Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, June 1998, p. 1484-1487, Vol. 42, No. 6
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Antiviral Activities of 9-R-2-Phosphonomethoxypropyl
Adenine (PMPA) and Bis(isopropyloxymethylcarbonyl)PMPA against Various
Drug-Resistant Human Immunodeficiency Virus Strains
Ranga V.
Srinivas1,* and
Arnold
Fridland1,2
Department of Infectious Diseases, St. Jude
Children's Research Hospital,1 and
Department of Pharmacology, University of
Tennessee,2 Memphis, Tennessee
Received 31 October 1997/Returned for modification 12 January
1998/Accepted 13 March 1998
 |
ABSTRACT |
9-R-2-Phosphonomethoxypropyl adenine (PMPA) is an
acyclic nucleoside phosphonate analog that has demonstrated efficacy
against human immunodeficiency virus (HIV). We recently described the synthesis, metabolism, and biological activities of
bis(isopropyloxymethylcarbonyl)PMPA [bis(poc)PMPA] as an orally
bioavailable prodrug for PMPA. Among a large panel of drug-resistant
HIV type 1 variants, only the K65R virus was resistant to PMPA. K65R
virus also showed reduced susceptibility to bis(poc)PMPA, although the
prodrug could still inhibit these viruses at submicromolar, nontoxic
concentrations. Among a panel of seven primary clinical isolates from
patients with diverse treatment histories, only one isolate showed
reduced susceptibility to PMPA and was found to carry three mutations (M41L, T69N, R73K) in its reverse transcriptase catalytic domain.
| |
TEXT |
9-R-2-Phosphonomethoxypropyl
adenine (PMPA), a member of the acyclic nucleoside phosphonate family
of antiviral agents, is a potent inhibitor of both hepadnaviruses and
retroviruses including the human immunodeficiency virus (HIV) (for a
review, see reference 2). PMPA is highly effective
for the pre- or postexposure prophylaxis of simian immunodeficiency
virus (SIV) infection in rhesus monkeys and prevents the establishment
of SIV if it is administered 48 h before or 4 or 24 h after
virus inoculation (35). PMPA is also effective against
chronic SIVmne infection in cynomolgus monkeys
(36). A single daily dose of PMPA administered
subcutaneously reduces plasma SIV RNA levels by >99% within 2 weeks
of treatment. PMPA is currently undergoing phase I/II clinical trials
for the treatment of HIV infection in AIDS patients. Preliminary
results have shown that PMPA given intravenously appears to be safe and is well tolerated, and it caused a 1.1 log reduction of the HIV RNA
levels after the administration of only eight doses (7). PMPA is poorly absorbed after oral administration, presumably due to
the negative charges on the phosphonyl group. We recently described a
bis(isopropyloxymethylcarbonyl) ester of PMPA, designated bis(poc)PMPA,
which functions as an orally available prodrug of PMPA (3).
Phase I/II clinical trials with bis(poc)PMPA are ongoing. Current
treatment guidelines recommend the use of two or more nucleoside
inhibitors plus a protease inhibitor (4). Understanding of
the cross-resistance patterns of different drugs within a class is
essential for determining suitable drug combinations. Toward this end,
we have investigated the susceptibility of a panel of drug-resistant
HIV isolates with various phenotypes for their susceptibility to PMPA
and bis(poc)PMPA.
Antiviral activities of PMPA and bis(poc)PMPA.
The synthesis
of PMPA and bis(poc)PMPA has been described before (1). PMPA
and bis(poc)PMPA were generously supplied by Norbert Bischofberger
(Gilead Sciences, Foster City, Calif.). The antiviral and cytotoxic
activities of these compounds in human peripheral blood mononuclear
cells (PBMCs) or the T-lymphocytic MT-2 cell line were determined by
HIV type 1 (HIV-1) p24 yield reduction assays as described previously
(29, 30). PMPA was a potent inhibitor of HIV-1 replication,
with effective antiviral concentrations of ~0.6 and ~0.2 µM in
MT-2 cells and PBMCs, respectively (Table
1). PMPA was also relatively nontoxic to
cells, with 50% inhibitory concentrations (IC50s) of
~1,200 to 1,250 µM, and it had a high therapeutic index.
Bis(poc)PMPA was ~30- to 90-fold more potent than PMPA in both its
antiviral and cytotoxic effects, with little change in its therapeutic
index. Thus, bis(poc)PMPA appears to be an effective prodrug for the
efficient intracellular delivery of PMPA.
Efficacy of PMPA against various drug-resistant HIV isolates.
Table 2 summarizes the sources,
phenotypes, and genotypes of the mutant viruses used in this study. The
genotypic information on the isolates is from the literature, while the
phenotypes of the mutants were confirmed prior to antiviral assays with
PMPA and bis(poc)PMPA. Interestingly, all isolates with the exception of the K65R virus were susceptible to PMPA and bis(poc)PMPA. The K65R
virus was about eightfold less susceptible to PMPA than the wild-type
Hxb2 molecular clone. Likewise, bis(poc)PMPA was about ninefold less
active against the K65R virus, although the virus was still inhibited
by submicromolar concentrations of the drug that were well below the
drug's cytotoxic concentration.
With the increasing use of protease inhibitors, HIV variants with
resistance to one or more protease inhibitors are emerging.
Although
protease inhibitors and PMPA target different viral gene
products,
protease and reverse transcriptase (RT) are both processed
from a
common precursor polyprotein. However, neither a saquinavir-resistant
HIV variant (
16), nor an HIV variant resistant to multiple
protease
inhibitors (
6) showed any cross-resistance to PMPA
or bis(poc)PMPA
(Table
2).
Inhibition of virion-associated RT activity by PMPApp.
K65R RT
shows diminished chain termination in the presence of ddCTP
(13). We therefore investigated whether K65R RT is resistant to inhibition by PMPApp, the biologically active intracellular derivative of PMPA and bis(poc)PMPA. Virion-associated RT activity and
its inhibition by PMPApp were determined by using MS-2 phage RNA as a
heteropolymeric template and a synthetic oligonucleotide (5'-CGT
TAG CCA CTC CGA AGT GCG T-3') complementary to residues 3326 to
3347 of MS-2 RNA (8) as the primer. The reactions were initiated by the addition of HIV-1IIIB, and K65R virus
preparations concentrated 100-fold by ultracentrifugation. RT reactions
were carried out for 90 min at 37°C in the presence of
32P-dATP, unlabelled dCTP, dGTP, and dTTP, and various
concentrations of PMPApp. At the end of the incubation period, samples
were spotted onto DE-81 filters, washed three times in 2× SSC (1× SSC
is 0.15 M NaCl plus 0.015 M sodium citrate), rinsed in 95% ethanol,
and air dried prior to scintillation counting. As shown in Fig.
1, PMPApp was 10-fold less effective in
inhibiting RT from K65R virus (IC50, ~1 µM) than it was
in inhibiting RT from wild-type IIIB virus (IC50, ~0.1
µM) or purified recombinant RT from HIV-1 BH-10 (IC50,
~0.1 µM) (data not shown). The concordance between the reduced
susceptibility of virion-associated RT activity to inhibition by PMPApp
in vitro and the phenotypic resistance of the K65R virus in cell
culture suggests that screening for enzymatic resistance may provide a
surrogate approach to the rapid detection and characterization of at
least a subset of PMPA-resistant mutants.
View larger version (12K):
[in this window]
[in a new window]
|
FIG. 1.
Inhibition of virion-associated RT activity by PMPApp.
Two independent experiments were done in triplicate with different
PMPApp concentration ranges. The results (mean ± standard
deviation) of one experiment are presented. The values are indicated as
percentage of the control RT activity. The amount of radioactivity
incorporated in the control was 8.1 × 105 cpm for
K65R virus and 1.5 × 106 cpm for
HIV-1IIIB.
|
|
Susceptibility of primary clinical isolates to PMPA and
bis(poc)PMPA.
We also investigated the antiviral efficacy of PMPA
against primary isolates from treatment-naive patients or from patients experiencing treatment failure (Table 3).
The treatment histories of these subjects are summarized in Table 3.
Six of the seven isolates studied were highly susceptible to PMPA. One
isolate from a patient previously treated with zidovudine (AZT) and ddI showed reduced sensitivity to PMPA and bis(poc)PMPA. The catalytic domain of RT from this isolate was amplified by PCR and was cloned into
plasmid vectors and analyzed by automated dye-terminator sequencing.
One of the three clones sequenced contained nonconservative mutations
that, compared to wild-type RT sequences, resulted in amino acid
changes at codons 41 (M41V), 69 (T69N), and 73 (R73K) (28a).
The M41V mutation has previously been associated with AZT resistance
(17), while a mutation at T69 (T69N) leads to ddI and ddC
resistance (9). Mutagenesis studies are in progress to
determine whether one or more of these mutations are associated with
the reduced sensitivity to PMPA. These results nevertheless suggest
that primary clinical isolates are generally sensitive to PMPA,
although occasional variants with reduced sensitivity may be
encountered in the clinic.
The K65R mutation determines HIV resistance to several other antiviral
agents including ddC, ddI, lamivudine (3TC),
9-(2-phosphonylmethoxyethyl)adenine
(PMEA), and 1592U89, as
well as dioxalane guanosine and other
dioxalane derivatives (
12,
14,
26,
34,
40). In a recent
study, K65R mutations were found to
appear in RT of SIV from PMPA-treated
newborn macaques, and the K65R
SIV showed reduced susceptibility
to PMPA (
38), although the
animals remained disease free for
more than 13 months. Recently,
Cherrington et al. (
5) described
the in vitro selection of
HIV-1 K65R variants with reduced sensitivity
to PMPA. Hence, the
selection of the K65R mutation by the use
of PMPA is a potential cause
of concern. Interestingly, K65R mutants
remain susceptible to AZT, and
the K65R mutation results in the
reversal of AZT resistance, at least
in the D67N, K70R, T215Y,
and K219Q background. Thus, it may be
possible to suppress the
emergence of the K65R mutation by combination
therapy with AZT.
The K65R mutation has been reported among isolates
from a small
proportion (~25%) of patients on monotherapy with ddI
(
39),
but it is rarely seen among isolates from patients
receiving ddI
and AZT (
15). Likewise, even though ddC can
select for the K65R
mutation in vitro, K65R mutants are not detected in
patients on
combination therapy with ddC and AZT (
32).
Together, these results
support the inclusion of AZT in therapeutic
regimens involving
PMPA (or other drugs affected by the K65R mutation).
HIV-1 variants that carry the Q151M mutation and that are resistant to
AZT, ddI, ddC, ddG, and stavudine (d4T; but not 3TC)
have been isolated
from patients receiving combination therapy
with AZT and ddI or AZT and
ddC. Additional mutations arising
at codons 62, 75, 77, and 116 enhance
the degree of antiviral
resistance in isolates carrying the Q151M
mutation (
27-28,
37).
It is interesting that Q151M mutants
remain sensitive to PMPA
and bis(poc)PMPA, suggesting that these
compounds may be particularly
useful in the treatment of patients
harboring HIV isolates with
the Q151 mutation.
Finally, bis(poc)PMPA appears to be much more potent than PMPA and
achieves much greater intracellular concentrations of PMPA,
PMPAp (PMPA
monophosphate), and PMPApp (
11,
21,
24). Bis(poc)PMPA
is
rapidly hydrolyzed by esterases within cells and plasma. After
oral
administration of bis(poc)PMPA, only PMPA, but not bis(poc)PMPA,
is
detected in the plasma. Thus, it is unclear whether high intracellular
PMPApp levels could be achieved in tissues and the circulation
following oral bis(poc)PMPA administration. Since the K65R virus
could
be inhibited by submicromolar concentrations of bis(poc)PMPA
that were
well below the levels resulting in toxicity, the use
of systemic
formulations of bis(poc)PMPA or other methods for
improving the
intracellular delivery of these compounds may provide
a novel approach
to limiting the problem of drug resistance.
| |
ACKNOWLEDGMENTS |
This work was supported in part by PHS grants RO1 AI27652 and
UO1-AI32908, by Cancer Center (CORE) grant P30 CA21765 from the
National Institutes of Health, and by the American Lebanese Syrian
Associated Charities. We are grateful to the following various
contributors to the NIH AIDS Research and Reference Reagent Program
(Rockville, Md.) for supplying the indicated reagents: Douglas Richman,
G910-6, G762, 1391-1, 1391-4, and N119; Brendan Larder and S. Kemp,
RTMF, RTMC, RTMDR-1, and HIV-174V; Emilio Emini,
HIV-1IIIB A17; John Mellors and Raymond Schinazzi,
HIV-1LAI-M184V; and Donald Dubin and Joseph Fitzgibbon,
pJF4a. We thank H. Mitsuya (National Institutes of Health, Bethesda,
Md.) for supplying pSUM-9, pSUM8, and pSUM12, and Mark Wainberg (McGill
University, Montreal, Quebec, Canada) for providing the HIV-1 K65R
molecular clone.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Infectious Diseases, SJCRH, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-2359. Fax: (901) 495-3099. E-mail:
rv.srinivas{at}stjude.org.
| |
REFERENCES |
| 1.
|
Armilli, M. N.,
C. U. Kim,
J. Dougherty,
A. Mulato,
R. Oliyai,
J. P. Shaw,
K. C. Cundy, and N. Bischofberger.
1997.
Synthesis, in vitro evaluation and oral bioavailability of [9-(2-phosphonylmethoxyethyl)adenine prodrugs.
Antivir. Chem. Chemother.
8:557-564.
|
| 2.
|
Balzarini, J., and E. De Clercq.
1995.
Acyclic purine nucleoside phosphonates as retrovirus inhibitors, p. 41-45.
In
D. J. Jeffries, and E. De Clercq (ed.), Antiviral chemotherapy. John Wiley & Sons, Inc., New York, N.Y.
|
| 3.
|
Bischofberger, N.,
L. Naesens,
E. De Clercq,
A. Fridland,
R. V. Srinivas,
B. L. Robbins,
M. Arimilli,
K. Cundy,
C. Kim,
S. Lacy,
W. Lee, and J. Shaw.
1997.
Bis(POC)PMPA, an orally bioavailable prodrug of the antiretroviral agent PMPA, abstr. 214, p. 104.
In
Program and abstracts of the 4th Conference on Retroviruses and Opportunistic Infections.
|
| 4.
|
Carpenter, C. C.,
M. A. Fischl,
S. M. Hammer,
M. S. Hirsch,
D. M. Jacobsen,
D. A. Katzenstein,
J. S. Montaner,
D. D. Richman,
M. S. Saag,
R. T. Schooley,
M. A. Thompson,
S. Vella,
P. G. Yeni, and P. A. Volberding.
1997.
Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA Panel.
JAMA
277:1962-1969[Abstract/Free Full Text].
|
| 5.
|
Cherrington, J. M.,
K. K. A. Van Rompay,
A. S. Multao,
M. L. Marthas,
C. J. Berardi,
S. Telm,
N. Bischofberger, and N. C. Pedersen.
1996.
Phenotypic and genotypic characterization of simian immunodeficiency viruses (SIV) with reduced susceptibility to PMPA isolated after PMPA therapy, abstr. 75.
In
Program and abstracts of Fifth International Workshop on HIV Drug Resistance.
|
| 6.
|
Condra, J. H.,
W. A. Schleif,
O. M. Blahy,
L. J. Gabryelski,
D. J. Graham,
J. C. Quintero,
A. Rhodes,
H. L. Robbins,
E. Roth,
M. Shivaprakash,
D. Titus,
T. Yang,
H. Teppler,
K. E. Squires,
P. J. Deutsch, and E. A. Emini.
1995.
In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors.
Nature
374:569-571[Medline].
|
| 7.
| Deeks, S. G., P. Barditch-Grovo, P. Lietman, F. Hwang, K. Cundy, J. Rooney, N. Nellman, and J. Khan. Unpublished
data.
|
| 8.
|
Fiers, W.,
R. Contreras,
F. Duerinck,
G. Haegeman,
D. Iserentant,
J. Merregaert,
W. Min Jou,
F. Molemans,
A. Raeymaekers,
A. Van den Berghe,
G. Volckaert, and M. Ysebaert.
1976.
Complete nucleotide sequence of bacteriophage MS2 RNA: primary and secondary structure of the replicase gene.
Nature
260:500-507[Medline].
|
| 9.
|
Fitzgibbon, J. E.,
F.-M. Howell,
C. A. Haberzettl,
S. J. Sperber,
D. J. Gockle, and D. T. Dubin.
1992.
Human immunodeficiency virus type I pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine.
Antimicrob. Agents Chemother.
36:153-157[Abstract/Free Full Text].
|
| 10.
|
Foli, A.,
K. M. Sogocio,
B. Anderson,
M. Kavlick,
M. W. Saville,
M. A. Wainberg,
Z. Gu,
J. M. Cherrington,
H. Mitsuya, and R. Yarchoan.
1996.
In vitro selection and molecular characterization of human immunodeficiency virus type 1 with reduced sensitivity to 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA).
Antivir. Res.
32:91-98[Medline].
|
| 11.
|
Fridland, A.,
B. L. Robbins,
R. V. Srinivas,
M. Armili,
C. Kim, and N. Bischofberger.
1997.
Antiretroviral activity and metabolism of bis(poc)PMPA, an oral prodrug of PMPA, abstr. 27, p. A49.
In
Program and abstracts of the Tenth International Conference on Antiviral Research.
|
| 12.
|
Gu, Z.,
Q. Gao,
X. Li,
M. A. Parniak, and M. A. Wainberg.
1994.
Identification of a mutation at codon 65 in the IKKF motif reverse transcriptase that encodes human immunodeficiency virus resistance to 2',3'-dideoxycytidine and 2',3'-dideoxy-3'-thiacytidine.
Antimicrob. Agents Chemother.
38:275-281[Abstract/Free Full Text].
|
| 13.
|
Gu, Z.,
E. J. Arts,
M. A. Parniak, and M. A. Wainberg.
1995.
Mutated K65R recombinant reverse transcriptase of human immunodeficiency virus type 1 shows diminished chain termination in the presence of 2',3'-dideoxycytidine 5'-triphosphate and other drugs.
Proc. Natl. Acad. Sci. USA
92:2760-2764[Abstract/Free Full Text].
|
| 14.
|
Gu, Z.,
H. Salomon,
J. Cherrington,
A. S. Mulato,
M. S. Chen,
R. Yarchoan,
A. Foli,
K. M. Sogocio, and M. A. Wainberg.
1995.
K65R mutation of human immunodeficiency virus type 1 reverse transcriptase encodes cross-resistance to 9-(2-phosphonylmethoxyethyl)adenine.
Antimicrob. Agents Chemother.
39:1888-1891[Abstract].
|
| 15.
|
Holodniy, M.,
L. Mole,
D. Margolis,
J. Moss,
H. Dong,
E. Boyer,
M. Urdea,
J. Kolberg, and S. Eastman.
1995.
Determination of human immunodeficiency virus RNA in plasma and cellular viral DNA genotypic zidovudine resistance and viral load during zidovudine-didanosine combination therapy.
J. Virol.
69:3510-3516[Abstract].
|
| 16.
|
Jacobsen, H.,
K. Yasargil,
D. L. Winslow,
J. C. Craig,
A. Kröhn,
I. B. Duncan, and J. Mous.
1995.
Characterization of human immunodeficiency virus type 1 mutants with decreased sensitivity to proteinase inhibitor Ro 31-8959.
Virology
206:527-534[Medline].
|
| 17.
|
Kellam, P.,
C. A. Boucher, and B. A. Larder.
1992.
Fifth mutation in human immunodeficiency virus type I reverse transcriptase contributes to the development of high-level resistance to zidovudine.
Proc. Natl. Acad. Sci. USA
89:1934-1938[Abstract/Free Full Text].
|
| 18.
|
Larder, B. A., and S. D. Kemp.
1989.
Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT).
Science
246:1155-1158[Abstract/Free Full Text].
|
| 19.
|
Larder, B. A.,
G. Darby, and D. D. Richman.
1989.
HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy.
Science
243:1731-1734[Abstract/Free Full Text].
|
| 20.
|
Larder, B. A.,
P. Kellam, and S. D. Kemp.
1993.
Convergent combination therapy can select viable multidrug-resistant HIV-1 in vitro.
Nature
365:451-453[Medline].
|
| 21.
|
Naesens, L.,
N. Bischofberger,
M. Arimili,
C. Kim, and E. De Clercq.
1997.
Antiretrovirus activity and pharmacokinetics in mice of bis(poc)PMPA, the bis(isopropyloxycarbonyloxymethyl) oral prodrug of PMPA, abstr. 28, p. A50.
In
Abstracts of the Tenth International Conference on Antiviral Research.
|
| 22.
|
Nunberg, J. H.,
W. A. Schleif,
E. J. Boots,
J. A. O'Brien,
J. C. Quintero,
J. M. Hoffman,
E. A. Emini, and M. E. Goldman.
1991.
Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors.
J. Virol.
65:4887-4892[Abstract/Free Full Text].
|
| 23.
|
Richman, D. D.,
D. Havlir,
J. Corbeil,
D. Looney,
C. Ignacio,
S. A. Spector,
J. Sullivan,
S. Cheeseman,
K. Barringer,
D. Pauletti,
C. K. Shih,
M. Myers, and J. Griffin.
1994.
Nevirapine resistance mutations of human immunodeficiency virus type I selected during therapy.
J. Virol.
68:1660-1666[Abstract/Free Full Text].
|
| 24.
| Robbins, B., R. V. Srinivas, C. Kim, N. Bischofberger, and A. Fridland. Anti-human immunodeficiency virus
activity and cellular metabolism of a potential prodrug of the acyclic
nucleoside phosphonate
9-R-(2-phosphonomethoxypropyl)adenine (PMPA),
bis(isopropyloxymethylcarbonyl) PMPA. Antimicrob. Agents
Chemother. 42:612-617.
|
| 25.
|
Schinazi, R. F.,
R. M. Lloyd, Jr.,
M. H. Nguyen,
D. L. Cannon,
A. McMillan,
N. Ilksoy,
C. K. Chu,
D. C. Liotta,
H. Z. Bazmi, and J. W. Mellors.
1993.
Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides.
Antimicrob. Agents Chemother.
37:875-881[Abstract/Free Full Text].
|
| 26.
|
Schinazi, R. F.,
B. A. Larder, and J. W. Mellors.
1996.
Mutations in retroviral genes associated with drug resistance.
Int. Antivir. News
4:95-107.
|
| 27.
|
Shafer, R. W.,
M. J. Kozal,
M. A. Winters,
A. K. Iversen,
D. A. Katzenstein,
M. V. Ragni,
W. A. Meyer, 3rd,
P. Gupta,
S. Rasheed,
R. Coombs, et al.
1994.
Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations.
J. Infect. Dis.
169:722-729[Medline].
|
| 28.
|
Shirasaka, T.,
M. F. Kavlick,
T. Ueno,
W. Y. Gao,
E. Kojima,
M. L. Alcaide,
S. Chokekijchai,
B. M. Roy,
E. Arnold,
R. Yarchoan, and H. Mitsuya.
1995.
Emergence of human immunodeficiency virus type I variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides.
Proc. Natl. Acad. Sci. USA
92:1-5[Free Full Text].
|
| 28a.
| Srinivas, R. V. Unpublished results.
|
| 29.
|
Srinivas, R. V., and J. L. Hurwitz.
1997.
HIV growth, inhibition and measurement, p. 1959-1973.
In
I. Lefkowitz (ed.), The immunology methods manual. Academic Press, Inc., New York, N.Y.
|
| 30.
|
Srinivas, R. V.,
B. L. Robbins,
M. Connelly,
Y.-F. Gong,
N. Bischoffberger, and A. Fridland.
1993.
Metabolism and in vitro antiretroviral activities of bis(pivaloyloxymethyl) prodrugs of acyclic nucleoside phosphonates.
Antimicrob. Agents Chemother.
37:2247-2250[Abstract/Free Full Text].
|
| 31.
|
St. Clair, M. H.,
J. L. Martin,
G. Tudor-Williams,
M. C. Bach,
C. L. Vavro,
D. M. King,
P. Kellam,
S. D. Kemp, and B. A. Larder.
1991.
Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase.
Science
253:1557-1559[Abstract/Free Full Text].
|
| 32.
|
Sylvester, S.,
A. Caliendo,
K. Sepkowitz,
M. Fischl,
D. Jayaweera,
G. Simon,
J. Lalezari,
R. Mitsuyas, and R. D'Aquila.
1996.
HIV-1 resistance mutations and plasma RNA levels during ZDV+ddC combination therapy, abstr. 107.
In
Program and abstracts of the 3rd Conference on Retrovioruses and Opportunistic Infections.
|
| 33.
|
Tanaka, M.,
R. V. Srinivas,
T. Ueno,
M. F. Kavlick,
F. K. Hui,
A. Fridland,
J. S. Driscoll, and H. Mitsuya.
1997.
In vitro induction of human immunodeficiency virus type 1 variants resistant to 2'- -fluoro-2',3'-dideoxyadenosine.
Antimicrob. Agents Chemother.
41:1313-1318[Abstract].
|
| 34.
|
Tisdale, M.,
N. R. Parry,
D. Cousens,
M. H. St. Clair, and L. R. Boone.
1996.
Anti-HIV activity of (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2cyclopentene-1-methanol (1592U89), abstr. I82, p. 92.
In
Program and abstracts of the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 35.
|
Tsai, C. C.,
K. E. Follis,
T. W. Beck,
A. Sabo,
N. Bischofberger, and P. J. Dailey.
1997.
Effects of (R)-9-(2-phosphonylmethoxypropyl)adenine monotherapy on chronic SIV infection in macaques.
AIDS Res. Hum. Retroviruses
13:707-712[Medline].
|
| 36.
|
Tsai, C. C.,
K. E. Follis,
A. Sabo,
T. W. Beck,
R. F. Grant,
N. Bischofberger,
R. E. Benveniste, and R. Black.
1995.
Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl) adenine.
Science
270:1197-1199[Abstract/Free Full Text].
|
| 37.
|
Ueno, T.,
T. Shirasaka, and H. Mitsuya.
1995.
Enzymatic characterization of human immunodeficiency virus type 1 reverse transcriptase resistant to multiple 2',3'-dideoxynucleoside 5'-triphosphates.
J. Biol. Chem.
270:23605-23611[Abstract/Free Full Text].
|
| 38.
|
Van Rompay, K. K. A.,
J. M. Cherrington,
M. L. Marthas,
C. J. Berardi,
A. S. Mulato,
A. Spinner,
R. P. Tarara,
D. R. Canfield,
S. Telm,
N. Bischofberger, and N. C. Pedersen.
1996.
PMPA therapy of established SIV infection of infant rhesus macaques.
Antimicrob. Agents Chemother.
40:2586-2591[Abstract].
|
| 39.
|
Winters, M. A.,
R. W. Shafer,
R. A. Jellinger,
G. Mamtora,
T. Gingeras, and T. C. Merigan.
1997.
Human immunodeficiency virus type 1 reverse transcriptase genotype and drug susceptibility changes in infected individuals receiving dideoxyinosine monotherapy for 1 to 2 years.
Antimicrob. Agents Chemother.
41:757-762[Abstract].
|
| 40.
|
Zhang, D.,
A. M. Caliendo,
J. J. Eton,
K. M. DeVore,
J. C. Kaplan,
M. S. Hirsch, and R. T. D'Aquila.
1994.
Resistance to 2',3'-dideoxycytidine conferred by a mutation in codon 65 of the human immunodeficiency virus type I reverse transcriptase.
Antimicrob. Agents Chemother.
38:282-287[Abstract/Free Full Text].
|
Antimicrobial Agents and Chemotherapy, June 1998, p. 1484-1487, Vol. 42, No. 6
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Covens, K., Dekeersmaeker, N., Schrooten, Y., Weber, J., Schols, D., Quinones-Mateu, M. E., Vandamme, A.-M., Van Laethem, K.
(2009). Novel Recombinant Virus Assay for Measuring Susceptibility of Human Immunodeficiency Virus Type 1 Group M Subtypes To Clinically Approved Drugs. J. Clin. Microbiol.
47: 2232-2242
[Abstract]
[Full Text]
-
Ambrose, Z., Palmer, S., Boltz, V. F., Kearney, M., Larsen, K., Polacino, P., Flanary, L., Oswald, K., Piatak, M. Jr., Smedley, J., Shao, W., Bischofberger, N., Maldarelli, F., Kimata, J. T., Mellors, J. W., Hu, S.-L., Coffin, J. M., Lifson, J. D., KewalRamani, V. N.
(2007). Suppression of Viremia and Evolution of Human Immunodeficiency Virus Type 1 Drug Resistance in a Macaque Model for Antiretroviral Therapy. J. Virol.
81: 12145-12155
[Abstract]
[Full Text]
-
Wolf, K., Walter, H., Beerenwinkel, N., Keulen, W., Kaiser, R., Hoffmann, D., Lengauer, T., Selbig, J., Vandamme, A.-M., Korn, K., Schmidt, B.
(2003). Tenofovir Resistance and Resensitization. Antimicrob. Agents Chemother.
47: 3478-3484
[Abstract]
[Full Text]
-
De Clercq, E.
(2003). Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections. Clin. Microbiol. Rev.
16: 569-596
[Abstract]
[Full Text]
-
Squires, K., Pozniak, A. L., Pierone, G. Jr., Steinhart, C. R., Berger, D., Bellos, N. C., Becker, S. L., Wulfsohn, M., Miller, M. D., Toole, J. J., Coakley, D. F., Cheng, A., for the Study 907 Team*,
(2003). Tenofovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1 Infection: A Randomized Trial. ANN INTERN MED
139: 313-320
[Abstract]
[Full Text]
-
Grim, S. A, Romanelli, F.
(2003). Tenofovir Disoproxil Fumarate. The Annals of Pharmacotherapy
37: 849-859
[Abstract]
[Full Text]
-
Mansky, L. M., Le Rouzic, E., Benichou, S., Gajary, L. C.
(2003). Influence of Reverse Transcriptase Variants, Drugs, and Vpr on Human Immunodeficiency Virus Type 1 Mutant Frequencies. J. Virol.
77: 2071-2080
[Abstract]
[Full Text]
-
McColl, D. J., Miller, M. D.
(2003). The use of tenofovir disoproxil fumarate for the treatment of nucleoside-resistant HIV-1. J Antimicrob Chemother
51: 219-223
[Full Text]
-
Gupta, P., Collins, K. B., Ratner, D., Watkins, S., Naus, G. J., Landers, D. V., Patterson, B. K.
(2002). Memory CD4+ T Cells Are the Earliest Detectable Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Cells in the Female Genital Mucosal Tissue during HIV-1 Transmission in an Organ Culture System. J. Virol.
76: 9868-9876
[Abstract]
[Full Text]
-
Birkus, G., Hajek, M., Kramata, P., Votruba, I., Holy, A., Otova, B.
(2002). Tenofovir Diphosphate Is a Poor Substrate and a Weak Inhibitor of Rat DNA Polymerases {alpha}, {delta}, and {varepsilon}. Antimicrob. Agents Chemother.
46: 1610-1613
[Abstract]
[Full Text]
-
Shafer, R. W.
(2002). Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance. Clin. Microbiol. Rev.
15: 247-277
[Abstract]
[Full Text]
-
Harrigan, P. R., Miller, M. D., McKenna, P., Brumme, Z. L., Larder, B. A.
(2002). Phenotypic Susceptibilities to Tenofovir in a Large Panel of Clinically Derived Human Immunodeficiency Virus Type 1 Isolates. Antimicrob. Agents Chemother.
46: 1067-1072
[Abstract]
[Full Text]
-
Barditch-Crovo, P., Deeks, S. G., Collier, A., Safrin, S., Coakley, D. F., Miller, M., Kearney, B. P., Coleman, R. L., Lamy, P. D., Kahn, J. O., McGowan, I., Lietman, P. S.
(2001). Phase I/II Trial of the Pharmacokinetics, Safety, and Antiretroviral Activity of Tenofovir Disoproxil Fumarate in Human Immunodeficiency Virus-Infected Adults. Antimicrob. Agents Chemother.
45: 2733-2739
[Abstract]
[Full Text]
-
Shah, F. S., Curr, K. A., Hamburgh, M. E., Parniak, M., Mitsuya, H., Arnez, J. G., Prasad, V. R.
(2000). Differential Influence of Nucleoside Analog-resistance Mutations K65R and L74V on the Overall Mutation Rate and Error Specificity of Human Immunodeficiency Virus Type 1 Reverse Transcriptase. J. Biol. Chem.
275: 27037-27044
[Abstract]
[Full Text]
Top
Abstract
Text
