Differential Regulation of the HIV-1 LTR by Specific NF-κB Subunits in HSV-1-Infected Cells

In a previous study, we reported that 1- O-octadecyl- sn-glycero-3-foscarnet (ODG-PFA) was 40 to 93 times more potent than free foscarnet (PFA) in human cytomegalovirus (HCMV)-, herpes simplex virus type 1 (HSV-1)- and human immunodeficiency virus type 1 (HIV-1)-infected cells. To evaluate the effect of substituting a 1- S-alkyl thioether for a 1- O-alkyl ether, we synthesized a series of PFA conjugates of 1- S-alkyl- sn-thioglycerols with varied 1- S-alkyl chain lengths. To establish structure–activity relationships we measured the in vitro antiviral activity of liposomal formulations of the drugs in cells infected with HCMV, HSV-1 or HIV-1. The optimum 1- S-alkyl chain length in the series was 16 to 18 carbon atoms. We compared the antiviral activity of 16- and 18-carbon alkyl thioglycerol versus alkylglycerol prodrugs and did not observe any significant differences in their antiviral activities. The series' most active member, 1- S-octadecyl- sn-glycero-3-foscarnet (ODSG-PFA) was 56-, eight- and 45-fold more active than PFA in HCMV-, HSV-1- and HIV-1-infected cells in vitro. The oral absorption of PFA and 1-S-octadecyl-sn-thioglycero-3-PFA was compared in mice by measuring plasma levels of 14C after oral administration of radiolabelled compounds. The peak plasma level of 14C was sevenfold higher following administration of [14C]ODSG-PFA than following an equimolar dose of [14C]PFA. Area-under-the-curve was 23-fold greater for ODSG-PFA than for PFA. Like previously reported alkyloxyether–lipid PFA conjugates, alkylthioether conjugates provided enhanced antiviral activity and oral bioavailability. However, S-ether conjugates may be metabolized differently than O-ether conjugates. More detailed in vivo pharmacokinetic evaluation of the alkyl-thioether–PFA conjugates is required.

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Assembly of VP26 in herpes simplex virus-1 capsid implicated by 3-D structure of recombinant capsid

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100140579 ◽

1995 ◽

Vol 53 ◽

pp. 840-841

Author(s):

Z. Hong Zhou ◽

Jing He ◽

Joanita Jakana ◽

J. D. Tatman ◽

Frazer J. Rixon ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

3D Structure ◽

Structure Study ◽

Herpes Simplex Virus 1 ◽

Shell Proteins ◽

Life Threatening ◽

Infected Cells ◽

Simplex Virus ◽

Hsv 1

Herpes simplex virus-1 (HSV-1) is a ubiquitous virus which is implicated in diseases ranging from self-curing cold sores to life-threatening infections. The 2500 Å diameter herpes virion is composed of a glycoprotein spike containing, lipid envelope, enclosing a protein layer (the tegument) in which is embedded the capsid (which contains the dsDNA genome). The B-, and A- and C-capsids, representing different morphogenetic stages in HSV-1 infected cells, are composed of 7, and 5 structural proteins respectively. The three capsid types are organized in similar T=16 icosahedral shells with 12 pentons, 150 hexons, and 320 connecting triplexes. Our previous 3D structure study at 26 Å revealed domain features of all these structural components and suggested probable locations for the outer shell proteins, VP5, VP26, VP19c and VP23. VP5 makes up most of both pentons and hexons. VP26 appeared to bind to the VP5 subunit in hexon but not to that in penton.

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Faculty Opinions recommendation of Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726369545.793518839 ◽

2016 ◽

Author(s):

Stephen J Kent

Keyword(s):

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Infected Cells ◽

Hiv 1

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Faculty Opinions recommendation of Elimination of HIV-1-infected cells by broadly neutralizing antibodies.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726190699.793517949 ◽

2016 ◽

Author(s):

Boris Matija Peterlin

Keyword(s):

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Infected Cells ◽

Hiv 1

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Induction of Autophagy to Achieve a Human Immunodeficiency Virus Type 1 Cure

Cells ◽

10.3390/cells10071798 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1798

Author(s):

Grant R. Campbell ◽

Stephen A. Spector

Keyword(s):

Human Immunodeficiency Virus ◽

Antiretroviral Therapy ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Functional Cure ◽

Immunodeficiency Virus ◽

Latently Infected ◽

Infected Cells ◽

Hiv 1

Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells, which drive viral rebound post-interruption of antiretroviral therapy, remains the major roadblock to a cure. Therefore, the targeted elimination or permanent silencing of this latently infected reservoir is a major focus of HIV-1 research. The most studied approach in the development of a cure is the activation of HIV-1 expression to expose latently infected cells for immune clearance while inducing HIV-1 cytotoxicity—the “kick and kill” approach. However, the complex and highly heterogeneous nature of the latent reservoir, combined with the failure of clinical trials to reduce the reservoir size casts doubt on the feasibility of this approach. This concern that total elimination of HIV-1 from the body may not be possible has led to increased emphasis on a “functional cure” where the virus remains but is unable to reactivate which presents the challenge of permanently silencing transcription of HIV-1 for prolonged drug-free remission—a “block and lock” approach. In this review, we discuss the interaction of HIV-1 and autophagy, and the exploitation of autophagy to kill selectively HIV-1 latently infected cells as part of a cure strategy. The cure strategy proposed has the advantage of significantly decreasing the size of the HIV-1 reservoir that can contribute to a functional cure and when optimised has the potential to eradicate completely HIV-1.

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PCIP-seq: simultaneous sequencing of integrated viral genomes and their insertion sites with long reads

Genome Biology ◽

10.1186/s13059-021-02307-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Maria Artesi ◽

Vincent Hahaut ◽

Basiel Cole ◽

Laurens Lambrechts ◽

Fereshteh Ashrafi ◽

...

Keyword(s):

Viral Genome ◽

Clonal Expansion ◽

Endogenous Retroviruses ◽

Viral Genomes ◽

Short Read Sequencing ◽

Long Reads ◽

Infected Cells ◽

Insertion Sites ◽

Viral Insertion ◽

Hiv 1

AbstractThe integration of a viral genome into the host genome has a major impact on the trajectory of the infected cell. Integration location and variation within the associated viral genome can influence both clonal expansion and persistence of infected cells. Methods based on short-read sequencing can identify viral insertion sites, but the sequence of the viral genomes within remains unobserved. We develop PCIP-seq, a method that leverages long reads to identify insertion sites and sequence their associated viral genome. We apply the technique to exogenous retroviruses HTLV-1, BLV, and HIV-1, endogenous retroviruses, and human papillomavirus.

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Antiviral Activity of the G-Quadruplex Ligand TMPyP4 against Herpes Simplex Virus-1

Viruses ◽

10.3390/v13020196 ◽

2021 ◽

Vol 13 (2) ◽

pp. 196

Author(s):

Sara Artusi ◽

Emanuela Ruggiero ◽

Matteo Nadai ◽

Beatrice Tosoni ◽

Rosalba Perrone ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Dna Replication ◽

Herpes Simplex ◽

Antiviral Activity ◽

Herpes Simplex Virus 1 ◽

Tem Analysis ◽

Infected Cells ◽

Simplex Virus ◽

Hsv 1

The herpes simplex virus 1 (HSV-1) genome is extremely rich in guanine tracts that fold into G-quadruplexes (G4s), nucleic acid secondary structures implicated in key biological functions. Viral G4s were visualized in HSV-1 infected cells, with massive virus cycle-dependent G4-formation peaking during viral DNA replication. Small molecules that specifically interact with G4s have been shown to inhibit HSV-1 DNA replication. We here investigated the antiviral activity of TMPyP4, a porphyrin known to interact with G4s. The analogue TMPyP2, with lower G4 affinity, was used as control. We showed by biophysical analysis that TMPyP4 interacts with HSV-1 G4s, and inhibits polymerase progression in vitro; in infected cells, it displayed good antiviral activity which, however, was independent of inhibition of virus DNA replication or entry. At low TMPyP4 concentration, the virus released by the cells was almost null, while inside the cell virus amounts were at control levels. TEM analysis showed that virus particles were trapped inside cytoplasmatic vesicles, which could not be ascribed to autophagy, as proven by RT-qPCR, western blot, and immunofluorescence analysis. Our data indicate a unique mechanism of action of TMPyP4 against HSV-1, and suggest the unprecedented involvement of currently unknown G4s in viral or antiviral cellular defense pathways.

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Extended Interactions between HIV-1 Viral RNA and tRNALys3 Are Important to Maintain Viral RNA Integrity

International Journal of Molecular Sciences ◽

10.3390/ijms22010058 ◽

2020 ◽

Vol 22 (1) ◽

pp. 58

Author(s):

Thomas Gremminger ◽

Zhenwei Song ◽

Juan Ji ◽

Avery Foster ◽

Kexin Weng ◽

...

Keyword(s):

Reverse Transcription ◽

Potential Interaction ◽

Viral Rna ◽

Primer Binding Site ◽

Rna Integrity ◽

Immunodeficiency Virus ◽

Infected Cells ◽

Extended Interaction ◽

Hiv 1

The reverse transcription of the human immunodeficiency virus 1 (HIV-1) initiates upon annealing of the 3′-18-nt of tRNALys3 onto the primer binding site (PBS) in viral RNA (vRNA). Additional intermolecular interactions between tRNALys3 and vRNA have been reported, but their functions remain unclear. Here, we show that abolishing one potential interaction, the A-rich loop: tRNALys3 anticodon interaction in the HIV-1 MAL strain, led to a decrease in viral infectivity and reduced the synthesis of reverse transcription products in newly infected cells. In vitro biophysical and functional experiments revealed that disruption of the extended interaction resulted in an increased affinity for reverse transcriptase (RT) and enhanced primer extension efficiency. In the absence of deoxyribose nucleoside triphosphates (dNTPs), vRNA was degraded by the RNaseH activity of RT, and the degradation rate was slower in the complex with the extended interaction. Consistently, the loss of vRNA integrity was detected in virions containing A-rich loop mutations. Similar results were observed in the HIV-1 NL4.3 strain, and we show that the nucleocapsid (NC) protein is necessary to promote the extended vRNA: tRNALys3 interactions in vitro. In summary, our data revealed that the additional intermolecular interaction between tRNALys3 and vRNA is likely a conserved mechanism among various HIV-1 strains and protects the vRNA from RNaseH degradation in mature virions.

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Highly Productive Infection with Pseudotyped Human Immunodeficiency Virus Type 1 (HIV-1) Indicates No Intracellular Restrictions to HIV-1 Replication in Primary Human Astrocytes

Journal of Virology ◽

10.1128/jvi.75.17.7925-7933.2001 ◽

2001 ◽

Vol 75 (17) ◽

pp. 7925-7933 ◽

Cited By ~ 82

Author(s):

Mario Canki ◽

Janice Ngee Foong Thai ◽

Wei Chao ◽

Anuja Ghorpade ◽

Mary Jane Potash ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Productive Infection ◽

Human Astrocytes ◽

Immunodeficiency Virus ◽

Infected Cells ◽

Virus Expression ◽

Hiv 1

ABSTRACT Human astrocytes can be infected with human immunodeficiency virus type 1 (HIV-1) in vitro and in vivo, but, in contrast to T lymphocytes and macrophages, virus expression is inefficient. To investigate the HIV-1 life cycle in human fetal astrocytes, we infected cells with HIV-1 pseudotyped with envelope glycoproteins of either amphotropic murine leukemia virus or vesicular stomatitis virus. Infection by both pseudotypes was productive and long lasting and reached a peak of 68% infected cells and 1.7 μg of viral p24 per ml of culture supernatant 7 days after virus inoculation and then continued with gradually declining levels of virus expression through 7 weeks of follow-up. This contrasted with less than 0.1% HIV-1 antigen-positive cells and 400 pg of extracellular p24 per ml at the peak of astrocyte infection with native HIV-1. Cell viability and growth kinetics were similar in infected and control cells. Northern blot analysis revealed the presence of major HIV-1 RNA species of 9, 4, and 2 kb in astrocytes exposed to pseudotyped (but not wild-type) HIV-1 at 2, 14, and 28 days after infection. Consistent with productive infection, the 9- and 4-kb viral transcripts in astrocytes infected by pseudotyped HIV-1 were as abundant as the 2-kb mRNA during 4 weeks of follow-up, and both structural and regulatory viral proteins were detected in infected cells by immunoblotting or cell staining. The progeny virus released by these cells was infectious. These results indicate that the major barrier to HIV-1 infection of primary astrocytes is at virus entry and that astrocytes have no intrinsic intracellular restriction to efficient HIV-1 replication.

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