Research

18 pages, 1888 KiB

Open AccessArticle

The E3 Ubiquitin-Protein Ligase Cullin 3 Regulates HIV-1 Transcription

by Simon Langer, Xin Yin, Arturo Diaz, Alex J. Portillo, David E. Gordon, Umu H. Rogers, John M. Marlett, Nevan J. Krogan, John A. T. Young, Lars Pache and Sumit K. Chanda

Cells 2020, 9(9), 2010; https://doi.org/10.3390/cells9092010 - 01 Sep 2020

Cited by 4 | Viewed by 4195

Abstract

The infectious life cycle of the human immunodeficiency virus type 1 (HIV-1) is characterized by an ongoing battle between a compendium of cellular proteins that either promote or oppose viral replication. On the one hand, HIV-1 utilizes dependency factors to support and sustain [...] Read more.

The infectious life cycle of the human immunodeficiency virus type 1 (HIV-1) is characterized by an ongoing battle between a compendium of cellular proteins that either promote or oppose viral replication. On the one hand, HIV-1 utilizes dependency factors to support and sustain infection and complete the viral life cycle. On the other hand, both inducible and constitutively expressed host factors mediate efficient and functionally diverse antiviral processes that counteract an infection. To shed light into the complex interplay between HIV-1 and cellular proteins, we previously performed a targeted siRNA screen to identify and characterize novel regulators of viral replication and identified Cullin 3 (Cul3) as a previously undescribed factor that negatively regulates HIV-1 replication. Cul3 is a component of E3-ubiquitin ligase complexes that target substrates for ubiquitin-dependent proteasomal degradation. In the present study, we show that Cul3 is expressed in HIV-1 target cells, such as CD4+ T cells, monocytes, and macrophages and depletion of Cul3 using siRNA or CRISPR/Cas9 increases HIV-1 infection in immortalized cells and primary CD4+ T cells. Conversely, overexpression of Cul3 reduces HIV-1 infection in single replication cycle assays. Importantly, the antiviral effect of Cul3 was mapped to the transcriptional stage of the viral life cycle, an effect which is independent of its role in regulating the G1/S cell cycle transition. Using isogenic viruses that only differ in their promotor region, we find that the NF-κB/NFAT transcription factor binding sites in the LTR are essential for Cul3-dependent regulation of viral gene expression. Although Cul3 effectively suppresses viral gene expression, HIV-1 does not appear to antagonize the antiviral function of Cul3 by targeting it for degradation. Taken together, these results indicate that Cul3 is a negative regulator of HIV-1 transcription which governs productive viral replication in infected cells. Full article

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

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18 pages, 1758 KiB

Open AccessFeature PaperArticle

Protective Effect of Probiotic Bacteria and Estrogen in Preventing HIV-1-Mediated Impairment of Epithelial Barrier Integrity in Female Genital Tract

by Sara Dizzell, Aisha Nazli, Gregor Reid and Charu Kaushic

Cells 2019, 8(10), 1120; https://doi.org/10.3390/cells8101120 - 21 Sep 2019

Cited by 17 | Viewed by 6352

Abstract

Approximately 40% of global HIV-1 transmission occurs in the female genital tract (FGT) through heterosexual transmission. Epithelial cells lining the FGT provide the first barrier to HIV-1 entry. Previous studies have suggested that certain hormonal contraceptives or a dysbiosis of the vaginal microbiota [...] Read more.

Approximately 40% of global HIV-1 transmission occurs in the female genital tract (FGT) through heterosexual transmission. Epithelial cells lining the FGT provide the first barrier to HIV-1 entry. Previous studies have suggested that certain hormonal contraceptives or a dysbiosis of the vaginal microbiota can enhance HIV-1 acquisition in the FGT. We examined the effects of lactobacilli and female sex hormones on the barrier functions and innate immune responses of primary endometrial genital epithelial cells (GECs). Two probiotic strains, Lactobacillus reuteri RC-14 and L. rhamnosus GR-1, were tested, as were sex hormones estrogen (E2), progesterone (P4), and the hormonal contraceptive medroxyprogesterone acetate (MPA). Our results demonstrate that probiotic lactobacilli enhance barrier function without affecting cytokines. Treatment of GECs with MPA resulted in reduced barrier function. In contrast, E2 treatment enhanced barrier function and reduced production of proinflammatory cytokines. Comparison of hormones plus lactobacilli as a pre-treatment prior to HIV exposure revealed a dominant effect of lactobacilli in preventing loss of barrier function by GECs. In summary, the combination of E2 and lactobacilli had the best protective effect against HIV-1 seen by enhancement of barrier function and reduction in proinflammatory cytokines. These studies provide insights into how probiotic lactobacilli in the female genital microenvironment can alter HIV-1-mediated barrier disruption and how the combination of E2 and lactobacilli may decrease susceptibility to primary HIV infection. Full article

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

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18 pages, 5310 KiB

Open AccessArticle

Humoral Response to the HIV-1 Envelope V2 Region in a Thai Early Acute Infection Cohort

by Hung V. Trinh, Neelakshi Gohain, Peter T. Pham, Christopher Hamlin, Hongshuo Song, Eric Sanders-Buell, Meera Bose, Leigh A. Eller, Sodsai Tovanabutra, Nelson L. Michael, Merlin L. Robb, M. Gordon Joyce and Mangala Rao

Cells 2019, 8(4), 365; https://doi.org/10.3390/cells8040365 - 19 Apr 2019

Cited by 6 | Viewed by 4170 | Correction

Abstract

Reduced risk of HIV-1 infection correlated with antibody responses to the envelope variable 1 and 2 regions in the RV144 vaccine trial. To understand the relationship between antibody responses, V2 sequence, and structure, plasma samples (n = 16) from an early acute HIV-1 [...] Read more.

Reduced risk of HIV-1 infection correlated with antibody responses to the envelope variable 1 and 2 regions in the RV144 vaccine trial. To understand the relationship between antibody responses, V2 sequence, and structure, plasma samples (n = 16) from an early acute HIV-1 infection cohort from Thailand infected with CRF01_AE strain were analyzed for binding to V2 peptides by surface plasmon resonance. Five participants with a range of V2 binding responses at week 24 post-infection were further analyzed against a set of four overlapping V2 peptides that were designed based on envelope single-genome amplification. Antibody responses that were relatively consistent over the four segments of the V2 region or a focused response to the C-strand (residues 165–186) of the V2 region were observed. Viral escape in the V2 region resulted in significantly reduced antibody binding. Structural modeling indicated that the C-strand and the sites of viral variation were highly accessible in the open conformation of the HIV-1 Env trimer. V2 residues, 165–186 are preferentially targeted during acute infection. Residues 169–184 were also preferentially targeted by the protective immune response in the RV144 trial, thus emphasizing the importance of these residues for vaccine design. Full article

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

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Review

Jump to: Research, Other

23 pages, 1077 KiB

Open AccessReview

An Overview on ERAP Roles in Infectious Diseases

by Irma Saulle, Chiara Vicentini, Mario Clerici and Mara Biasin

Cells 2020, 9(3), 720; https://doi.org/10.3390/cells9030720 - 14 Mar 2020

Cited by 33 | Viewed by 5338

Abstract

Endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 (ERAPs) are crucial enzymes shaping the major histocompatibility complex I (MHC I) immunopeptidome. In the ER, these enzymes cooperate in trimming the N-terminal residues from precursors peptides, so as to generate optimal-length antigens to fit into [...] Read more.

Endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 (ERAPs) are crucial enzymes shaping the major histocompatibility complex I (MHC I) immunopeptidome. In the ER, these enzymes cooperate in trimming the N-terminal residues from precursors peptides, so as to generate optimal-length antigens to fit into the MHC class I groove. Alteration or loss of ERAPs function significantly modify the repertoire of antigens presented by MHC I molecules, severely affecting the activation of both NK and CD8⁺ T cells. It is, therefore, conceivable that variations affecting the presentation of pathogen-derived antigens might result in an inadequate immune response and onset of disease. After the first evidence showing that ERAP1-deficient mice are not able to control Toxoplasma gondii infection, a number of studies have demonstrated that ERAPs are control factors for several infectious organisms. In this review we describe how susceptibility, development, and progression of some infectious diseases may be affected by different ERAPs variants, whose mechanism of action could be exploited for the setting of specific therapeutic approaches. Full article

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

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18 pages, 732 KiB

Open AccessReview

Sensor Sensibility—HIV-1 and the Innate Immune Response

by Xin Yin, Simon Langer, Zeli Zhang, Kristina M. Herbert, Sunnie Yoh, Renate König and Sumit K. Chanda

Cells 2020, 9(1), 254; https://doi.org/10.3390/cells9010254 - 20 Jan 2020

Cited by 60 | Viewed by 9619

Abstract

Innate immunity represents the human immune system’s first line of defense against a pathogenic intruder and is initiated by the recognition of conserved molecular structures known as pathogen-associated molecular patterns (PAMPs) by specialized cellular sensors, called pattern recognition receptors (PRRs). Human immunodeficiency virus [...] Read more.

Innate immunity represents the human immune system’s first line of defense against a pathogenic intruder and is initiated by the recognition of conserved molecular structures known as pathogen-associated molecular patterns (PAMPs) by specialized cellular sensors, called pattern recognition receptors (PRRs). Human immunodeficiency virus type 1 (HIV-1) is a unique human RNA virus that causes acquired immunodeficiency syndrome (AIDS) in infected individuals. During the replication cycle, HIV-1 undergoes reverse transcription of its RNA genome and integrates the resulting DNA into the human genome. Subsequently, transcription of the integrated provirus results in production of new virions and spreading infection of the virus. Throughout the viral replication cycle, numerous nucleic acid derived PAMPs can be recognized by a diverse set of innate immune sensors in infected cells. However, HIV-1 has evolved efficient strategies to evade or counteract this immune surveillance and the downstream responses. Understanding the molecular underpinnings of the concerted actions of the innate immune system, as well as the corresponding viral evasion mechanisms during infection, is critical to understanding HIV-1 transmission and pathogenesis, and may provide important guidance for the design of appropriate adjuvant and vaccine strategies. Here, we summarize current knowledge of the molecular basis for sensing HIV-1 in human cells, including CD4⁺ T cells, dendritic cells, and macrophages. Furthermore, we discuss the underlying mechanisms by which innate sensing is regulated, and describe the strategies developed by HIV-1 to evade sensing and immune responses. Full article

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

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25 pages, 1542 KiB

Open AccessReview

Vpr and Its Cellular Interaction Partners: R We There Yet?

by Helena Fabryova and Klaus Strebel

Cells 2019, 8(11), 1310; https://doi.org/10.3390/cells8111310 - 24 Oct 2019

Cited by 29 | Viewed by 5773

Abstract

Vpr is a lentiviral accessory protein that is expressed late during the infection cycle and is packaged in significant quantities into virus particles through a specific interaction with the P6 domain of the viral Gag precursor. Characterization of the physiologically relevant function(s) of [...] Read more.

Vpr is a lentiviral accessory protein that is expressed late during the infection cycle and is packaged in significant quantities into virus particles through a specific interaction with the P6 domain of the viral Gag precursor. Characterization of the physiologically relevant function(s) of Vpr has been hampered by the fact that in many cell lines, deletion of Vpr does not significantly affect viral fitness. However, Vpr is critical for virus replication in primary macrophages and for viral pathogenesis in vivo. It is generally accepted that Vpr does not have a specific enzymatic activity but functions as a molecular adapter to modulate viral or cellular processes for the benefit of the virus. Indeed, many Vpr interacting factors have been described by now, and the goal of this review is to summarize our current knowledge of cellular proteins targeted by Vpr. Full article

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

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15 pages, 956 KiB

Open AccessReview

New Challenges of HIV-1 Infection: How HIV-1 Attacks and Resides in the Central Nervous System

by Victoria Rojas-Celis, Fernando Valiente-Echeverría, Ricardo Soto-Rifo and Daniela Toro-Ascuy

Cells 2019, 8(10), 1245; https://doi.org/10.3390/cells8101245 - 13 Oct 2019

Cited by 50 | Viewed by 8801

Abstract

Acquired immunodeficiency syndrome (AIDS) has become one of the most devastating pandemics in recorded history. The main causal agent of AIDS is the human immunodeficiency virus (HIV), which infects various cell types of the immune system that express the CD4 receptor on their [...] Read more.

Acquired immunodeficiency syndrome (AIDS) has become one of the most devastating pandemics in recorded history. The main causal agent of AIDS is the human immunodeficiency virus (HIV), which infects various cell types of the immune system that express the CD4 receptor on their surfaces. Today, combined antiretroviral therapy (cART) is the standard treatment for all people with HIV; although it has improved the quality of life of people living with HIV (PLWH), it cannot eliminate the latent reservoir of the virus. Therefore HIV/AIDS has turned from a fatal disease to a chronic disease requiring lifelong treatment. Despite significant viral load suppression, it has been observed that at least half of patients under cART present HIV-associated neurocognitive disorders (HAND), which have been related to HIV-1 infection and replication in the central nervous system (CNS). Several studies have focused on elucidating the mechanism by which HIV-1 can invade the CNS and how it can generate the effects seen in HAND. This review summarizes the research on HIV-1 and its interaction with the CNS with an emphasis on the generation of HAND, how the virus enters the CNS, the relationship between HIV-1 and cells of the CNS, and the effect of cART on these cells. Full article

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

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27 pages, 2967 KiB

Open AccessFeature PaperReview

Plasma Membrane-Associated Restriction Factors and Their Counteraction by HIV-1 Accessory Proteins

by Peter W. Ramirez, Shilpi Sharma, Rajendra Singh, Charlotte A. Stoneham, Thomas Vollbrecht and John Guatelli

Cells 2019, 8(9), 1020; https://doi.org/10.3390/cells8091020 - 02 Sep 2019

Cited by 20 | Viewed by 5080

Abstract

The plasma membrane is a site of conflict between host defenses and many viruses. One aspect of this conflict is the host’s attempt to eliminate infected cells using innate and adaptive cell-mediated immune mechanisms that recognize features of the plasma membrane characteristic of [...] Read more.

The plasma membrane is a site of conflict between host defenses and many viruses. One aspect of this conflict is the host’s attempt to eliminate infected cells using innate and adaptive cell-mediated immune mechanisms that recognize features of the plasma membrane characteristic of viral infection. Another is the expression of plasma membrane-associated proteins, so-called restriction factors, which inhibit enveloped virions directly. HIV-1 encodes two countermeasures to these host defenses: The membrane-associated accessory proteins Vpu and Nef. In addition to inhibiting cell-mediated immune-surveillance, Vpu and Nef counteract membrane-associated restriction factors. These include BST-2, which traps newly formed virions at the plasma membrane unless counteracted by Vpu, and SERINC5, which decreases the infectivity of virions unless counteracted by Nef. Here we review key features of these two antiviral proteins, and we review Vpu and Nef, which deplete them from the plasma membrane by co-opting specific cellular proteins and pathways of membrane trafficking and protein-degradation. We also discuss other plasma membrane proteins modulated by HIV-1, particularly CD4, which, if not opposed in infected cells by Vpu and Nef, inhibits viral infectivity and increases the sensitivity of the viral envelope glycoprotein to host immunity. Full article

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

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Graphical abstract

35 pages, 1494 KiB

Open AccessReview

Interplay between Intrinsic and Innate Immunity during HIV Infection

by Louis Bergantz, Frédéric Subra, Eric Deprez, Olivier Delelis and Clémence Richetta

Cells 2019, 8(8), 922; https://doi.org/10.3390/cells8080922 - 17 Aug 2019

Cited by 23 | Viewed by 7539

Abstract

Restriction factors are antiviral components of intrinsic immunity which constitute a first line of defense by blocking different steps of the human immunodeficiency virus (HIV) replication cycle. In immune cells, HIV infection is also sensed by several pattern recognition receptors (PRRs), leading to [...] Read more.

Restriction factors are antiviral components of intrinsic immunity which constitute a first line of defense by blocking different steps of the human immunodeficiency virus (HIV) replication cycle. In immune cells, HIV infection is also sensed by several pattern recognition receptors (PRRs), leading to type I interferon (IFN-I) and inflammatory cytokines production that upregulate antiviral interferon-stimulated genes (ISGs). Several studies suggest a link between these two types of immunity. Indeed, restriction factors, that are generally interferon-inducible, are able to modulate immune responses. This review highlights recent knowledge of the interplay between restriction factors and immunity inducing antiviral defenses. Counteraction of this intrinsic and innate immunity by HIV viral proteins will also be discussed. Full article

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

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Other

Jump to: Research, Review

6 pages, 253 KiB

Open AccessViewpoint

CCR5 Promoter Polymorphism −2459G > A: Forgotten or Ignored?

by Rajeev K. Mehlotra

Cells 2019, 8(7), 651; https://doi.org/10.3390/cells8070651 - 28 Jun 2019

Cited by 9 | Viewed by 3040

Abstract

C-C chemokine receptor 5 (CCR5) polymorphisms, particularly a 32-base pair deletion (∆32) in the open reading frame and −2459G > A in the promoter, are well known for their associations with HIV-1 infection and/or disease progression in a variety of studies. [...] Read more.

C-C chemokine receptor 5 (CCR5) polymorphisms, particularly a 32-base pair deletion (∆32) in the open reading frame and −2459G > A in the promoter, are well known for their associations with HIV-1 infection and/or disease progression in a variety of studies. In this era of an HIV cure, where all the emphasis is on ∆32, it seems that −2459G > A has been forgotten or ignored. There is significant importance in the incorporation of the CCR5 −2459G > A genotype information into studies evaluating new immunologic and chemotherapeutic strategies, and those designing and implementing better treatment strategies with current antiretroviral therapy, doing so would enable a better understanding of the response to the intervention, due to a mechanistic or constitutive explanation. Until we find a strategy, whether a stem-cell transplantation or CCR5 editing approach or something else, that delivers a cure to the millions, we should make use of every piece of information that may help curtail HIV/AIDS as a threat to public health. Full article

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

2 pages, 177 KiB

Open AccessCorrection

Correction: Trinh, H.V., et al. Humoral Response to the HIV-1 Envelope V2 Region in a Thai Early Acute Infection Cohort. Cells 2019, 8, 365

by Hung V. Trinh, Neelakshi Gohain, Peter T. Pham, Christopher Hamlin, Hongshuo Song, Eric Sanders-Buell, Meera Bose, Leigh A. Eller, Swati Jain, Gherman Uritskiy, Venigalla B. Rao, Sodsai Tovanabutra, Nelson L. Michael, Merlin L. Robb, M. Gordon Joyce and Mangala Rao

Cells 2019, 8(6), 554; https://doi.org/10.3390/cells8060554 - 06 Jun 2019

Cited by 2 | Viewed by 2031

Abstract

In the original version of our article [...] Full article

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

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