cells from acute and chronically SIV infected rhesus macaques, which negatively correlated with the frequency of jejunum CD4⁺ T cells. No significant changes in intestinal TGF-β receptor II expression were observed but increased production of the pSMAD2/3 protein and SMAD3 gene expression in jejunum tissues that were accompanied by a downregulation of SMAD7 protein and gene expression. Enhanced TGF-β production by intestinal CD3⁻CD20⁻CD68⁺ cells and increased TGF-β/SMAD-dependent signaling might be due to a disruption of a negative feedback loop mediated by SMAD7. This suggests that SIV infection impacts the SMAD-dependent signaling pathway of TGF-β and provides a potential framework for further study to understand the role of viral factor(s) in modulating TGF-β production and downregulating SMAD7 expression in SIV. Regulation of mucosal TGF-β expression by therapeutic TGF-β blockers may help to create effective antiviral mucosal immune responses. Full article

(This article belongs to the Special Issue HIV and Host Interactions)

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Review

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21 pages, 2016 KiB

Open AccessReview

Senotherapeutics in Cancer and HIV

by Laura Sánchez-Díaz, Asunción Espinosa-Sánchez, José-Ramón Blanco and Amancio Carnero

Cells 2022, 11(7), 1222; https://doi.org/10.3390/cells11071222 - 04 Apr 2022

Cited by 8 | Viewed by 4387

Abstract

Cellular senescence is a stress-response mechanism that contributes to homeostasis maintenance, playing a beneficial role during embryogenesis and in normal adult organisms. In contrast, chronic senescence activation may be responsible for other events such as age-related disorders, HIV and cancer development. Cellular senescence [...] Read more.

Cellular senescence is a stress-response mechanism that contributes to homeostasis maintenance, playing a beneficial role during embryogenesis and in normal adult organisms. In contrast, chronic senescence activation may be responsible for other events such as age-related disorders, HIV and cancer development. Cellular senescence activation can be triggered by different insults. Regardless of the inducer, there are several phenotypes generally shared among senescent cells: cell division arrest, an aberrant shape, increased size, high granularity because of increased numbers of lysosomes and vacuoles, apoptosis resistance, defective metabolism and some chromatin alterations. Senescent cells constitute an important area for research due to their contributions to the pathogenesis of different diseases such as frailty, sarcopenia and aging-related diseases, including cancer and HIV infection, which show an accelerated aging. Hence, a new pharmacological category of treatments called senotherapeutics is under development. This group includes senolytic drugs that selectively attack senescent cells and senostatic drugs that suppress SASP factor delivery, inhibiting senescent cell development. These new drugs can have positive therapeutic effects on aging-related disorders and act in cancer as antitumor drugs, avoiding the undesired effects of senescent cells such as those from SASP. Here, we review senotherapeutics and how they might affect cancer and HIV disease, two very different aging-related diseases, and review some compounds acting as senolytics in clinical trials. Full article

(This article belongs to the Special Issue HIV and Host Interactions)

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16 pages, 840 KiB

Open AccessReview

Chemotherapy-Induced Hepatotoxicity in HIV Patients

by Silvia Bressan, Alessandra Pierantoni, Saman Sharifi, Sergio Facchini, Vincenzo Quagliariello, Massimiliano Berretta and Monica Montopoli

Cells 2021, 10(11), 2871; https://doi.org/10.3390/cells10112871 - 25 Oct 2021

Cited by 5 | Viewed by 2740

Abstract

Human immunodeficiency virus (HIV) affects more than 37 million people globally, and in 2020, more than 680,000 people died from HIV-related causes. Recently, these numbers have decrease substantially and continue to reduce thanks to the use of antiretroviral therapy (ART), thus making HIV [...] Read more.

Human immunodeficiency virus (HIV) affects more than 37 million people globally, and in 2020, more than 680,000 people died from HIV-related causes. Recently, these numbers have decrease substantially and continue to reduce thanks to the use of antiretroviral therapy (ART), thus making HIV a chronic disease state for those dependent on lifelong use of ART. However, patients with HIV have an increased risk of developing some type of cancer compared to patients without HIV. Therefore, treatment of patients who are diagnosed with both HIV and cancer represents a complicated scenario because of the risk associated with drug–drug interaction (DDIs) and related toxicity. Selection of an alternative chemotherapy or ART or temporarily discontinuation of ART constitute a strategy to manage the risk of DDIs. Temporarily withholding ART is the less desirable clinical plan but risks and benefits must be considered in each scenario. In this review we focus on the hepatotoxicity associated with a simultaneous treatment with ART and chemotherapeutic drugs and mechanisms behind. Moreover, we also discuss the effect on the liver caused by the association of immunotherapeutic drugs, which have recently been used in clinical trials and also in HIV patients. Full article

(This article belongs to the Special Issue HIV and Host Interactions)

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20 pages, 1574 KiB

Open AccessReview

The Landscape of IFN/ISG Signaling in HIV-1-Infected Macrophages and Its Possible Role in the HIV-1 Latency

by Masyelly Rojas, Patricia Luz-Crawford, Ricardo Soto-Rifo, Sebastián Reyes-Cerpa and Daniela Toro-Ascuy

Cells 2021, 10(9), 2378; https://doi.org/10.3390/cells10092378 - 09 Sep 2021

Cited by 9 | Viewed by 4950

Abstract

A key characteristic of Human immunodeficiency virus type 1 (HIV-1) infection is the generation of latent viral reservoirs, which have been associated with chronic immune activation and sustained inflammation. Macrophages play a protagonist role in this context since they are persistently infected while [...] Read more.

A key characteristic of Human immunodeficiency virus type 1 (HIV-1) infection is the generation of latent viral reservoirs, which have been associated with chronic immune activation and sustained inflammation. Macrophages play a protagonist role in this context since they are persistently infected while being a major effector of the innate immune response through the generation of type-I interferons (type I IFN) and IFN-stimulated genes (ISGs). The balance in the IFN signaling and the ISG induction is critical to promote a successful HIV-1 infection. Classically, the IFNs response is fine-tuned by opposing promotive and suppressive signals. In this context, it was described that HIV-1-infected macrophages can also synthesize some antiviral effector ISGs and, positive and negative regulators of the IFN/ISG signaling. Recently, epitranscriptomic regulatory mechanisms were described, being the N6-methylation (m6A) modification on mRNAs one of the most relevant. The epitranscriptomic regulation can affect not only IFN/ISG signaling, but also type I IFN expression, and viral fitness through modifications to HIV-1 RNA. Thus, the establishment of replication-competent latent HIV-1 infected macrophages may be due to non-classical mechanisms of type I IFN that modulate the activation of the IFN/ISG signaling network. Full article

(This article belongs to the Special Issue HIV and Host Interactions)

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13 pages, 548 KiB

Open AccessReview

Immune Checkpoint Inhibitors in People Living with HIV/AIDS: Facts and Controversies

by Valeria Castelli, Andrea Lombardi, Emanuele Palomba, Giorgio Bozzi, Riccardo Ungaro, Laura Alagna, Davide Mangioni, Antonio Muscatello, Alessandra Bandera and Andrea Gori

Cells 2021, 10(9), 2227; https://doi.org/10.3390/cells10092227 - 27 Aug 2021

Cited by 18 | Viewed by 2905

Abstract

Immune checkpoint inhibitors (ICIs) are reshaping the landscape of cancer treatment, redefining the prognosis of several tumors. They act by restoring the cytotoxic activity of tumor-specific T lymphocytes that are in a condition of immune exhaustion. The same condition has been widely described [...] Read more.

Immune checkpoint inhibitors (ICIs) are reshaping the landscape of cancer treatment, redefining the prognosis of several tumors. They act by restoring the cytotoxic activity of tumor-specific T lymphocytes that are in a condition of immune exhaustion. The same condition has been widely described in chronic HIV infection. In this review, we dissect the role of ICIs in people living with HIV/AIDS (PLWHIV). First, we provide an overview of the immunologic scenario. Second, we discuss the possible use of ICIs as adjuvant treatment of HIV to achieve elimination of the viral reservoir. Third, we examine the influence of HIV infection on ICI safety and effectiveness. Finally, we describe how the administration of ICIs impacts opportunistic infections. Full article

(This article belongs to the Special Issue HIV and Host Interactions)

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14 pages, 660 KiB

Open AccessReview

Membrane Interference Against HIV-1 by Intrinsic Antiviral Factors: The Case of IFITMs

by Federico Marziali and Andrea Cimarelli

Cells 2021, 10(5), 1171; https://doi.org/10.3390/cells10051171 - 11 May 2021

Cited by 13 | Viewed by 3309

Abstract

HIV-1 is a complex retrovirus that is adapted to replicate in cells of the immune system. To do so, HIV-1, like other viruses, developed strategies to use several cellular processes to its advantage, but had also to come to terms with an arsenal [...] Read more.

HIV-1 is a complex retrovirus that is adapted to replicate in cells of the immune system. To do so, HIV-1, like other viruses, developed strategies to use several cellular processes to its advantage, but had also to come to terms with an arsenal of cellular innate defense proteins, or antiviral factors, that target more or less efficiently, virtually every step of the virus replicative cycle. Among antiviral restriction factors, the family of interferon-induced transmembrane proteins (IFITMs) has emerged as a crucial component of cellular innate defenses for their ability to interfere with both early and late phases of viral replication by inhibiting cellular and viral membranes fusion. Here, we review the enormous advances made since the discovery of IFITMs as interferon-regulated genes more than thirty years ago, with a particular focus on HIV-1 and on the elements that modulate its susceptibility or resistance towards members of this family. Given the recent advances of the field in the elucidation of the mechanism of IFITM inhibition and on the mechanism(s) of viral resistance, we expect that future years will bring novel insights into the definition of the multiple facets of IFITMs and on their possible use for novel therapeutical approaches. Full article

(This article belongs to the Special Issue HIV and Host Interactions)

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