Amino Acid Preferences for a Critical Substrate Binding Subsite of Retroviral Proteases in Type 1 Cleavage Sites

ABSTRACT The specificities of the proteases of 11 retroviruses representing each of the seven genera of the family Retroviridae were studied using a series of oligopeptides with amino acid substitutions in the P2 position of a naturally occurring type 1 cleavage site (Val-Ser-Gln-Asn-Tyr↓Pro-Ile-Val-Gln; the arrow indicates the site of cleavage) in human immunodeficiency virus type 1 (HIV-1). This position was previously found to be one of the most critical in determining the substrate specificity differences of retroviral proteases. Specificities at this position were compared for HIV-1, HIV-2, equine infectious anemia virus, avian myeloblastosis virus, Mason-Pfizer monkey virus, mouse mammary tumor virus, Moloney murine leukemia virus, human T-cell leukemia virus type 1, bovine leukemia virus, human foamy virus, and walleye dermal sarcoma virus proteases. Three types of P2 preferences were observed: a subgroup of proteases preferred small hydrophobic side chains (Ala and Cys), and another subgroup preferred large hydrophobic residues (Ile and Leu), while the protease of HIV-1 preferred an Asn residue. The specificity distinctions among the proteases correlated well with the phylogenetic tree of retroviruses prepared solely based on the protease sequences. Molecular models for all of the proteases studied were built, and they were used to interpret the results. While size complementarities appear to be the main specificity-determining features of the S2 subsite of retroviral proteases, electrostatic contributions may play a role only in the case of HIV proteases. In most cases the P2 residues of naturally occurring type 1 cleavage site sequences of the studied proteases agreed well with the observed P2 preferences.

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Amino Acid Preferences of Retroviral Proteases for Amino-Terminal Positions in a Type 1 Cleavage Site

Journal of Virology ◽

10.1128/jvi.00418-08 ◽

2008 ◽

Vol 82 (20) ◽

pp. 10111-10117 ◽

Cited By ~ 18

Author(s):

Helga Eizert ◽

Pálma Bander ◽

Péter Bagossi ◽

Tamás Sperka ◽

Gabriella Miklóssy ◽

...

Keyword(s):

Amino Acid ◽

Virus Type ◽

Cleavage Site ◽

Equine Infectious Anemia Virus ◽

Leukemia Virus ◽

Foamy Virus ◽

Amino Terminal ◽

Retroviral Proteases ◽

Hiv 1

ABSTRACT The specificities of the proteases of 11 retroviruses were studied using a series of oligopeptides with amino acid substitutions in the P1, P3, and P4 positions of a naturally occurring type 1 cleavage site (Val-Ser-Gln-Asn-Tyr↓Pro-Ile-Val-Gln) in human immunodeficiency virus type 1 (HIV-1). Previously, the substrate specificity of the P2 site was studied for the same representative set of retroviral proteases, which included at least one member from each of the seven genera of the family Retroviridae (P. Bagossi, T. Sperka, A. Fehér, J. Kádas, G. Zahuczky, G. Miklóssy, P. Boross, and J. Tözsér, J. Virol. 79:4213-4218, 2005). Our enzyme set comprised the proteases of HIV-1, HIV-2, equine infectious anemia virus, avian myeloblastosis virus (AMV), Mason-Pfizer monkey virus, mouse mammary tumor virus (MMTV), Moloney murine leukemia virus, human T-lymphotropic virus type 1, bovine leukemia virus, walleye dermal sarcoma virus, and human foamy virus. Molecular models were used to interpret the similarities and differences in specificity between these retroviral proteases. The results showed that the retroviral proteases had similar preferences (Phe and Tyr) for the P1 position in this sequence context, but differences were found for the P3 and P4 positions. Importantly, the sizes of the P3 and P4 residues appear to be a major contributor for specificity. The substrate specificities correlated well with the phylogenetic tree of the retroviruses. Furthermore, while the specificities of some enzymes belonging to different genera appeared to be very similar (e.g., those of AMV and MMTV), the specificities of the primate lentiviral proteases substantially differed from that observed for a nonprimate lentiviral protease.

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Naturally Occurring Amino Acid Polymorphisms in Human Immunodeficiency Virus Type 1 (HIV-1) Gag p7NC and the C-Cleavage Site Impact Gag-Pol Processing by HIV-1 Protease

Virology ◽

10.1006/viro.2001.1184 ◽

2002 ◽

Vol 292 (1) ◽

pp. 137-149 ◽

Cited By ~ 11

Author(s):

Maureen M. Goodenow ◽

Gregory Bloom ◽

Stephanie L. Rose ◽

Steven M. Pomeroy ◽

Patricia O. O'Brien ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Amino Acid ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Cleavage Site ◽

Naturally Occurring ◽

Immunodeficiency Virus ◽

Hiv 1

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Analysis of the Interaction of Primate Retroviruses with the Human RNA Interference Machinery

Journal of Virology ◽

10.1128/jvi.01390-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12218-12226 ◽

Cited By ~ 127

Author(s):

Jennifer Lin ◽

Bryan R. Cullen

Keyword(s):

Rna Interference ◽

Virus Type ◽

Leukemia Virus ◽

Foamy Virus ◽

Human Cells ◽

Small Interfering Rnas ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

Hiv 1

ABSTRACT The question of whether retroviruses, including human immunodeficiency virus type 1 (HIV-1), interact with the cellular RNA interference machinery has been controversial. Here, we present data showing that neither HIV-1 nor human T-cell leukemia virus type 1 (HTLV-1) expresses significant levels of either small interfering RNAs or microRNAs in persistently infected T cells. We also demonstrate that the retroviral nuclear transcription factors HIV-1 Tat and HTLV-1 Tax, as well as the Tas transactivator encoded by primate foamy virus, fail to inhibit RNA interference in human cells. Moreover, the stable expression of physiological levels of HIV-1 Tat did not globally inhibit microRNA production or expression in infected human cells. Together, these data argue that HIV-1 and HTLV-1 neither induce the production of viral small interfering RNAs or microRNAs nor repress the cellular RNA interference machinery in infected cells.

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Human Immunodeficiency Virus Type 1 Resistance to the Small Molecule Maturation Inhibitor 3-O-(3′,3′-Dimethylsuccinyl)-Betulinic Acid Is Conferred by a Variety of Single Amino Acid Substitutions at the CA-SP1 Cleavage Site in Gag

Journal of Virology ◽

10.1128/jvi.01626-06 ◽

2006 ◽

Vol 80 (24) ◽

pp. 12095-12101 ◽

Cited By ~ 45

Author(s):

Jing Zhou ◽

Chin Ho Chen ◽

Christopher Aiken

Keyword(s):

Human Immunodeficiency Virus ◽

Amino Acid ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Betulinic Acid ◽

Cleavage Site ◽

Amino Acid Substitutions ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The compound 3-O-(3′,3′-dimethylsuccinyl)-betulinic acid (DSB) potently and specifically inhibits human immunodeficiency virus type 1 (HIV-1) replication by delaying the cleavage of the CA-SP1 junction in Gag, leading to impaired maturation of the viral core. In this study, we investigated HIV-1 resistance to DSB by analyzing HIV-1 mutants encoding a variety of individual amino acid substitutions in the CA-SP1 cleavage site. Three of the substitutions were lethal to HIV-1 replication owing to a deleterious effect on particle assembly. The remaining mutants exhibited a range of replication efficiencies; however, each mutant was capable of replicating in the presence of concentrations of DSB that effectively inhibited wild-type HIV-1. Mutations conferring resistance to DSB also led to impaired binding of the compound to immature HIV-1 virions and loss of DSB-mediated inhibition of cleavage of Gag. Surprisingly, two of the DSB-resistant mutants retained an intermediate ability to bind the compound, suggesting that binding of DSB to immature HIV-1 particles may not be sufficient for antiviral activity. Overall, our results indicate that Gag amino acids L363 and A364 are critical for inhibition of HIV-1 replication by DSB and suggest that these residues form key contacts with the drug in the context of the assembling HIV-1 particle. These results have implications for the design of and screening for novel inhibitors of HIV-1 maturation.

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The Eukaryotic Translation Initiation Factor 4GI Is Cleaved by Different Retroviral Proteases

Journal of Virology ◽

10.1128/jvi.77.23.12392-12400.2003 ◽

2003 ◽

Vol 77 (23) ◽

pp. 12392-12400 ◽

Cited By ~ 53

Author(s):

Enrique Álvarez ◽

Luis Menéndez-Arias ◽

Luis Carrasco

Keyword(s):

Protein Synthesis ◽

Virus Type ◽

Leukemia Virus ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Intact Cells ◽

Immunodeficiency Virus ◽

Retroviral Proteases ◽

Hiv 1

ABSTRACT The initiation factor eIF4G plays a central role in the regulation of translation. In picornaviruses, as well as in human immunodeficiency virus type 1 (HIV-1), cleavage of eIF4G by the viral protease leads to inhibition of protein synthesis directed by capped cellular mRNAs. In the present work, cleavage of both eIF4GI and eIF4GII has been analyzed by employing the proteases encoded within the genomes of several members of the family Retroviridae, e.g., Moloney murine leukemia virus (MoMLV), mouse mammary tumor virus, human T-cell leukemia virus type 1, HIV-2, and simian immunodeficiency virus. All of the retroviral proteases examined were able to cleave the initiation factor eIF4GI both in intact cells and in cell-free systems, albeit with different efficiencies. The eIF4GI hydrolysis patterns obtained with HIV-1 and HIV-2 proteases were very similar to each other but rather different from those obtained with MoMLV protease. Both eIF4GI and eIF4GII were cleaved very efficiently by the MoMLV protease. However, eIF4GII was a poor substrate for HIV proteases. Proteolytic cleavage of eIF4G led to a profound inhibition of cap-dependent translation, while protein synthesis driven by mRNAs containing internal ribosome entry site elements remained unaffected or was even stimulated in transfected cells.

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Serological survey of HIV-1, HIV-2 and human T-cell leukemia virus type 1 for suspected AIDS cases in Ghana

AIDS ◽

10.1097/00002030-199409000-00006 ◽

1994 ◽

Vol 8 (9) ◽

pp. 1257-1261 ◽

Cited By ~ 13

Author(s):

Osamu Hishida ◽

Nana K. Ayisi ◽

Michael Aidoo ◽

James Brandful ◽

William Ampofo ◽

...

Keyword(s):

T Cell ◽

Virus Type ◽

Leukemia Virus ◽

Serological Survey ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

T Cell Leukemia Virus ◽

Hiv 1

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Extensive editing of a small fraction of human T-cell leukemia virus type 1 genomes by four APOBEC3 cytidine deaminases

Journal of General Virology ◽

10.1099/vir.0.80973-0 ◽

2005 ◽

Vol 86 (9) ◽

pp. 2489-2494 ◽

Cited By ~ 67

Author(s):

Renaud Mahieux ◽

Rodolphe Suspène ◽

Frédéric Delebecque ◽

Michel Henry ◽

Olivier Schwartz ◽

...

Keyword(s):

T Cell ◽

Virus Type ◽

Leukemia Virus ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Cytidine Deaminases ◽

Human T Cell ◽

T Cell Leukemia Virus ◽

Hiv 1

In the absence of the human immunodeficiency virus type 1 (HIV-1) Vif protein, the host-cell cytidine deaminases APOBEC3F and -3G are co-packaged along with virion RNA. Upon infection of target cells, nascent single-stranded DNA can be edited extensively, invariably giving rise to defective genomes called G→A hypermutants. Although human T-cell leukemia virus type 1 (HTLV-1) replicates in the same cell type as HIV-1, it was shown here that HTLV-1 is relatively resistant to the antiviral effects mediated by human APOBEC3B, -3C, -3F and -3G. Nonetheless, a small percentage of genomes (0·1<f<5 %) were edited extensively: up to 97 % of cytidine targets were deaminated. In contrast, hypermutated HTLV-1 genomes were not identified in peripheral blood mononuclear cell DNA from ten patients with non-malignant HTLV-1 infection. Thus, although HTLV-1 DNA can indeed be edited by at least four APOBEC3 cytidine deaminases in vitro, they are conspicuously absent in vivo.

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A Multifunctional Domain in Human CRM1 (Exportin 1) Mediates RanBP3 Binding and Multimerization of Human T-Cell Leukemia Virus Type 1 Rex Protein

Molecular and Cellular Biology ◽

10.1128/mcb.23.23.8751-8761.2003 ◽

2003 ◽

Vol 23 (23) ◽

pp. 8751-8761 ◽

Cited By ~ 21

Author(s):

Yoshiyuki Hakata ◽

Masami Yamada ◽

Hisatoshi Shida

Keyword(s):

Amino Acid ◽

T Cell ◽

Virus Type ◽

Leukemia Virus ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Human T Cell ◽

T Cell Leukemia Virus

ABSTRACT Human CRM1 (hCRM1) functions in the Rex-mediated mRNA export of human T-cell leukemia virus type 1 (HTLV-1) as an export receptor and as an inducing factor for Rex multimerization on its cognate RNA. Although there are only 24 amino acid differences between hCRM1 and rat CRM1 (rCRM1), rCRM1 can hardly support Rex activity, suggesting a role for rCRM1 as a determinant restricting the host range of HTLV-1. Here, we used a series of mutants, which were generated by interchanging residues of these CRM1s, to examine the relationship of hCRM1 functions. The functions for Rex multimerization and binding to nuclear export signals are mapped to different amino acid residues, and these are separable, suggesting that CRM1 not only functions as an export receptor but also participates in the formation of the RNA export complex through higher-ordered interaction with Rex. The region for the interaction with RanBP3, comprising four residues (amino acids [aa] 411, 414, 474, and 481), and the region for Rex multimerization, including two residues (aa 411 and 414), form an overlapped domain. Our results provide the molecular basis underlying the species-specific ability of HTLV-1 to propagate in human cells.

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Conservation of a Neutralization Epitope of Human T-cell Leukemia Virus Type 1 (HTLV-1) among Currently Endemic Clinical Isolates in Okinawa, Japan

Pathogens ◽

10.3390/pathogens9020082 ◽

2020 ◽

Vol 9 (2) ◽

pp. 82

Author(s):

Mariko Mizuguchi ◽

Yoshiaki Takahashi ◽

Reiko Tanaka ◽

Takuya Fukushima ◽

Yuetsu Tanaka

Keyword(s):

Amino Acid ◽

T Cell ◽

Virus Type ◽

Leukemia Virus ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Neutralization Epitope ◽

Human T Cell ◽

T Cell Leukemia Virus

Approximately one-tenth of the 10 million individuals living with human T-cell leukemia virus type-1 (HTLV-1) worldwide live in Japan. Most of these infected individuals live in the southwest region of Japan, including Okinawa prefecture; however, currently no prophylactic vaccine against HTLV-1 infection is available. For preventing the HTLV-1 spread, we previously generated a humanized monoclonal antibody (hu-LAT-27) that mediates both neutralization and antibody-dependent cellular cytotoxicity (ADCC). The neutralization epitope of LAT-27 is a linear amino acid sequence from residue 191 to 196 (Leu-Pro-His-Ser-Asn-Leu) of the HTLV-1 envelope gp46 protein. Here, we found that the LAT-27 epitope is well conserved among HTLV-1 clinical isolates prevalent in Okinawa. The hu-LAT-27 treatment inhibited syncytium formation by these clinical HTLV-1 isolates. Although an amino acid substitution at residue 192 in the LAT-27 epitope from proline to serine was found in a few HTLV-1 isolates, hu-LAT-27 could still react with a synthetic peptide carrying this amino acid substitution. These findings demonstrate the wide spectrum of hu-LAT-27 reactivity, suggesting that hu-LAT-27 may be a candidate drug for prophylactic passive immunization against HTLV-1 infection.

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