Functional Characterization of the Protease of Human Endogenous Retrovirus, K10:  Can It Complement HIV-1 Protease?

Towler, Eric M.; Gulnik, Sergei V.; Bhat, Talapady N.; Xie, Donghua; Gustschina, Elena; Sumpter, Terry R.; Robertson, Nicole; Jones, Christopher; Sauter, Marlies; Mueller‐Lantzsch, Nikolaus; Debouck, Christine; Erickson, John W.

doi:10.1021/bi9818927

Cited by 50 publications

(65 citation statements)

References 23 publications

(30 reference statements)

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“…The site of N-terminal autoprocessing was determined with N-terminal amino acid sequencing. It was shown to be GKAAY-WASQ with the dash designating the scissile bond and was in agreement with previous findings (25). When analyzed with mass spectroscopy, the protein showed a molecular mass that was in agreement with the expected size and that also suggested that no C-terminal autoprocessing occurred (data not shown).…”

Section: Expression and Purification Of Herv-k10supporting

confidence: 90%

“…DNA coding for core region of HERV-K10 protease (25) was then amplified by polymerase chain reaction with Taq DNA polymerase (PerkinElmer Life Sciences). Oligonucleotides 5Ј-CTAGGAAGCTTCA-TATGGACTATAAAGGCGAAATTCAA-3Ј (PRT-A) and 5Ј-GCTGTGG-ATCCTTACTACATGGTGATTTCCGCACC-3Ј (PRT-B) were used as sense and antisense primer, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Cloning of the Full-length Version of HERV-K10 Protease-The cloning of the full-length version of HERV-K10 protease into pET21a(ϩ) and its site-directed mutagenesis was described previously (25).…”

Section: Methodsmentioning

confidence: 99%

“…3. The C-terminal boundary of the truncated version was chosen on the basis of sequence homology with the mature HIV-1 protease (25). An additional 58 amino acid residues included at the N-terminal end of the protein were expected to be cleaved off in an autocatalytic manner.…”

Section: Expression and Purification Of Herv-k10mentioning

confidence: 99%

“…In the study published by Sauter et al (16), authors reported that HIV-1-infected patients and especially patients with seminomas exhibit elevated titers of anti-HERV-K10 Gag antibodies. Towler et al (25) reported that HERV-K10 protease is highly resistant to a number of clinically used HIV-1 protease inhibitors, including ritonavir, indinavir, and saquinavir.…”

mentioning

confidence: 99%

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Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

Kuhelj¹,

Rizzo²,

Chang

et al. 2001

Journal of Biological Chemistry

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A full-length and C-terminally truncated version of human endogenous retrovirus (HERV)-K10 protease were expressed in Escherichia coli and purified to homogeneity. Both versions of the protease efficiently processed HERV-K10 Gag polyprotein substrate. HERV-K10 Gag was also cleaved by human immunodeficiency virus, type 1 (HIV-1) protease, although at different sites. To identify compounds that could inhibit protein processing dependent on the HERV-K10 protease, a series of cyclic ureas that had previously been shown to inhibit HIV-1 protease was tested. Several symmetric bisamides acted as very potent inhibitors of both the truncated and full-length form of HERV-K10 protease, in subnanomolar or nanomolar range, respectively. One of the cyclic ureas, SD146, can inhibit the processing of in vitro translated HERV-K10 Gag polyprotein substrate by HERV-K10 protease. In addition, in virus-like particles isolated from the teratocarcinoma cell line NCCIT, there is significant accumulation of Gag and Gag-Pol precursors upon treatment with SD146, suggesting the compound efficiently blocks HERV-K Gag processing in cells. This is the first report of an inhibitor able to block cell-associated processing of Gag polypeptides of an endogenous retrovirus.

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Section: Expression and Purification Of Herv-k10supporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Expression and Purification Of Herv-k10mentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

Kuhelj¹,

Rizzo²,

Chang

et al. 2001

Journal of Biological Chemistry

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Increased immunoglobulin G, but not M, binding to endogenous retroviral antigens in HIV-1 infected persons

et al. 2000

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The modes of interaction between products of human endogenous retroviral (HERV) sequences and the immune system are largely unknown. In HIV infected persons, an exogenous retrovirus adds further complexity to the situation. Therefore, 14 synthetic peptides with sequences derived from conserved regions of various endogenous retroviruses (ERVs) and from related exogenous retroviruses were used to search for IgG and IgM antibodies that bind to such antigens in 15 HIV-1 seropositive and 17 seronegative immunosuppressed patients. IgG binding to three peptides, namely, the C-terminal half of murine leukemia virus (MLV) capsid protein, the conserved portion of HERV-H transmembrane protein, and the Pol region of human mouse mammary tumor virus (MMTV)-like (HML3) sequence, was observed in both groups. Binding was, however, more frequent and more firm in HIV-1 positive samples (P<0.0001, Wilcoxon rank sum test). IgM binding to the same peptides showed no significant differentiation between the two groups of patients. Binding to both immunoglobulin isotypes was sometimes variable over time in both groups. No correlation of either IgG or IgM peptide binding with progression to AIDS in HIV-1 infected individuals was observed. Inhibition studies using analogous endogenous and exogenous retroviral peptides, including HIV-1, demonstrated specificity of the IgG antibodies for a narrow range of MLV- and MMTV-like retroviral antigens, and excluded cross-reactivity of antibodies to HIV-1 as a cause of these observations. Thus, unlike IgG, IgM binding to retroviral antigens was ubiquitous. It is suggested that anti-HERV IgM belong to a class of natural antibodies and might serve as primers in the mediation of humoral immune responses to more or less related exogenous retroviruses. Increased IgG binding in HIV-1 infected individuals could result from such priming, or reflect higher HERV antigen expression.

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Development of human endogenous retrovirus type K‐ related treatments for human diseases

Dai,

Fan,

Qin

2024

Journal of Medical Virology

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Human endogenous retroviruses (HERVs) constitute approximately 8% of the human genome and have long been regarded as silent passengers within our genomes. However, the reactivation of HERVs has been increasingly linked to a range of human diseases, particularly the HERV‐K (HML‐2) family. Many studies are dedicated to elucidating the potential role of HERV‐K in pathogenicity. While the underlying mechanisms require further investigation, targeting HERV‐K transactivation emerges as a promising avenue for treating human diseases, including cancer, autoimmune disorders, neurodegenerative conditions, and infectious diseases. In this review, we summarize recent advancements in the development of HERV‐K‐targeted therapeutic strategies against various human diseases, including antiretroviral drugs, immunotherapy, and vaccines.

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Functional Characterization of the Protease of Human Endogenous Retrovirus, K10: Can It Complement HIV-1 Protease?

Cited by 50 publications

References 23 publications

Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

Increased immunoglobulin G, but not M, binding to endogenous retroviral antigens in HIV-1 infected persons

Development of human endogenous retrovirus type K‐ related treatments for human diseases

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