Polymorphisms in Human APOBEC3H Differentially Regulate Ubiquitination and Antiviral Activity

The APOBEC3 family of cytidine deaminases are an important part of the host innate immune defense against endogenous retroelements and retroviruses like Human Immunodeficiency Virus (HIV). APOBEC3H (A3H) is the most polymorphic of the human APOBEC3 genes, with four major haplotypes circulating in the population. Haplotype II is the only antivirally-active variant of A3H, while the majority of the population possess independently destabilizing polymorphisms present in haplotype I (R105G) and haplotypes III and IV (N15del). In this paper, we show that instability introduced by either polymorphism is positively correlated with degradative ubiquitination, while haplotype II is protected from this modification. Inhibiting ubiquitination by mutating all of the A3H lysines increased the expression of haplotypes III and IV, but these stabilized forms of haplotype III and IV had a strict nuclear localization, and did not incorporate into virions, nor exhibit antiviral activity. Fusion chimeras with haplotype II allowed for stabilization, cytoplasmic retention, and packaging of the N15del-containing haplotype III, but the haplotype III component of these chimeras was unable to restrict HIV-1 on its own. Thus, the evolutionary loss of A3H activity in many humans involves functional deficiencies independent of protein stability.

Download Full-text

Polymorphisms in human APOBEC3H differentially regulate ubiquitination and antiviral activity

10.1101/2020.02.07.939439 ◽

2020 ◽

Cited By ~ 1

Author(s):

Nicholas M. Chesarino ◽

Michael Emerman

Keyword(s):

Antiviral Activity ◽

Nuclear Localization ◽

Retention Mechanism ◽

Immune Defense ◽

Innate Immune ◽

Cytidine Deaminases ◽

Innate Immune Defense ◽

Immunodeficiency Virus ◽

Apobec3 Family ◽

Active Variant

AbstractThe APOBEC3 family of cytidine deaminases are an important part of the host innate immune defense against endogenous retroelements and retroviruses like human immunodeficiency virus (HIV). APOBEC3H (A3H) is the most polymorphic of the human APOBEC3 genes, with four major haplotypes circulating in the population. Haplotype II is the only antivirally-active variant of A3H, while the majority of the population possess independently destabilizing polymorphisms present in haplotype I (R105G) and haplotypes III and IV (N15del). Here, we show that instability introduced by either polymorphism is positively correlated with degradative ubiquitination, while haplotype II is protected from this modification. Inhibiting ubiquitination by mutating all of the A3H lysines increased expression of haplotypes III and IV, but these stabilized forms of haplotype III and IV had a strict nuclear localization, and did not incorporate into virions, nor exhibit antiviral activity, thus separating stabilization from function. On the other hand, the instability and functional deficiencies of haplotype III could be rescued by fusion to haplotype II, supporting a model by which antiviral A3H is actively stabilized through a cytoplasmic retention mechanism. Thus, the evolutionary loss of A3H activity in many humans involves functional deficiencies independent of protein stability.

Download Full-text

The roles of grouper TANK in innate immune defense against iridovirus and nodavirus infections

Fish & Shellfish Immunology ◽

10.1016/j.fsi.2020.06.017 ◽

2020 ◽

Vol 104 ◽

pp. 506-516

Author(s):

Jingguang Wei ◽

Chen Li ◽

Jisheng Ou ◽

Xin Zhang ◽

Zetian Liu ◽

...

Keyword(s):

Immune Defense ◽

Innate Immune ◽

Innate Immune Defense

Download Full-text

Human TRIM5α: Autophagy Connects Cell-Intrinsic HIV-1 Restriction and Innate Immune Sensor Functioning

Viruses ◽

10.3390/v13020320 ◽

2021 ◽

Vol 13 (2) ◽

pp. 320 ◽

Cited By ~ 1

Author(s):

Alexandra P. M. Cloherty ◽

Anusca G. Rader ◽

Brandon Compeer ◽

Carla M. S. Ribeiro

Keyword(s):

Therapeutic Potential ◽

Innate Immune ◽

Health Concern ◽

Restriction Factor ◽

Viral Reservoirs ◽

Minimal Restriction ◽

Immunodeficiency Virus ◽

A Cell ◽

Species Specific ◽

Hiv 1

Human immunodeficiency virus-1 (HIV-1) persists as a global health concern, with an incidence rate of approximately 2 million, and estimated global prevalence of over 35 million. Combination antiretroviral treatment is highly effective, but HIV-1 patients that have been treated still suffer from chronic inflammation and residual viral replication. It is therefore paramount to identify therapeutically efficacious strategies to eradicate viral reservoirs and ultimately develop a cure for HIV-1. It has been long accepted that the restriction factor tripartite motif protein 5 isoform alpha (TRIM5α) restricts HIV-1 infection in a species-specific manner, with rhesus macaque TRIM5α strongly restricting HIV-1, and human TRIM5α having a minimal restriction capacity. However, several recent studies underscore human TRIM5α as a cell-dependent HIV-1 restriction factor. Here, we present an overview of the latest research on human TRIM5α and propose a novel conceptualization of TRIM5α as a restriction factor with a varied portfolio of antiviral functions, including mediating HIV-1 degradation through autophagy- and proteasome-mediated mechanisms, and acting as a viral sensor and effector of antiviral signaling. We have also expanded on the protective antiviral roles of autophagy and outline the therapeutic potential of autophagy modulation to intervene in chronic HIV-1 infection.

Download Full-text

From Capsids to Complexes: Expanding the Role of TRIM5α in the Restriction of Divergent RNA Viruses and Elements

Viruses ◽

10.3390/v13030446 ◽

2021 ◽

Vol 13 (3) ◽

pp. 446

Author(s):

Kevin M. Rose ◽

Stephanie J. Spada ◽

Rebecca Broeckel ◽

Kristin L. McNally ◽

Vanessa M. Hirsch ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Molecular Basis ◽

Human Population ◽

Rna Viruses ◽

Arms Race ◽

Innate Immune ◽

Immunodeficiency Virus ◽

Underlying Mechanisms ◽

Hiv 1

An evolutionary arms race has been ongoing between retroviruses and their primate hosts for millions of years. Within the last century, a zoonotic transmission introduced the Human Immunodeficiency Virus (HIV-1), a retrovirus, to the human population that has claimed the lives of millions of individuals and is still infecting over a million people every year. To counteract retroviruses such as this, primates including humans have evolved an innate immune sensor for the retroviral capsid lattice known as TRIM5α. Although the molecular basis for its ability to restrict retroviruses is debated, it is currently accepted that TRIM5α forms higher-order assemblies around the incoming retroviral capsid that are not only disruptive for the virus lifecycle, but also trigger the activation of an antiviral state. More recently, it was discovered that TRIM5α restriction is broader than previously thought because it restricts not only the human retroelement LINE-1, but also the tick-borne flaviviruses, an emergent group of RNA viruses that have vastly different strategies for replication compared to retroviruses. This review focuses on the underlying mechanisms of TRIM5α-mediated restriction of retroelements and flaviviruses and how they differ from the more widely known ability of TRIM5α to restrict retroviruses.

Download Full-text

In Vitro Antiviral Activity and Cross-Resistance Profile of PL-100, a Novel Protease Inhibitor of Human Immunodeficiency Virus Type 1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00149-07 ◽

2007 ◽

Vol 51 (11) ◽

pp. 4036-4043 ◽

Cited By ~ 21

Author(s):

Serge Dandache ◽

Guy Sévigny ◽

Jocelyn Yelle ◽

Brent R. Stranix ◽

Neil Parkin ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Antiviral Activity ◽

Highly Active Antiretroviral Therapy ◽

Cross Resistance ◽

Drug Resistant ◽

Resistance Profile ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Despite the success of highly active antiretroviral therapy, the current emergence and spread of drug-resistant variants of human immunodeficiency virus (HIV) stress the need for new inhibitors with distinct properties. We designed, produced, and screened a library of compounds based on an original l-lysine scaffold for their potentials as HIV type 1 (HIV-1) protease inhibitors (PI). One candidate compound, PL-100, emerged as a specific and noncytotoxic PI that exhibited potent inhibition of HIV-1 protease and viral replication in vitro (Ki , ∼36 pM, and 50% effective concentration [EC50], ∼16 nM, respectively). To confirm that PL-100 possessed a favorable resistance profile, we performed a cross-resistance study using a panel of 63 viral strains from PI-experienced patients selected for the presence of primary PI mutations known to confer resistance to multiple PIs now in clinical use. The results showed that PL-100 retained excellent antiviral activity against almost all of these PI-resistant viruses and that its performance in this regard was superior to those of atazanavir, amprenavir, indinavir, lopinavir, nelfinavir, and saquinavir. In almost every case, the increase in the EC50 for PL-100 observed with viruses containing multiple mutations in protease was far less than that obtained with the other drugs tested. These data underscore the potential for PL-100 to be used in the treatment of drug-resistant HIV disease and argue for its further development.

Download Full-text

Black carp STING functions importantly in innate immune defense against RNA virus

Fish & Shellfish Immunology ◽

10.1016/j.fsi.2017.08.037 ◽

2017 ◽

Vol 70 ◽

pp. 13-24 ◽

Cited By ~ 8

Author(s):

Liang Lu ◽

Xu Wang ◽

Sizhong Wu ◽

Xuejiao Song ◽

Ziqi Zou ◽

...

Keyword(s):

Rna Virus ◽

Immune Defense ◽

Innate Immune ◽

Black Carp ◽

Innate Immune Defense

Download Full-text

Trimeric heptad repeat synthetic peptides HR1 and HR2 efficiently inhibit HIV-1 entry

Bioscience Reports ◽

10.1042/bsr20192196 ◽

2019 ◽

Vol 39 (9) ◽

Author(s):

Olfa Mzoughi ◽

Meritxell Teixido ◽

Rémi Planès ◽

Manutea Serrero ◽

Ibtissem Hamimed ◽

...

Keyword(s):

Antiviral Activity ◽

Heptad Repeat ◽

Fusion Activity ◽

Helical Structures ◽

Fusion Inhibitors ◽

Immunodeficiency Virus ◽

Antiviral Activities ◽

Physical Interactions ◽

Kinetics Of ◽

Hiv 1

Abstract The trimeric heptad repeat domains HR1 and HR2 of the human immunodeficiency virus 1 (HIV-1) gp41 play a key role in HIV-1-entry by membrane fusion. To develop efficient inhibitors against this step, the corresponding trimeric-N36 and C34 peptides were designed and synthesized. Analysis by circular dichroism of monomeric and trimeric N36 and C34 peptides showed their capacities to adopt α-helical structures and to establish physical interactions. At the virological level, while trimeric-C34 conserves the same high anti-fusion activity as monomeric-C34, trimerization of N36-peptide induced a significant increase, reaching 500-times higher in anti-fusion activity, against R5-tropic virus-mediated fusion. This result was associated with increased stability of the N36 trimer peptide with respect to the monomeric form, as demonstrated by the comparative kinetics of their antiviral activities during 6-day incubation in a physiological medium. Collectively, our findings demonstrate that while the trimerization of C34 peptide had no beneficial effect on its stability and antiviral activity, the trimerization of N36 peptide strengthened both stability and antiviral activity. This approach, promotes trimers as new promising HIV-1 inhibitors and point to future development aimed toward innovative peptide fusion inhibitors, microbicides or as immunogens.

Download Full-text

The Thiocarboxanilide Nonnucleoside Inhibitor UC781 Restores Antiviral Activity of 3′-Azido-3′-Deoxythymidine (AZT) against AZT-Resistant Human Immunodeficiency Virus Type 1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.2.259 ◽

1999 ◽

Vol 43 (2) ◽

pp. 259-263 ◽

Cited By ~ 37

Author(s):

Gadi Borkow ◽

Dominique Arion ◽

Mark A. Wainberg ◽

Michael A. Parniak

Keyword(s):

Human Immunodeficiency Virus ◽

Antiviral Activity ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Wild Type Virus ◽

Wild Type ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT N-[4-Chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide (UC781) is an exceptionally potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. We found that a 1:1 molar combination of UC781 and 3′-azido-3′-deoxythymidine (AZT) showed high-level synergy in inhibiting the replication of AZT-resistant virus, implying that UC781 can restore antiviral activity to AZT against AZT-resistant HIV-1. Neither the nevirapine plus AZT nor the 2′,5′-bis-O-(t-butyldimethylsilyl)-3′-spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide plus AZT combinations had this effect. Studies with purified HIV-1 reverse transcriptase (from a wild type and an AZT-resistant mutant) showed that UC781 was a potent inhibitor of the pyrophosphorolytic cleavage of nucleotides from the 3′ end of the DNA polymerization primer, a process that we have proposed to be critical for the phenotypic expression of AZT resistance. Combinations of UC781 plus AZT did not act in synergy to inhibit the replication of either wild-type virus or UC781-resistant HIV-1. Importantly, the time to the development of viral resistance to combinations of UC781 plus AZT is significantly delayed compared to the time to the development of resistance to either drug alone.

Download Full-text