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Antimicrobial Agents and Chemotherapy, May 2003, p. 1774-1775, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1774-1775.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

Lamivudine Resistance in Human T-Cell Leukemia Virus Type 1 May Be Due to a Polymorphism at Codon 118 (V->I) of the Reverse Transcriptase


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In a recent report, Balestrieri et al. (1) asserted that the effect of lamivudine (3TC) against human T-cell leukemia virus type 1 (HTLV-1) at therapeutic concentrations is seen mainly on cell proliferation, with little or no direct antiviral effect. These findings are supported by biochemical studies that have shown a high level of 3TC resistance by the reverse transcriptase (RT) of HTLV-1 (3). We and others have examined the efficacy of 3TC in HTLV-1-infected patients with HTLV-1-associated myelopathy-tropical spastic paraparesis (6, 8). In most of these patients, we saw a reduction in HTLV-1 proviral DNA load following several weeks of therapy. However, in almost all cases this decline in HTLV-1 viremia was transient and most patients regained baseline HTLV-1 load titers after a while. Despite experiencing virological failure, only silent mutations and few amino acid changes in the HTLV-1 RT could be recognized after extensive analyses, which hardly could explain high levels of 3TC resistance. Furthermore, none of the HTLV-1-positive patients examined so far have developed genetic changes during therapy with 3TC in the conserved LPQG (Q151 M) or YMDD (M184V) motifs, which are associated with resistance to this drug in other lentiviruses (7). Taken together, these data suggest that HTLV-1 RT presents primary resistance to 3TC, and codons other than 151 or 184 could be implicated.

In human immunodeficiency virus type 1 (HIV-1), a novel set of mutations in the RT, E44D and V118I, has been reported to produce 3TC resistance in the absence of the M184V mutation (5). In order to examine the possible role of these mutations in HTLV-1, we compared the amino acid sequence of the pol gene of HTLV-1 (GenBank D13784) and subtype B HIV-1 (HXB2; GenBank K03455). Alignment was performed with the CLUSTAL X program. Whereas the aspartic acid at residue 44 was not found in the HTLV-1 RT, 118I was recognized as the consensus amino acid in HTLV-1.

In vitro studies of HIV-1 have shown that an isoleucine at position 118 decreases the rate of 3TC incorporation, and this reduction does not depend on the presence of classical AZT mutations (M. Girouard, K. Diallo, B. Marchand, S. McCormick, M. A. Wainberg, and M. Götte, XI Int. HIV Drug Resist. Workshop, Seville, Spain, abstr. 26, 2002). Resistance to 3TC develops when less of the drug monophosphate gets incorporated into the nascent cDNA due to steric conformation changes in the RT. In contrast, resistance to AZT and many other nucleoside analogs develops mainly as result of pyrophosphorolysis, by which there is an increased excision and removal of the incorporated chain terminator nucleotides (2). The V118I mutation produces an alteration of the structure-dependent binding in the HIV-1 RT which translates into lower affinity for 3TC. Although HIV-1 and HTLV-1 share only ~20% of amino acid sequence identity, their RT enzymes are quite similar. In fact, RTs from almost all lentiviruses share similar tertiary structures in palm and finger domains, in spite of high divergence in their amino acid residues (4). Taking into account all these considerations, the presence of an isoleucine at codon 118 could be in part responsible for a natural 3TC resistance by HTLV-1. Biochemical and site-direct mutagenesis studies should be conducted to confirm our hypothesis. In the meantime, for the benefit of patients with HTLV-1-associated myelopathy-tropical spastic paraparesis, antiretroviral therapy should no longer include 3TC.


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  1. Balestrieri, E., G. Forte, C. Matteucci, A. Mastino, and B. Macchi. 2002. Effect of lamivudine on transmission of human T-cell lymphotropic virus type 1 to adult peripheral blood mononuclear cells in vitro. Antimicrob. Agents Chemother. 46:3080-3083.[Abstract/Free Full Text]
  2. de Mendoza, C., O. Gallego, and V. Soriano. 2002. Mechanisms of resistance to antiretroviral drugs—clinical implications. AIDS Rev. 4:64-82.[Medline]
  3. García-Lerma, J. G., S. Nidtha, and W. Heneine. 2001. Susceptibility of human T cell leukemia virus type 1 to reverse transcriptase inhibitors: evidence for resistance to lamivudine. J. Infect. Dis. 184:507-510.[CrossRef][Medline]
  4. Halvas, E. K., E. S. Svarovskaia, E. O. Freed, and V. K. Pathak. 2000. Wild-type and YMDD mutant murine leukemia virus reverse transcriptases are resistant to 2',3'-dideoxy-3'-thiacytidine. J. Virol. 74:6669-6674.[Abstract/Free Full Text]
  5. Hertogs, K., S. Bloor, V. de Vroey, C. van den Eynde, P. Dehertogh, A. van Cauwenberge, M. Stürmer, T. Alcorn, S. Wegner, M. van Houtte, V. Miller, and B. Larder. 2000. A novel human immunodeficiency virus type I reverse transcriptase mutational pattern confers phenotypic lamivudine resistance in the absence of mutation 184V. Antimicrob. Agents Chemother. 44:568-573.[Abstract/Free Full Text]
  6. Machuca, A., B. Rodés, and V. Soriano. 2001. The effect of antiretroviral therapy on HTLV infection. Virus Res. 78:93-100.[CrossRef][Medline]
  7. Qari, S. H., S. Magre, J. G. García-Lerma, A. I. Hussain, Y. Takeuchi, C. Patience, R. A. Weiss, and W. Heneine. 2001. Susceptibility of the porcine endogenous retroviruses to reverse transcriptase and protease inhibitors. J. Virol. 75:1048-1053.[Abstract/Free Full Text]
  8. Taylor, G. P., S. Hall, S. Navarrete, C. Michie, R. Davis, A. Witkover, M. Rossor, M. Nowak, P. Rudge, E. Matutes, C. Bangham, and J. Weber. 1999. Effect of lamivudine on human T-cell leukemia virus type 1 (HTLV-1) DNA copy number, T-cell phenotype, and anti-Tax cytotoxic T-cell frequency in patients with HTLV-1-associated myelopathy. J. Virol. 73:10289-10295.[Abstract/Free Full Text]
Carlos Toro
Berta Rodés
Carmen de Mendoza
Vincent Soriano*
Service of Infectious Diseases
Hospital Carlos III
Instituto de Salud Carlos III
Madrid, Spain

* Phone: 34 91 4532500
Fax: 34 91 7336614
E-mail: vsoriano{at}dragonet.es


Authors' Reply


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Toro et al. hypothesize, on the basis of amino acid sequence comparison at GenBank, that the low potency of 3TC in inhibiting HTLV-1 infection might be owed to the presence of an isoleucine at position 118 in HTLV-1 RT, conferring natural resistance to 3TC treatment. An identical mutational pattern, due to a V->I change, has been found to be associated to 3TC resistance during potent antiretroviral treatment in HIV-I infection. We thank the authors for this comment on our recent paper and personally agree on this possibility. In fact, their hypothesis suggests a possible reason underlying the poor activity of 3TC in protecting peripheral blood mononuclear cells from HTLV-1 infection in vitro described previously by Balestrieri et al. (1). Moreover, we also concur with the twomain conclusions they reach. First, only future laboratory investigations focused on this specific point and based on site-directed mutagenesis techniques will confirm their hypothesis. Second, their GenBank-based hypothesis, taken together with clinical observations (3, 4), biochemical studies (2), and our data, strongly suggests that 3TC, as an antiretroviral, should not be included in the therapy of HTLV-1-infected patients. Interestingly, such a univocal conclusion derives from results achieved using completely different experimental approaches. Moreover, the letter of Toro et al. offers the opportunity to emphasize, in our opinion, two important additional aspects. The first is that although it is estimated that 10 to 20 million people worldwide are infected with HTLV-1, the only antiviral approach pursued until now was the "recycling" for HTLV-1-infected patients of anti-HIV-developed drugs. Considering that molecules structurally different from those currently used in anti-HIV therapy could be necessary in order to reach their goal, we think there is urgent need for coordinated research, encompassing molecular, cellular, and clinical studies, to ensure the development of new drugs exerting a real anti-HTLV-1 activity and a more keen and focused use of the antiviral therapy in HTLV-1 infection. The second is that in the future, in any case, given that an anti-HIV effect is not a warranty for an anti-HTLV-1 action and considering that our data demonstrate that the anti-HTLV-1 antiviral efficacy can be well predicted by in vitro assays, neither 3TC nor other antiviral drug should be administered to HTLV-1-infected patients without preventive, specific in vitro testing.


   REFERENCES 
Top
 Letter
 References
 Letter 
 References 
 

  1. Balestrieri, E., G. Forte, C. Matteucci, A. Mastino, and B. Macchi. 2002. Effect of lamivudine on transmission of human T-cell lymphotropic virus type 1 to adult peripheral blood mononuclear cells in vitro. Antimicrob. Agents Chemother. 46:3080-3083.
  2. Garcia-Lerma, J. G., S. Nidtha, and W. Heneine. 2001. Susceptibility of human T cell leukemia virus type I to reverse-transcriptase inhibitors: evidence of resistance to lamivudine. J. Infect. Dis. 184:507-510.
  3. Machuca, A., and V. Soriano. 2000. In vivo fluctuation of HTLV-1 and HTLV-1I proviral load in patients receiving antiretroviral drugs. J. Acquir. Immune Defic. Syndr. 24:189-193.
  4. Taylor, G. P., S. E. Hall, S. Navarrete, C. A. Michie, R. Davis, A. D. Witkover, M. Rossor, M. A. Nowak, P. Rudge, E. Matutes, C. R. M. Bangham, and J. N. Weber. 1999. Effect of lamivudine on human T-cell leukemia virus type I (HTLV-1) DNA copy number, T-cell phenotype, and anti-Tax cytotoxic T-cell frequency in patients with HTLV-1-associated myelopathy. J. Virol 73:10289-10295.
Beatrice Macchi*
Department of Neuroscience
University of Rome Tor Vergata
Rome, Italy
IRCCS
S. Lucia, Italy

Emanuela Balestrieri
Antonio Mastino
Department of Microbiological, Genetic,  and Molecular Science
University of Messina
Messina, Italy

* Fax: 39 06 2042728
E-mail: macchi{at}med.uniroma2.it

Antimicrobial Agents and Chemotherapy, May 2003, p. 1774-1775, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1774-1775.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.




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