HIV Type 1 Protease Inhibitors Fail to Inhibit HTLV-I Gag Processing in Infected Cells

Pettit, Steve C.; Sánchez, Ricardo Rubio; Smith, Terri; Wehbie, Robert S.; Derse, David; Swanstrom, Ronald

doi:10.1089/aid.1998.14.1007

Cited by 21 publications

(16 citation statements)

References 60 publications

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“…Only compound 3 inhibited the PR up to 10 M (5). Four of the HIV-1 PR inhibitors used in clinical practice were also tested on HTLV-1 Gag processing in vitro and did not show any effect (50). These results demonstrate the large differences in specificity of the two enzymes.…”

Section: Mutations Affecting the S3/s1-binding Sites Of Htlv-1 Protease-mentioning

confidence: 88%

Narrow Substrate Specificity and Sensitivity toward Ligand-binding Site Mutations of Human T-cell Leukemia Virus Type 1 Protease

Kádas

Weber

Bagossi

et al. 2004

Journal of Biological Chemistry

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Human T-cell leukemia virus type 1 (HTLV-1) is associated with a number of human diseases; therefore, its protease is a potential target for chemotherapy. To compare the specificity of HTLV-1 protease with that of human immunodeficiency virus type 1 (HIV-1) protease, oligopeptides representing naturally occurring cleavage sites in various retroviruses were tested. The number of hydrolyzed peptides as well as the specificity constants suggested a substantially broader specificity of the HIV protease. Amino acid residues of HTLV-1 protease substrate-binding sites were replaced by equivalent ones of HIV-1 protease. Most of the single and multiple mutants had altered specificity and a dramatically reduced folding and catalytic capability, suggesting that mutations are not well tolerated in HTLV-1 protease. The catalytically most efficient mutant was that with the flap residues of HIV-1 protease. The inhibition profile of the mutants was also determined for five inhibitors used in clinical practice and inhibitor analogs of HTLV-1 cleavage sites. Except for indinavir, the HIV-1 protease inhibitors did not inhibit wild type and most of the mutant HTLV-1 proteases. The wild type HTLV-1 protease was inhibited by the reduced peptide bond-containing substrate analogs, whereas the mutants showed various degrees of weakened binding capability. Most interesting, the enzyme with HIV-1-like residues in the flap region was the most sensitive to the HIV-1 protease inhibitors and least sensitive to the HTLV-1 protease inhibitors, indicating that the flap plays an important role in defining the specificity differences of retroviral proteases.

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Section: Mutations Affecting the S3/s1-binding Sites Of Htlv-1 Protease-mentioning

confidence: 88%

Narrow Substrate Specificity and Sensitivity toward Ligand-binding Site Mutations of Human T-cell Leukemia Virus Type 1 Protease

Kádas

Weber

Bagossi

et al. 2004

Journal of Biological Chemistry

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“…Retroviral NCs perform a variety of essential functions throughout the viral life cycle, and there are many differences between HIV-1 and HTLV-1 that may explain why the CTD is retained in one case but not in the other (77)(78)(79)(80)(81). In addition, the viruses appear to have evolved different mechanisms to resist cellular restriction factors such as human APOBEC3G.…”

Section: Discussionmentioning

confidence: 99%

C-terminal Domain Modulates the Nucleic Acid Chaperone Activity of Human T-cell Leukemia Virus Type 1 Nucleocapsid Protein via an Electrostatic Mechanism

Qualley

Stewart-Maynard

Wang

et al. 2010

Journal of Biological Chemistry

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Retroviral nucleocapsid (NC) proteins are molecular chaperones that facilitate nucleic acid (NA) remodeling events critical in viral replication processes such as reverse transcription. Surprisingly, the NC protein from human T-cell leukemia virus type 1 (HTLV-1) is an extremely poor NA chaperone. Using bulk and single molecule methods, we find that removal of the anionic C-terminal domain (CTD) of HTLV-1 NC results in a protein with chaperone properties comparable with that of other retroviral NCs. Increasing the ionic strength of the solution also improves the chaperone activity of full-length HTLV-1 NC. To determine how the CTD negatively modulates the chaperone activity of HTLV-1 NC, we quantified the thermodynamics and kinetics of wild-type and mutant HTLV-1 NC/NA interactions. The wild-type protein exhibits very slow dissociation kinetics, and removal of the CTD or mutations that eliminate acidic residues dramatically increase the protein/DNA interaction kinetics. Taken together, these results suggest that the anionic CTD interacts with the cationic N-terminal domain intramolecularly when HTLV-1 NC is not bound to nucleic acids, and similar interactions occur between neighboring molecules when NC is NA-bound. The intramolecular N-terminal domain-CTD attraction slows down the association of the HTLV-1 NC with NA, whereas the intermolecular interaction leads to multimerization of HTLV-1 NC on the NA. The latter inhibits both NA/NC aggregation and rapid protein dissociation from singlestranded DNA. These features make HTLV-1 NC a poor NA chaperone, despite its robust duplex destabilizing capability. Nucleic acid (NA)5 chaperones are proteins that facilitate NA remodeling and annealing (1). Retroviral nucleocapsid proteins (NC) are essential NA chaperones (2-4) that facilitate many steps in the retroviral life cycle, including dimerization of the RNA genome (5-10), reverse transcription (11-14), annealing of the tRNA primer to the primer-binding site (7,(15)(16)(17)(18)(19)(20)(21)(22), and integration of viral DNA into the host genome (23-27). Previous work has shown that NCs from different retroviruses display a wide range of NA chaperone activities (28). A modelannealing reaction involving complementary trans-activation response element (TAR) RNA and DNA hairpins derived from the R region of the HIV-1 genome was used to characterize NCs from human immunodeficiency virus, type 1 (HIV-1), Rous sarcoma virus, murine leukemia virus, and human T-cell leukemia virus, type 1 (HTLV-1) (28). Surprisingly, the annealing activity of these NCs varies by 5 orders of magnitude; HIV-1 NC was the most efficient chaperone and HTLV-1 NC was the least efficient. A single molecule (SM) Förster resonance energy transfer (FRET) study confirmed the observation that HTLV-1 NC is a very poor NA chaperone (29).To determine the physical origin of these differences in retroviral NC chaperone activity, we measured the NA aggregation and duplex destabilization activity for each protein (28). Both of these capabilities, together with rap...

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“…Conversely, at least two studies have shown that a nucleoside analogue, such as lamivudine, known for its ability to control HIV infection, was not as effective toward HTLV-1 infection in vitro, probably due to some natural resistance (12,40). Similarly, none of the inhibitors designed to act against the HIV-1 proteinases was able to efficiently inhibit Gag processing in HTLV-1-infected cells (31).…”

Section: Discussionmentioning

confidence: 99%

Effect of Phosphonated Carbocyclic 2′-Oxa-3′-Aza-Nucleoside on Human T-Cell Leukemia Virus Type 1 Infection In Vitro

Balestrieri¹,

Matteucci

Ascolani

et al. 2008

Antimicrob Agents Chemother

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The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is an oncogenic retrovirus endemic in certain areas of the world including Japan and North and South America, where about 5% of the estimated 20 million HTLV-1-infected people develop HTLV-1-associated diseases (10,11,43), such as adult T-cell leukemia (ATL), human myelopathy/tropical spastic paraparesis (/TSP), or other minor inflammatory diseases. A number of studies have shown that HTLV-1 infects different types of cells (e.g., lymphocytes, monocytes, and fibroblasts) but preferentially T lymphocytes with a CD4 ϩ phenotype, which become immortalized following infection (26). In HTLV-1 infection viremia is essentially a "cytoviremia," since the virus is cell associated. In fact, cell-free virions are rarely infectious, and spreading of the virus in vivo does not require the extracellular release of viral particles. The spread of the virus within an individual host is most commonly recognized as being through the mitotic pathway, in which cell divisions and clonal expansion of infected cells ensure a constant level of viral load. However, recently it has been highlighted that the HTLV-1 viral load in vivo is also sustained by cell-tocell contact, involving intercellular viral spread. In particular, this "horizontal" spread allows the transfer of HTLV-1 infectious viral particles across the cell-cell junction by the generation of "virological synapses" between infected and uninfected cells (19,21). Transmission of HTLV-1 via cell-to-cell contact involves both integrin (3) and cytoskeleton proteins and participation of Env protein-cell receptor interactions (37). Either way, efficient transmission of HTLV-1 to noninfected cells implies reverse transcriptase (RT) dependency.In recent years, a number of strategies for therapeutic intervention have been pursued in the treatment of ATL or TSP, based on conventional chemotherapy or innovative approaches. However, until now, limited advances have been achieved in improving the therapy for HTLV-1-associated diseases. Therefore, symptomatic HTLV-1-infected patients still have inadequate treatment options with poor prognoses. Among the novel approaches for treating HTLV-1-related diseases, the use of topoisomerase 1 or 2 inhibitors in a pilot phase II study in refractory ATL did not provide satisfactory results (41). Similarly, treatments with the nucleoside analogue 2Ј deoxycoformycin (39) or inhibitors of AMP synthesis resulted in a limited response in ATL patients (42). Interestingly, studies based on a different strategy of chemotherapeutic intervention showed that ATL patients transiently responded to combined therapy with the nucleoside reverse transcriptase inhibitor (NRTI) azidothymidine (AZT) and interferon (IFN) (15) and that AZT treatment was beneficial to TSP patients (33), giving more encouraging results. In addition, a transient response to therapy with the NRTI lamivudine alone (38) or in combination with AZT (25) has been reported for human myelopathy/TSP. Moreover, IFN-␣ has been shown to have some ...

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HIV Type 1 Protease Inhibitors Fail to Inhibit HTLV-I Gag Processing in Infected Cells

Cited by 21 publications

References 60 publications

Narrow Substrate Specificity and Sensitivity toward Ligand-binding Site Mutations of Human T-cell Leukemia Virus Type 1 Protease

Narrow Substrate Specificity and Sensitivity toward Ligand-binding Site Mutations of Human T-cell Leukemia Virus Type 1 Protease

C-terminal Domain Modulates the Nucleic Acid Chaperone Activity of Human T-cell Leukemia Virus Type 1 Nucleocapsid Protein via an Electrostatic Mechanism

Effect of Phosphonated Carbocyclic 2′-Oxa-3′-Aza-Nucleoside on Human T-Cell Leukemia Virus Type 1 Infection In Vitro

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