Selection of biomarkers for HIV-1 latency by integrated analysis

Abstract Background Long noncoding RNAs (lncRNAs) can regulate gene expression in a cis-regulatory fashion or as “microRNA sponges”. However, the expression and functions of lncRNAs during early human immunodeficiency virus (HIV) infection (EHI) remain unclear. Methods 3 HAART-naive EHI patients and 3 healthy controls (HCs) were recruited in this study to perform RNA sequencing and microRNA (miRNA) sequencing. The expression profiles of lncRNAs, mRNAs and miRNAs were obtained, and the potential roles of lncRNAs were analysed based on discovering lncRNA cis-regulatory target mRNAs and constructing lncRNA–miRNA–mRNA competing endogenous RNA (ceRNA) networks. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on 175 lncRNA-associated differentially expressed (DE) mRNAs to investigate the potential functions of DE lncRNAs in ceRNA networks. Results A total of 242 lncRNAs, 1240 mRNAs and 21 mature known miRNAs were determined as differentially expressed genes in HAART-naive EHI patients compared to HCs. Among DE lncRNAs, 44 lncRNAs were predicted to overlap with 41 target mRNAs, and 107 lncRNAs might regulate their nearby DE mRNAs. Two DE lncRNAs might regulate their cis-regulatory target mRNAs BTLA and ZAP70, respectively, which were associated with immune activation. In addition, the ceRNA networks comprised 160 DE lncRNAs, 21 DE miRNAs and 175 DE mRNAs. Seventeen DE lncRNAs were predicted to regulate HIF1A and TCF7L2, which are involved in the process of HIV-1 replication. Twenty DE lncRNAs might share miRNA response elements (MREs) with FOS, FOSB and JUN, which are associated with both immune activation and HIV-1 replication. Conclusions This study revealed that lncRNAs might play a critical role in HIV-1 replication and immune activation during EHI. These novel findings are helpful for understanding of the pathogenesis of HIV infection and provide new insights into antiviral therapy.

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Exploring New Scaffolds for the Dual Inhibition of HIV-1 RT Polymerase and Ribonuclease Associated Functions

Molecules ◽

10.3390/molecules26133821 ◽

2021 ◽

Vol 26 (13) ◽

pp. 3821

Author(s):

Rita Meleddu ◽

Angela Corona ◽

Simona Distinto ◽

Filippo Cottiglia ◽

Serenella Deplano ◽

...

Keyword(s):

Single Agent ◽

Hiv Reverse Transcriptase ◽

Substitution Pattern ◽

Associated Functions ◽

Dual Inhibition ◽

Hiv Rt ◽

Therapeutic Protocols ◽

Anti Hiv ◽

Hiv 1 ◽

Selection Of

Current therapeutic protocols for the treatment of HIV infection consist of the combination of diverse anti-retroviral drugs in order to reduce the selection of resistant mutants and to allow for the use of lower doses of each single agent to reduce toxicity. However, avoiding drugs interactions and patient compliance are issues not fully accomplished so far. Pursuing on our investigation on potential anti HIV multi-target agents we have designed and synthesized a small library of biphenylhydrazo 4-arylthiazoles derivatives and evaluated to investigate the ability of the new derivatives to simultaneously inhibit both associated functions of HIV reverse transcriptase. All compounds were active towards the two functions, although at different concentrations. The substitution pattern on the biphenyl moiety appears relevant to determine the activity. In particular, compound 2-{3-[(2-{4-[4-(hydroxynitroso)phenyl]-1,3-thiazol-2-yl} hydrazin-1-ylidene) methyl]-4-methoxyphenyl} benzamide bromide (EMAC2063) was the most potent towards RNaseH (IC50 = 4.5 mM)- and RDDP (IC50 = 8.0 mM) HIV RT-associated functions.

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Signature Nucleotide Polymorphisms at Positions 64 and 65 in Reverse Transcriptase Favor the Selection of the K65R Resistance Mutation in HIV‐1 Subtype C

The Journal of Infectious Diseases ◽

10.1086/605894 ◽

2009 ◽

Vol 200 (8) ◽

pp. 1202-1206 ◽

Cited By ~ 41

Author(s):

Cédric F. Invernizzi ◽

Dimitrios Coutsinos ◽

Maureen Oliveira ◽

Daniela Moisi ◽

Bluma G. Brenner ◽

...

Keyword(s):

Reverse Transcriptase ◽

Resistance Mutation ◽

Nucleotide Polymorphisms ◽

Subtype C ◽

Hiv 1 ◽

Selection Of

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Carnavalesk taalgebruik en de constructie van lokale identiteiten

Dutch Journal of Applied Linguistics ◽

10.1075/dujal.1.1.04cor ◽

2012 ◽

Vol 1 (1) ◽

pp. 15-40 ◽

Cited By ~ 3

Author(s):

Leonie M.E.A. Cornips ◽

Vincent de Rooij ◽

Irene Stengs

Keyword(s):

Interdisciplinary Approach ◽

Integrated Analysis ◽

Cultural Elements ◽

Language And Culture ◽

Norms And Values ◽

Southern Netherlands ◽

Interdisciplinary Study ◽

The City ◽

Selection Of

This article aims to encourage the interdisciplinary study of ‘languaculture,’ an approach to language and culture in which ideology, linguistic and cultural forms, as well as praxis are studied in relation to one another. An integrated analysis of the selection of linguistic and cultural elements provides insight into how these choices arise from internalized norms and values, and how people position themselves toward received categories and hegemonic ideologies. An interdisciplinary approach will stimulate a rethinking of established concepts and methods of research. It will also lead to a mutual strengthening of linguistic, sociolinguistic, and anthropological research. This contribution focuses on Limburg and the linguistic political context of this Southern-Netherlands region where people are strongly aware of their linguistic distinctiveness. The argument of the paper is based on a case study of languaculture, viz. the carnivalesque song ‘Naar Talia’ (To Italy) by the Getske Boys from the city of Heerlen.

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Relationship between Functional Profile of HIV-1 Specific CD8 T Cells and Epitope Variability with the Selection of Escape Mutants in Acute HIV-1 Infection

PLoS Pathogens ◽

10.1371/journal.ppat.1001273 ◽

2011 ◽

Vol 7 (2) ◽

pp. e1001273 ◽

Cited By ~ 75

Author(s):

Guido Ferrari ◽

Bette Korber ◽

Nilu Goonetilleke ◽

Michael K. P. Liu ◽

Emma L. Turnbull ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Functional Profile ◽

Escape Mutants ◽

Acute Hiv ◽

Hiv 1 ◽

Selection Of

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Selection of HLA-B57-associated Gag A146P mutant by HLA-B∗48:01-restricted Gag140-147-specific CTLs in chronically HIV-1-infected Japanese

Microbes and Infection ◽

10.1016/j.micinf.2011.03.009 ◽

2011 ◽

Vol 13 (8-9) ◽

pp. 766-770 ◽

Cited By ~ 1

Author(s):

Takuya Naruto ◽

Hayato Murakoshi ◽

Takayuki Chikata ◽

Madoka Koyanagi ◽

Yuka Kawashima ◽

...

Keyword(s):

Specific Ctls ◽

Hiv 1 ◽

Selection Of

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Mutations in Both the U5 Region and the Primer-Binding Site Influence the Selection of the tRNA Used for the Initiation of HIV-1 Reverse Transcription

Virology ◽

10.1006/viro.1996.0437 ◽

1996 ◽

Vol 222 (2) ◽

pp. 401-414 ◽

Cited By ~ 33

Author(s):

Sang-Moo Kang ◽

John K. Wakefield ◽

Casey D. Morrow

Keyword(s):

Binding Site ◽

Reverse Transcription ◽

Primer Binding Site ◽

Hiv 1 ◽

Selection Of

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Identification of a Structural Element in HIV-1 Gag Required for Virus Particle Assembly and Maturation

mBio ◽

10.1128/mbio.01567-18 ◽

2018 ◽

Vol 9 (5) ◽

Cited By ~ 6

Author(s):

Mariia Novikova ◽

Lucas J. Adams ◽

Juan Fontana ◽

Anna T. Gres ◽

Muthukumar Balasubramaniam ◽

...

Keyword(s):

Virus Assembly ◽

Critical Role ◽

Replication Cycle ◽

Structural Defects ◽

Fold Axis ◽

Structural Element ◽

Particle Assembly ◽

Compensatory Mutations ◽

Hiv 1 ◽

Selection Of

ABSTRACTLate in the HIV-1 replication cycle, the viral structural protein Gag is targeted to virus assembly sites at the plasma membrane of infected cells. The capsid (CA) domain of Gag plays a critical role in the formation of the hexameric Gag lattice in the immature virion, and, during particle release, CA is cleaved from the Gag precursor by the viral protease and forms the conical core of the mature virion. A highly conserved Pro-Pro-Ile-Pro (PPIP) motif (CA residues 122 to 125) [PPIP(122–125)] in a loop connecting CA helices 6 and 7 resides at a 3-fold axis formed by neighboring hexamers in the immature Gag lattice. In this study, we characterized the role of this PPIP(122–125) loop in HIV-1 assembly and maturation. While mutations P123A and P125A were relatively well tolerated, mutation of P122 and I124 significantly impaired virus release, caused Gag processing defects, and abolished infectivity. X-ray crystallography indicated that the P122A and I124A mutations induce subtle changes in the structure of the mature CA lattice which were permissive forin vitroassembly of CA tubes. Transmission electron microscopy and cryo-electron tomography demonstrated that the P122A and I124A mutations induce severe structural defects in the immature Gag lattice and abrogate conical core formation. Propagation of the P122A and I124A mutants in T-cell lines led to the selection of compensatory mutations within CA. Our findings demonstrate that the CA PPIP(122–125) loop comprises a structural element critical for the formation of the immature Gag lattice.IMPORTANCECapsid (CA) plays multiple roles in the HIV-1 replication cycle. CA-CA domain interactions are responsible for multimerization of the Gag polyprotein at virus assembly sites, and in the mature virion, CA monomers assemble into a conical core that encapsidates the viral RNA genome. Multiple CA regions that contribute to the assembly and release of HIV-1 particles have been mapped and investigated. Here, we identified and characterized a Pro-rich loop in CA that is important for the formation of the immature Gag lattice. Changes in this region disrupt viral production and abrogate the formation of infectious, mature virions. Propagation of the mutants in culture led to the selection of second-site compensatory mutations within CA. These results expand our knowledge of the assembly and maturation steps in the viral replication cycle and may be relevant for development of antiviral drugs targeting CA.

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Integrated Analysis of Residue Coevolution and Protein Structures Capture Key Protein Sectors in HIV-1 Proteins

PLoS ONE ◽

10.1371/journal.pone.0117506 ◽

2015 ◽

Vol 10 (2) ◽

pp. e0117506 ◽

Cited By ~ 9

Author(s):

Yuqi Zhao ◽

Yanjie Wang ◽

Yuedong Gao ◽

Gonghua Li ◽

Jingfei Huang

Keyword(s):

Protein Structures ◽

Integrated Analysis ◽

Hiv 1

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A Novel Genetic Pathway of Human Immunodeficiency Virus Type 1 Resistance to Stavudine Mediated by the K65R Mutation

Journal of Virology ◽

10.1128/jvi.77.10.5685-5693.2003 ◽

2003 ◽

Vol 77 (10) ◽

pp. 5685-5693 ◽

Cited By ~ 58

Author(s):

J. Gerardo García-Lerma ◽

Hamish MacInnes ◽

Diane Bennett ◽

Patrick Reid ◽

Soumya Nidtha ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Phenotypic Expression ◽

Cross Resistance ◽

Phenotypic Characterization ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Selection Of

ABSTRACT Stavudine (d4T) and zidovudine (AZT) are thymidine analogs widely used in the treatment of human immunodeficiency virus type 1 (HIV-1)-infected persons. Resistance to d4T is not fully understood, although the selection of AZT resistance mutations in patients treated with d4T suggests that both drugs have similar pathways of resistance. Through the analysis of genotypic changes in nine recombinant viruses cultured with d4T, we identified a new pathway for d4T resistance mediated by K65R, a mutation not selected by AZT. Passaged viruses were derived from treatment-naïve persons or HIV-1HXB2 and had wild-type reverse transcriptase (RT) or T215C/D mutations. K65R was selected in seven viruses and was associated with a high level of enzymatic resistance to d4T-triphosphate (median, 16-fold; range, 5- to 48-fold). The role of K65R in d4T resistance was confirmed in site-directed mutants generated in three different RT backgrounds. Phenotypic assays based on recombinant single-cycle replication or a whole-virus multiple replication cycle were unable to detect d4T resistance in d4T-selected mutants with K65R but detected cross-resistance to other nucleoside RT inhibitors. Four of the six viruses that had 215C/D mutations at baseline acquired the 215Y mutation alone or in association with K65R. Mutants having K65R and T215Y replicated less efficiently than viruses that had T215Y only, suggesting that selection of T215Y in patients treated with d4T may be favored. Our results demonstrate that K65R plays a role in d4T resistance and indicate that resistance pathways for d4T and AZT may not be identical. Biochemical analysis and improved replication assays are both required for a full phenotypic characterization of resistance to d4T. These findings highlight the complexity of the genetic pathways of d4T resistance and its phenotypic expression.

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