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

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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Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HIV Replication and PD-1 Expression on CD4+ T Cells

Viruses ◽

10.3390/v13050753 ◽

2021 ◽

Vol 13 (5) ◽

pp. 753

Author(s):

Mohammad Haque ◽

Fengyang Lei ◽

Xiaofang Xiong ◽

Yijie Ren ◽

Hao-Yun Peng ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Adoptive Transfer ◽

Cd4 T Cells ◽

Viral Antigen ◽

Peritoneal Macrophages ◽

Hiv Replication ◽

Specific Ctls ◽

Immunodeficiency Virus ◽

Hiv 1

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.

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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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Different Abilities of Escape Mutant-Specific Cytotoxic T Cells To Suppress Replication of Escape Mutant and Wild-Type Human Immunodeficiency Virus Type 1 in New Hosts

Journal of Virology ◽

10.1128/jvi.01452-07 ◽

2007 ◽

Vol 82 (1) ◽

pp. 138-147 ◽

Cited By ~ 28

Author(s):

Mamoru Fujiwara ◽

Junko Tanuma ◽

Hirokazu Koizumi ◽

Yuka Kawashima ◽

Kazutaka Honda ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Escape Mutant ◽

Wild Type ◽

Specific Ctls ◽

Immunodeficiency Virus ◽

New Hosts ◽

Hiv 1 ◽

Hla Molecules

ABSTRACT There is much evidence that in human immunodeficiency virus type 1 (HIV-1)-infected individuals, strong cytotoxic T lymphocyte (CTL)-mediated immune pressure results in the selection of HIV-1 mutants that have escaped from wild-type-specific CTLs. If escape mutant-specific CTLs are not elicited in new hosts sharing donor HLA molecules, the transmission of these mutants results in the accumulation of escape mutants in the population. However, whether escape mutant-specific CTLs are definitively not elicited in new hosts sharing donor HLA molecules still remains unclear. A previous study showed that a Y-to-F substitution at the second position (2F) of the Nef138-10 epitope is significantly detected in HLA-A*2402+ hemophilic donors. Presently, we confirmed that this 2F mutant was an escape mutant by demonstrating strong and weak abilities of Nef138-10-specific CTL clones to suppress replication of the wild-type and 2F mutant viruses, respectively. We demonstrated the existence of the 2F-specific CTLs in three new hosts who had been primarily infected with the 2F mutant. The 2F-specific CTL clones suppressed the replication of both wild-type and mutant viruses. However, the abilities of these clones to suppress replication of the 2F virus were much weaker than those of wild-type-specific and the 2F-specific ones to suppress replication of the wild-type virus. These findings indicate that the 2F mutant is conserved in HIV-1-infected donors having HLA-A*2402, because the 2F-specific CTLs failed to completely suppress the 2F mutant replication and effectively prevented viral reversion in new hosts carrying HLA-A*2402.

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Histamine increases the level of IFNγ produced by HIV-1 specific CTLs and this production depends on total IgE level

Journal of Immunological Methods ◽

10.1016/j.jim.2011.10.006 ◽

2012 ◽

Vol 375 (1-2) ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

J. Hanzlikova ◽

D. Sedlacek ◽

M. Liska ◽

J. Gorcikova ◽

T. Vlas ◽

...

Keyword(s):

Total Ige ◽

Specific Ctls ◽

Hiv 1

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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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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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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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