Research

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19 pages, 3035 KiB

Open AccessArticle

The Inhibition of Gag-Pol Expression by the Restriction Factor Shiftless Is Dispensable for the Restriction of HIV-1 Infection

by Niklas Jäger, Shreya Ahana Ayyub, Frank Peske, David Liedtke, Jens Bohne, Markus Hoffmann, Marina V. Rodnina and Stefan Pöhlmann

Viruses 2024, 16(4), 583; https://doi.org/10.3390/v16040583 - 10 Apr 2024

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Abstract

The interferon-induced host cell protein Shiftless (SFL) inhibits −1 programmed ribosomal frameshifting (−1PRF) required for the expression of HIV-1 Gal-Pol and the formation of infectious HIV-1 particles. However, the specific regions in SFL required for antiviral activity and the mechanism by which SFL [...] Read more.

The interferon-induced host cell protein Shiftless (SFL) inhibits −1 programmed ribosomal frameshifting (−1PRF) required for the expression of HIV-1 Gal-Pol and the formation of infectious HIV-1 particles. However, the specific regions in SFL required for antiviral activity and the mechanism by which SFL inhibits −1PRF remain unclear. Employing alanine scanning mutagenesis, we found that basic amino acids in the predicted zinc ribbon motif of SFL are essential for the suppression of Gag-Pol expression but dispensable for anti-HIV-1 activity. We have shown that SFL inhibits the expression of the murine leukemia virus (MLV) Gag-Pol polyprotein and the formation of infectious MLV particles, although Gag-Pol expression of MLV is independent of −1PRF but requires readthrough of a stop codon. These findings indicate that SFL might inhibit HIV-1 infection by more than one mechanism and that SFL might target programmed translational readthrough as well as −1PRF signals, both of which are regulated by mRNA secondary structure elements. Full article

(This article belongs to the Special Issue Innate Sensing and Restriction of Retroviruses)

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15 pages, 4162 KiB

Open AccessArticle

A Variety of Mouse PYHIN Proteins Restrict Murine and Human Retroviruses

by Sümeyye Erdemci-Evin, Matteo Bosso, Veronika Krchlikova, Wibke Bayer, Kerstin Regensburger, Martha Mayer, Ulf Dittmer, Daniel Sauter, Dorota Kmiec and Frank Kirchhoff

Viruses 2024, 16(4), 493; https://doi.org/10.3390/v16040493 - 23 Mar 2024

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Abstract

PYHIN proteins are only found in mammals and play key roles in the defense against bacterial and viral pathogens. The corresponding gene locus shows variable deletion and expansion ranging from 0 genes in bats, over 1 in cows, and 4 in humans to [...] Read more.

PYHIN proteins are only found in mammals and play key roles in the defense against bacterial and viral pathogens. The corresponding gene locus shows variable deletion and expansion ranging from 0 genes in bats, over 1 in cows, and 4 in humans to a maximum of 13 in mice. While initially thought to act as cytosolic immune sensors that recognize foreign DNA, increasing evidence suggests that PYHIN proteins also inhibit viral pathogens by more direct mechanisms. Here, we examined the ability of all 13 murine PYHIN proteins to inhibit HIV-1 and murine leukemia virus (MLV). We show that overexpression of p203, p204, p205, p208, p209, p210, p211, and p212 strongly inhibits production of infectious HIV-1; p202, p207, and p213 had no significant effects, while p206 and p214 showed intermediate phenotypes. The inhibitory effects on infectious HIV-1 production correlated significantly with the suppression of reporter gene expression by a proviral Moloney MLV-eGFP construct and HIV-1 and Friend MLV LTR luciferase reporter constructs. Altogether, our data show that the antiretroviral activity of PYHIN proteins is conserved between men and mice and further support the key role of nuclear PYHIN proteins in innate antiviral immunity. Full article

(This article belongs to the Special Issue Innate Sensing and Restriction of Retroviruses)

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Review

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18 pages, 2779 KiB

Open AccessReview

Friends and Foes: The Ambivalent Role of Autophagy in HIV-1 Infection

by Susanne Klute and Konstantin M. J. Sparrer

Viruses 2024, 16(4), 500; https://doi.org/10.3390/v16040500 - 25 Mar 2024

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Abstract

Autophagy has emerged as an integral part of the antiviral innate immune defenses, targeting viruses or their components for lysosomal degradation. Thus, successful viruses, like pandemic human immunodeficiency virus 1 (HIV-1), evolved strategies to counteract or even exploit autophagy for efficient replication. Here, [...] Read more.

Autophagy has emerged as an integral part of the antiviral innate immune defenses, targeting viruses or their components for lysosomal degradation. Thus, successful viruses, like pandemic human immunodeficiency virus 1 (HIV-1), evolved strategies to counteract or even exploit autophagy for efficient replication. Here, we provide an overview of the intricate interplay between autophagy and HIV-1. We discuss the impact of autophagy on HIV-1 replication and report in detail how HIV-1 manipulates autophagy in infected cells and beyond. We also highlight tissue and cell-type specifics in the interplay between autophagy and HIV-1. In addition, we weigh exogenous modulation of autophagy as a putative double-edged sword against HIV-1 and discuss potential implications for future antiretroviral therapy and curative approaches. Taken together, we consider both antiviral and proviral roles of autophagy to illustrate the ambivalent role of autophagy in HIV-1 pathogenesis and therapy. Full article

(This article belongs to the Special Issue Innate Sensing and Restriction of Retroviruses)

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20 pages, 2928 KiB

Open AccessReview

The ISG15-Protease USP18 Is a Pleiotropic Enhancer of HIV-1 Replication

by Chaohui Lin, Edmund Osei Kuffour, Taolan Li, Christoph G. W. Gertzen, Jesko Kaiser, Tom Luedde, Renate König, Holger Gohlke and Carsten Münk

Viruses 2024, 16(4), 485; https://doi.org/10.3390/v16040485 - 22 Mar 2024

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Abstract

The innate immune response to viruses is formed in part by interferon (IFN)-induced restriction factors, including ISG15, p21, and SAMHD1. IFN production can be blocked by the ISG15-specific protease USP18. HIV-1 has evolved to circumvent host immune surveillance. This mechanism might involve USP18. [...] Read more.

The innate immune response to viruses is formed in part by interferon (IFN)-induced restriction factors, including ISG15, p21, and SAMHD1. IFN production can be blocked by the ISG15-specific protease USP18. HIV-1 has evolved to circumvent host immune surveillance. This mechanism might involve USP18. In our recent studies, we demonstrate that HIV-1 infection induces USP18, which dramatically enhances HIV-1 replication by abrogating the antiviral function of p21. USP18 downregulates p21 by accumulating misfolded dominant negative p53, which inactivates wild-type p53 transactivation, leading to the upregulation of key enzymes involved in de novo dNTP biosynthesis pathways and inactivated SAMHD1. Despite the USP18-mediated increase in HIV-1 DNA in infected cells, it is intriguing to note that the cGAS-STING-mediated sensing of the viral DNA is abrogated. Indeed, the expression of USP18 or knockout of ISG15 inhibits the sensing of HIV-1. We demonstrate that STING is ISGylated at residues K224, K236, K289, K347, K338, and K370. The inhibition of STING K289-linked ISGylation suppresses its oligomerization and IFN induction. We propose that human USP18 is a novel factor that potentially contributes in multiple ways to HIV-1 replication. Full article

(This article belongs to the Special Issue Innate Sensing and Restriction of Retroviruses)

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31 pages, 4761 KiB

Open AccessReview

HIV-1 Vpr Functions in Primary CD4⁺ T Cells

by Carlos Alberto Vanegas-Torres and Michael Schindler

Viruses 2024, 16(3), 420; https://doi.org/10.3390/v16030420 - 09 Mar 2024

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Abstract

HIV-1 encodes four accesory proteins in addition to its structural and regulatory genes. Uniquely amongst them, Vpr is abundantly present within virions, meaning it is poised to exert various biological effects on the host cell upon delivery. In this way, Vpr contributes towards [...] Read more.

HIV-1 encodes four accesory proteins in addition to its structural and regulatory genes. Uniquely amongst them, Vpr is abundantly present within virions, meaning it is poised to exert various biological effects on the host cell upon delivery. In this way, Vpr contributes towards the establishment of a successful infection, as evidenced by the extent to which HIV-1 depends on this factor to achieve full pathogenicity in vivo. Although HIV infects various cell types in the host organism, CD4⁺ T cells are preferentially targeted since they are highly permissive towards productive infection, concomitantly bringing about the hallmark immune dysfunction that accompanies HIV-1 spread. The last several decades have seen unprecedented progress in unraveling the activities Vpr possesses in the host cell at the molecular scale, increasingly underscoring the importance of this viral component. Nevertheless, it remains controversial whether some of these advances bear in vivo relevance, since commonly employed cellular models significantly differ from primary T lymphocytes. One prominent example is the “established” ability of Vpr to induce G2 cell cycle arrest, with enigmatic physiological relevance in infected primary T lymphocytes. The objective of this review is to present these discoveries in their biological context to illustrate the mechanisms whereby Vpr supports HIV-1 infection in CD4⁺ T cells, whilst identifying findings that require validation in physiologically relevant models. Full article

(This article belongs to the Special Issue Innate Sensing and Restriction of Retroviruses)

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18 pages, 1618 KiB

Open AccessReview

IFNα Subtypes in HIV Infection and Immunity

by Zehra Karakoese, Martha Ingola, Barbara Sitek, Ulf Dittmer and Kathrin Sutter

Viruses 2024, 16(3), 364; https://doi.org/10.3390/v16030364 - 27 Feb 2024

Viewed by 833

Abstract

Type I interferons (IFN), immediately triggered following most viral infections, play a pivotal role in direct antiviral immunity and act as a bridge between innate and adaptive immune responses. However, numerous viruses have evolved evasion strategies against IFN responses, prompting the exploration of [...] Read more.

Type I interferons (IFN), immediately triggered following most viral infections, play a pivotal role in direct antiviral immunity and act as a bridge between innate and adaptive immune responses. However, numerous viruses have evolved evasion strategies against IFN responses, prompting the exploration of therapeutic alternatives for viral infections. Within the type I IFN family, 12 IFNα subtypes exist, all binding to the same receptor but displaying significant variations in their biological activities. Currently, clinical treatments for chronic virus infections predominantly rely on a single IFNα subtype (IFNα2a/b). However, the efficacy of this therapeutic treatment is relatively limited, particularly in the context of Human Immunodeficiency Virus (HIV) infection. Recent investigations have delved into alternative IFNα subtypes, identifying certain subtypes as highly potent, and their antiviral and immunomodulatory properties have been extensively characterized. This review consolidates recent findings on the roles of individual IFNα subtypes during HIV and Simian Immunodeficiency Virus (SIV) infections. It encompasses their induction in the context of HIV/SIV infection, their antiretroviral activity, and the diverse regulation of the immune response against HIV by distinct IFNα subtypes. These insights may pave the way for innovative strategies in HIV cure or functional cure studies. Full article

(This article belongs to the Special Issue Innate Sensing and Restriction of Retroviruses)

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23 pages, 4437 KiB

Open AccessReview

Restriction of Viral Glycoprotein Maturation by Cellular Protease Inhibitors

by Rishikesh Lotke, Moritz Petersen and Daniel Sauter

Viruses 2024, 16(3), 332; https://doi.org/10.3390/v16030332 - 22 Feb 2024

Viewed by 894

Abstract

The human genome is estimated to encode more than 500 proteases performing a wide range of important physiological functions. They digest proteins in our food, determine the activity of hormones, induce cell death and regulate blood clotting, for example. During viral infection, however, [...] Read more.

The human genome is estimated to encode more than 500 proteases performing a wide range of important physiological functions. They digest proteins in our food, determine the activity of hormones, induce cell death and regulate blood clotting, for example. During viral infection, however, some proteases can switch sides and activate viral glycoproteins, allowing the entry of virions into new target cells and the spread of infection. To reduce unwanted effects, multiple protease inhibitors regulate the proteolytic processing of self and non-self proteins. This review summarizes our current knowledge of endogenous protease inhibitors, which are known to limit viral replication by interfering with the proteolytic activation of viral glycoproteins. We describe the underlying molecular mechanisms and highlight the diverse strategies by which protease inhibitors reduce virion infectivity. We also provide examples of how viruses evade the restriction imposed by protease inhibitors. Finally, we briefly outline how cellular protease inhibitors can be modified and exploited for therapeutic purposes. In summary, this review aims to summarize our current understanding of cellular protease inhibitors as components of our immune response to a variety of viral pathogens. Full article

(This article belongs to the Special Issue Innate Sensing and Restriction of Retroviruses)

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13 pages, 1670 KiB

Open AccessReview

Beyond Impairment of Virion Infectivity: New Activities of the Anti-HIV Host Cell Factor SERINC5

by Samy Sid Ahmed, Kathrin Bajak and Oliver T. Fackler

Viruses 2024, 16(2), 284; https://doi.org/10.3390/v16020284 - 12 Feb 2024

Viewed by 872

Abstract

Members of the serine incorporator (SERINC) protein family exert broad antiviral activity, and many viruses encode SERINC antagonists to circumvent these restrictions. Significant new insight was recently gained into the mechanisms that mediate restriction and antagonism. In this review, we summarize our current [...] Read more.

Members of the serine incorporator (SERINC) protein family exert broad antiviral activity, and many viruses encode SERINC antagonists to circumvent these restrictions. Significant new insight was recently gained into the mechanisms that mediate restriction and antagonism. In this review, we summarize our current understanding of the mode of action and relevance of SERINC proteins in HIV-1 infection. Particular focus will be placed on recent findings that provided important new mechanistic insights into the restriction of HIV-1 virion infectivity, including the discovery of SERINC’s lipid scramblase activity and its antagonism by the HIV-1 pathogenesis factor Nef. We also discuss the identification and implications of several additional antiviral activities by which SERINC proteins enhance pro-inflammatory signaling and reduce viral gene expression in myeloid cells. SERINC proteins emerge as versatile and multifunctional regulators of cell-intrinsic immunity against HIV-1 infection. Full article

(This article belongs to the Special Issue Innate Sensing and Restriction of Retroviruses)

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