scholarly journals HIV-1 Mutants that Escape the Cytotoxic T-Lymphocytes are Defective in Viral DNA Integration

2021 ◽  
Author(s):  
Muthukumar Balasubramaniam ◽  
Santosh Thapa ◽  
Benem-Orom Davids ◽  
Alex Bryer ◽  
Chaoyi Xu ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Human Leukocyte ◽  
Virus Infectivity ◽  
Viral Dna ◽  
Ctl Response ◽  
Dna Integration ◽  
Viral Dna Integration ◽  
Hiv 1 ◽  
Selection Of

ABSTRACTHIV-1 replication is durably controlled in certain untreated HIV-1-infected individuals expressing particular human leukocyte antigens (HLA). These HLAs tag infected cells for elimination by presenting specific viral epitopes to CD8+ cytotoxic T-lymphocytes (CTL). In individuals expressing HLA-B27, CTLs primarily target the capsid protein (CA)-derived KK10 epitope. Selection of CA mutation R264K helps HIV-1 escape the CTL response but severely diminishes virus infectivity. Here we report that the R264K mutation-associated infectivity defect arises primarily from impaired viral DNA integration. Strikingly, selection of the compensatory CA mutation S173A or depletion of host cyclophilin A largely rescues the R264K-associated integration and infectivity defects. Collectively, our study reveals novel mechanistic insights into the fitness defect incurred by an HIV-1 variant escaping a CA-directed CTL response.

Isolation of HIV-1-specific cytotoxic T lymphocytes using human leukocyte antigen-coated beads

AIDS ◽  
1999 ◽  
Vol 13 (14) ◽  
pp. 1991 ◽  
Author(s):  
Graham S. Ogg ◽  
Abigail S. King ◽  
P. Rod Dunbar ◽  
Andrew J. McMichael
Keyword(s):  
T Lymphocytes ◽  
Human Leukocyte Antigen ◽  
Cytotoxic T Lymphocytes ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Hiv 1

scholarly journals APOBEC3F and APOBEC3G Inhibit HIV-1 DNA Integration by Different Mechanisms

2010 ◽  
Vol 84 (10) ◽  
pp. 5250-5259 ◽  
Author(s):  
Jean L. Mbisa ◽  
Wei Bu ◽  
Vinay K. Pathak
Keyword(s):  
Catalytic Domain ◽  
Restriction Factors ◽  
Viral Dna ◽  
Dna Integration ◽  
Host Restriction ◽  
Antiviral Activities ◽  
Viral Cdna ◽  
Viral Dna Integration ◽  
Cytidine Deamination ◽  
Hiv 1

ABSTRACT APOBEC3F (A3F) and APBOBEC3G (A3G) both are host restriction factors that can potently inhibit human immunodeficiency virus type 1 (HIV-1) replication. Their antiviral activities are at least partially mediated by cytidine deamination, which causes lethal mutations of the viral genome. We recently showed that A3G blocks viral plus-strand DNA transfer and inhibits provirus establishment in the host genome (J. L. Mbisa, R. Barr, J. A. Thomas, N. Vandegraaff, I. J. Dorweiler, E. S. Svarovskaia, W. L. Brown, L. M. Mansky, R. J. Gorelick, R. S. Harris, A. Engelman, and V. K. Pathak, J. Virol. 81:7099-7110, 2007). Here, we investigated whether A3F similarly interferes with HIV-1 provirus formation. We observed that both A3F and A3G inhibit viral DNA synthesis and integration, but A3F is more potent than A3G in preventing viral DNA integration. We further investigated the mechanisms by which A3F and A3G block viral DNA integration by analyzing their effects on viral cDNA processing using Southern blot analysis. A3G generates a 6-bp extension at the viral U5 end of the 3′ long terminal repeat (3′-LTR), which is a poor substrate for integration; in contrast, A3F inhibits viral DNA integration by reducing the 3′ processing of viral DNA at both the U5 and U3 ends. Furthermore, we demonstrated that a functional C-terminal catalytic domain is more critical for A3G than A3F function in blocking HIV-1 provirus formation. Finally, we showed that A3F has a greater binding affinity for a viral 3′-LTR double-stranded DNA (dsDNA) oligonucleotide template than A3G. Taking these results together, we demonstrated that mechanisms utilized by A3F to prevent HIV-1 viral DNA integration were different from those of A3G, and that their target specificities and/or their affinities for dsDNA may contribute to their distinct mechanisms.

scholarly journals Contribution of Host Nucleoporin 62 in HIV-1 Integrase Chromatin Association and Viral DNA Integration

2012 ◽  
Vol 287 (13) ◽  
pp. 10544-10555 ◽  
Author(s):  
Zhujun Ao ◽  
Kallesh Danappa Jayappa ◽  
Binchen Wang ◽  
Yingfeng Zheng ◽  
Xiaoxia Wang ◽  
...  
Keyword(s):  
Viral Dna ◽  
Dna Integration ◽  
Viral Dna Integration ◽  
Hiv 1

scholarly journals Different In Vivo Effects of HIV-1 Immunodominant Epitope-Specific Cytotoxic T Lymphocytes on Selection of Escape Mutant Viruses

2010 ◽  
Vol 84 (11) ◽  
pp. 5508-5519 ◽  
Author(s):  
Hirokazu Koizumi ◽  
Masao Hashimoto ◽  
Mamoru Fujiwara ◽  
Hayato Murakoshi ◽  
Takayuki Chikata ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Neutralizing Antibodies ◽  
Escape Mutant ◽  
Escape Mutants ◽  
Hiv 1 ◽  
Selection Of ◽  
Strong Ability

ABSTRACT HIV-1 escape mutants are well known to be selected by immune pressure via HIV-1-specific cytotoxic T lymphocytes (CTLs) and neutralizing antibodies. The ability of the CTLs to suppress HIV-1 replication is assumed to be associated with the selection of escape mutants from the CTLs. Therefore, we first investigated the correlation between the ability of HLA-A*1101-restricted CTLs recognizing immunodominant epitopes in vitro and the selection of escape mutants. The result showed that there was no correlation between the ability of these CTLs to suppress HIV-1 replication in vitro and the appearance of escape mutants. The CTLs that had a strong ability to suppress HIV-1 replication in vitro but failed to select escape mutants expressed a higher level of PD-1 in vivo, whereas those that had a strong ability to suppress HIV-1 replication in vitro and selected escape mutants expressed a low level of PD-1. Ex vivo analysis of these CTLs revealed that the latter CTLs had a significantly stronger ability to recognize the epitope than the former ones. These results suggest that escape mutations are selected by HIV-1-specific CTLs that have a stronger ability to recognize HIV-1 in vivo but not in vitro.

scholarly journals Capsid-CPSF6 Interaction Licenses Nuclear HIV-1 Trafficking to Sites of Viral DNA Integration

2018 ◽  
Vol 24 (3) ◽  
pp. 392-404.e8 ◽  
Author(s):  
Vasudevan Achuthan ◽  
Jill M. Perreira ◽  
Gregory A. Sowd ◽  
Maritza Puray-Chavez ◽  
William M. McDougall ◽  
...  
Keyword(s):  
Viral Dna ◽  
Dna Integration ◽  
Viral Dna Integration ◽  
Hiv 1

scholarly journals Transcriptional Coactivator LEDGF/p75 Modulates Human Immunodeficiency Virus Type 1 Integrase-Mediated Concerted Integration

2007 ◽  
Vol 81 (8) ◽  
pp. 3969-3979 ◽  
Author(s):  
Krishan K. Pandey ◽  
Sapna Sinha ◽  
Duane P. Grandgenett
Keyword(s):  
Human Immunodeficiency Virus ◽  
Transcriptional Coactivator ◽  
Viral Dna ◽  
Dna Integration ◽  
Molar Ratios ◽  
Immunodeficiency Virus ◽  
Synaptic Complexes ◽  
Viral Dna Integration ◽  
Hiv 1

ABSTRACT Human transcriptional coactivator p75/lens epithelium-derived growth factor (LEDGF) binds human immunodeficiency virus type 1 (HIV-1) integrase (IN). We studied the effects of LEDGF on the assembly and activity of HIV-1 synaptic complexes, which, upon association with a target, mediate concerted integration of viral DNA substrates in vitro. We found that while augmenting single-ended viral DNA integration into target DNA, the host factor was able to either stimulate or abrogate concerted integration in a concentration-dependent manner. LEDGF modestly stimulated (two- to threefold) concerted integration at low molar ratios to IN (<1). The modest stimulation was independent of solution conditions and several different viral DNA substrates. In solution, concerted integration was inhibited if the molar ratios of LEDGF to IN were >1, apparently due to the disruption of IN-IN interactions essential for the formation of active synaptic complexes prior to their association with a circular target. The isolated IN binding domain of LEDGF was sufficient to stimulate and inhibit concerted integration, as observed with full-length protein, albeit at lower efficiencies. Our data show that LEDGF differentially affects IN-DNA complexes mediating single-ended viral DNA integration and synaptic complexes mediating concerted integration. Synaptic complexes associated with target, termed strand transfer complexes, are resistant to disruption by high concentrations of LEDGF. The results suggest that LEDGF may influence HIV-1 integration in vivo.

scholarly journals Selection of escape mutant by HLA-C-restricted HIV-1 Pol-specific cytotoxic T lymphocytes carrying strong ability to suppress HIV-1 replication

2010 ◽  
Vol 41 (1) ◽  
pp. 97-106 ◽  
Author(s):  
Kazutaka Honda ◽  
Nan Zheng ◽  
Hayato Murakoshi ◽  
Masao Hashimoto ◽  
Keiko Sakai ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Escape Mutant ◽  
Hiv 1 ◽  
Selection Of ◽  
Strong Ability

scholarly journals High frequency of cross-reactive cytotoxic T lymphocytes elicited during the virus-induced polyclonal cytotoxic T lymphocyte response.

1993 ◽  
Vol 177 (2) ◽  
pp. 317-327 ◽  
Author(s):  
S R Nahill ◽  
R M Welsh
Keyword(s):  
T Lymphocytes ◽  
Virus Infection ◽  
Cytotoxic T Lymphocytes ◽  
High Frequency ◽  
Class Ii ◽  
Class I ◽  
Direct Stimulation ◽  
Ctl Response ◽  
Cd4 Cell ◽  
Stimulation Of

Polyclonal stimulation of CD8+ cytotoxic T lymphocytes (CTL) occurs during infection with many viruses including those not known to transform CTL or encode superantigens. This polyclonal CTL response includes the generation of high levels of allospecific CTL directed against many class I haplotypes. In this report we investigated whether the allospecific CTL generated during an acute lymphocytic choriomeningitis virus (LCMV) infection of C57BL/6 mice were stimulated specifically by antigen recognition or nonspecifically by polyclonal mechanisms possibly involving lymphokines or superantigens. An examination of the ability of different strains of mice to induce high levels of CTL specific for a given alloantigen showed that most, but not all, strains generated high levels of allospecific CTL, and that their abilities to generate them mapped genetically to the major histocompatibility complex locus, exclusive of the class II region. This indicated that the virus-induced allospecific CTL generation was independent of the class II allotype, and mice depleted of CD4+ cells generated allospecific CTL, indicating independence of class II-CD4+ cell interactions and resulting CD4+ cell-secreted lymphokines. FACS staining with a variety of V beta-binding antibodies did not show a superantigen-like depletion or enrichment of any tested V beta + subset during infection. Several experiments provided evidence in support of direct stimulation of CD8+ cells via the T cell receptor: (a) both virus- and allo-specific killing were enriched within a given V beta subpopulation; (b) relative CTL precursor frequencies against different class I alloantigens changed during the course of virus infection; (c) the relative levels of virus-induced, allospecific CTL-mediated lysis at day 8 after infection did not parallel the CTL precursor frequencies before infection; and (d) limiting dilution analyses of day 8 LCMV-infected spleen cells stimulated by virus-infected syngeneic peritoneal exudate cells (PEC) revealed not only the expected virus-specific CTL clones, but also a high frequency of clones that were cross-reactive with allogeneic and virus-infected syngeneic targets. In addition to the virus cross-reactive allospecific CTL clones, virus-infected PEC also stimulated the generation of some allospecific clones that did not lyse virus-infected fibroblasts. Surprisingly, LCMV-infected PEC were much more efficient at stimulating allospecific CTL clones from day 8 LCMV-infected splenocytes than were allogeneic stimulators. These results indicate that at least part of the polyclonal allospecific CTL response elicited by acute virus infection is a consequence of the selective expansion of many clones of allospecific CTL which cross-react with virus-infected cells.(ABSTRACT TRUNCATED AT 400 WORDS)

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