A de novo approach to inferring within-host fitness effects during untreated HIV-1 infection

ABSTRACT The pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) is mediated mainly by mononuclear phagocyte (MP) secretory products and their interactions with neural cells. Viral infection and MP immune activation may affect leukocyte entry into the brain. One factor that influences central nervous system (CNS) monocyte migration is matrix metalloproteinases (MMPs). In the CNS, MMPs are synthesized by resident glial cells and affect the integrity of the neuropil extracellular matrix (ECM). To ascertain how MMPs influence HAD pathogenesis, we studied their secretion following MP differentiation, viral infection, and cellular activation. HIV-1-infected and/or immune-activated monocyte-derived macrophages (MDM) and human fetal microglia were examined for production of MMP-1, -2, -3, and -9. MMP expression increased significantly with MP differentiation. Microglia secreted high levels of MMPs de novo that were further elevated following CD40 ligand-mediated cell activation. Surprisingly, HIV-1 infection of MDM led to the down-regulation of MMP-9. In encephalitic brain tissue, MMPs were expressed within perivascular and parenchymal MP, multinucleated giant cells, and microglial nodules. These data suggest that MMP production in MP is dependent on cell type, differentiation, activation, and/or viral infection. Regulation of MMP expression by these factors may contribute to neuropil ECM degradation and leukocyte migration during HAD.

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Extending the Coding Potential of Viral Genomes with Overlapping Antisense ORFs: A Case for the De Novo Creation of the Gene Encoding the Antisense Protein ASP of HIV-1

Viruses ◽

10.3390/v14010146 ◽

2022 ◽

Vol 14 (1) ◽

pp. 146

Author(s):

Angelo Pavesi ◽

Fabio Romerio

Keyword(s):

De Novo ◽

Point Mutations ◽

Selective Advantage ◽

Genomic Region ◽

Fine Tuning ◽

Sequence Evolution ◽

Viral Genomes ◽

Stop Codons ◽

Hiv 1

Gene overprinting occurs when point mutations within a genomic region with an existing coding sequence create a new one in another reading frame. This process is quite frequent in viral genomes either to maximize the amount of information that they encode or in response to strong selective pressure. The most frequent scenario involves two different reading frames in the same DNA strand (sense overlap). Much less frequent are cases of overlapping genes that are encoded on opposite DNA strands (antisense overlap). One such example is the antisense ORF, asp in the minus strand of the HIV-1 genome overlapping the env gene. The asp gene is highly conserved in pandemic HIV-1 strains of group M, and it is absent in non-pandemic HIV-1 groups, HIV-2, and lentiviruses infecting non-human primates, suggesting that the ~190-amino acid protein that is expressed from this gene (ASP) may play a role in virus spread. While the function of ASP in the virus life cycle remains to be elucidated, mounting evidence from several research groups indicates that ASP is expressed in vivo. There are two alternative hypotheses that could be envisioned to explain the origin of the asp ORF. On one hand, asp may have originally been present in the ancestor of contemporary lentiviruses, and subsequently lost in all descendants except for most HIV-1 strains of group M due to selective advantage. Alternatively, the asp ORF may have originated very recently with the emergence of group M HIV-1 strains from SIVcpz. Here, we used a combination of computational and statistical approaches to study the genomic region of env in primate lentiviruses to shed light on the origin, structure, and sequence evolution of the asp ORF. The results emerging from our studies support the hypothesis of a recent de novo addition of the antisense ORF to the HIV-1 genome through a process that entailed progressive removal of existing internal stop codons from SIV strains to HIV-1 strains of group M, and fine tuning of the codon sequence in env that reduced the chances of new stop codons occurring in asp. Altogether, the study supports the notion that the HIV-1 asp gene encodes an accessory protein, providing a selective advantage to the virus.

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Expression of Cytoplasmic Incompatibility and Host Fitness Effects in Field Populations of Sogatella furcifera Infected With Cardinium

Journal of Economic Entomology ◽

10.1603/ec12268 ◽

2012 ◽

Vol 105 (6) ◽

pp. 2161-2166 ◽

Cited By ~ 6

Author(s):

Xiang-Fei Zhang ◽

Dong-Xiao Zhao ◽

Hao-Sen Li ◽

Xiao-Yue Hong

Keyword(s):

Cytoplasmic Incompatibility ◽

Sogatella Furcifera ◽

Host Fitness ◽

Fitness Effects

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Infection with Human Immunodeficiency Virus Type 1 Upregulates DNA Methyltransferase, Resulting in De Novo Methylation of the Gamma Interferon (IFN-γ) Promoter and Subsequent Downregulation of IFN-γ Production

Molecular and Cellular Biology ◽

10.1128/mcb.18.9.5166 ◽

1998 ◽

Vol 18 (9) ◽

pp. 5166-5177 ◽

Cited By ~ 118

Author(s):

Judy A. Mikovits ◽

Howard A. Young ◽

Paula Vertino ◽

Jean-Pierre J. Issa ◽

Paula M. Pitha ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Dna Methyltransferase ◽

De Novo ◽

Methylation Status ◽

Immunodeficiency Virus ◽

Ifn Γ ◽

Hiv 1 ◽

De Novo Methylation

ABSTRACT The immune response to pathogens is regulated by a delicate balance of cytokines. The dysregulation of cytokine gene expression, including interleukin-12, tumor necrosis factor alpha, and gamma interferon (IFN-γ), following human retrovirus infection is well documented. One process by which such gene expression may be modulated is altered DNA methylation. In subsets of T-helper cells, the expression of IFN-γ, a cytokine important to the immune response to viral infection, is regulated in part by DNA methylation such that mRNA expression inversely correlates with the methylation status of the promoter. Of the many possible genes whose methylation status could be affected by viral infection, we examined the IFN-γ gene as a candidate. We show here that acute infection of cells with human immunodeficiency virus type 1 (HIV-1) results in (i) increased DNA methyltransferase expression and activity, (ii) an overall increase in methylation of DNA in infected cells, and (iii) the de novo methylation of a CpG dinucleotide in the IFN-γ gene promoter, resulting in the subsequent downregulation of expression of this cytokine. The introduction of an antisense methyltransferase construct into lymphoid cells resulted in markedly decreased methyltransferase expression, hypomethylation throughout the IFN-γ gene, and increased IFN-γ production, demonstrating a direct link between methyltransferase and IFN-γ gene expression. The ability of increased DNA methyltransferase activity to downregulate the expression of genes like the IFN-γ gene may be one of the mechanisms for dysfunction of T cells in HIV-1-infected individuals.

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“Resistance” to PSC-RANTES Revisited: Two Mutations in Human Immunodeficiency Virus Type 1 HIV-1SF162 or Simian-Human Immunodeficiency Virus SHIVSF162-p3 Do Not Confer Resistance

Journal of Virology ◽

10.1128/jvi.01907-09 ◽

2010 ◽

Vol 84 (11) ◽

pp. 5842-5845 ◽

Cited By ~ 11

Author(s):

Rebecca Nedellec ◽

Mia Coetzer ◽

Michael M. Lederman ◽

Robin E. Offord ◽

Oliver Hartley ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Small Molecule ◽

Receptor Blockade ◽

Fitness Effects ◽

Allosteric Inhibitor ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Resistance of human immunodeficiency virus type 1 (HIV-1) to small-molecule CCR5 inhibitors is well demonstrated, but resistance to macromolecular CCR5 inhibitors (e.g., PSC-RANTES) that act by both CCR5 internalization and receptor blockade had not been reported until recently (3). The report of a single simian-human immunodeficiency virus SHIVSF162-p3 variant with one V3 and one gp41 sequence change in gp160 that conferred both altered replicative fitness and resistance to PSC-RANTES was therefore surprising. We introduced the same two mutations into both the parental HIV-1SF162 and the macaque-adapted SHIVSF162-p3 and found minor differences in entry fitness but no changes in sensitivity to inhibition by either PSC-RANTES or the small-molecule allosteric inhibitor TAK-779. We attribute the earlier finding to confounding fitness effects with inhibitor sensitivity.

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Novel dual role of dendritic cells in priming de novo CTL responses while inhibiting memory CTL responses to HIV-1 through the PD-L1 pathway

Journal of Virus Eradication ◽

10.1016/s2055-6640(20)30648-8 ◽

2017 ◽

Vol 3 ◽

pp. 36

Author(s):

T.M. Garcia-Bates ◽

M. Palma ◽

B. Macatangay ◽

C. Rinaldo ◽

R. Mailliard

Keyword(s):

Dendritic Cells ◽

De Novo ◽

Dual Role ◽

Hiv 1 ◽

Ctl Responses

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HIV-1 Nef stabilizes AP-1 on membranes without inducing ARF1-independent de novo attachment

Virology ◽

10.1016/j.virol.2005.09.045 ◽

2006 ◽

Vol 345 (1) ◽

pp. 148-155 ◽

Cited By ~ 9

Author(s):

Scott H. Coleman ◽

Douglas Hitchin ◽

Colleen M. Noviello ◽

John C. Guatelli

Keyword(s):

De Novo ◽

Hiv 1

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De Novo Design and Biophysical Characterization of an Affinity-Enhanced Protein Displaying the Structure of the Broadly Neutralizing HIV-1 2F5 Antibody Epitope

Biophysical Journal ◽

10.1016/j.bpj.2015.11.1860 ◽

2016 ◽

Vol 110 (3) ◽

pp. 346a

Author(s):

Isabelle Freire Tabosa Viana ◽

Eduardo Nascimento ◽

Jodi Craigo ◽

Marco Krieger ◽

Robbie Mailliard ◽

...

Keyword(s):

De Novo ◽

De Novo Design ◽

Biophysical Characterization ◽

Antibody Epitope ◽

Hiv 1

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De novo design and in-silico studies of novel 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid derivatives as HIV-1 reverse transcriptase inhibitors

Medicinal Chemistry Research ◽

10.1007/s00044-014-0945-9 ◽

2014 ◽

Vol 23 (8) ◽

pp. 3662-3670 ◽

Cited By ~ 9

Author(s):

Ashok Penta ◽

Subhash Chander ◽

S. Ganguly ◽

S. Murugesan

Keyword(s):

Carboxylic Acid ◽

Reverse Transcriptase ◽

In Silico ◽

De Novo ◽

De Novo Design ◽

Reverse Transcriptase Inhibitors ◽

In Silico Studies ◽

Hiv 1

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HIV-1–infected dendritic cells show 2 phases of gene expression changes, with lysosomal enzyme activity decreased during the second phase

Blood ◽

10.1182/blood-2008-12-194845 ◽

2009 ◽

Vol 114 (1) ◽

pp. 85-94 ◽

Cited By ~ 48

Author(s):

Andrew N. Harman ◽

Marianne Kraus ◽

Chris R. Bye ◽

Karen Byth ◽

Stuart G. Turville ◽

...

Keyword(s):

Gene Expression ◽

Dendritic Cells ◽

Antigen Processing ◽

De Novo ◽

Cathepsin L ◽

Transcriptional Response ◽

Differentially Expressed ◽

Second Phase ◽

Genes Encoding ◽

Hiv 1

AbstractDendritic cells (DCs) play a key role in the pathogenesis of HIV infection. HIV interacts with these cells through 2 pathways in 2 temporal phases, initially via endocytosis and then via de novo replication. Here the transcriptional response of human DCs to HIV-1 was studied in these phases and at different stages of the virus replication cycle using purified HIV-1 envelope proteins, and inactivated and viable HIV-1. No differential gene expression was detected in response to envelope. However, more than 100 genes were differentially expressed in response to entry of viable and inactivated HIV-1 in the first phase. A completely different set of genes was differentially expressed in the second phase, predominantly in response to viable HIV-1, including up-regulation of immune regulation genes, whereas genes encoding lysosomal enzymes were down-regulated. Cathepsins B, C, S, and Z RNA and protein decreased, whereas cathepsin L was increased, probably reflecting a concomitant decrease in cystatin C. The net effect was markedly diminished cathepsin activity likely to result in enhanced HIV-1 survival and transfer to contacting T lymphocytes but decreased HIV-1 antigen processing and presentation to these T cells.

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