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Antimicrobial Agents and Chemotherapy, March 2000, p. 783-786, Vol. 44, No. 3
Antiviral Drug Research Division, Gladstone
Institute of Virology and Immunology,1 and
Departments of Medicine and Microbiology and
Immunology,4 University of California, San
Francisco, California; Southern Research Institute, Frederick,
Maryland 21701-4756,2 and Department of
Virology, BioChem Pharma Inc., Laval, Quebec, Canada H7V
4A73
Received 21 July 1999/Returned for modification 22 October
1999/Accepted 29 November 1999
Oral administration of 2'-deoxy-3'-oxa-4'-thiocytidine (BCH-10652),
a nucleoside analog structurally similar to lamivudine (3TC), caused
dose-dependent inhibition of viral replication in SCID-hu Thy/Liv mice
infected with human immunodeficiency virus type 1 NL4-3 and with an
NL4-3 clone containing the M184V mutation in reverse transcriptase that
confers resistance to 3TC. These experiments demonstrate the utility of
this mouse model for evaluating drug resistance and for performing
direct comparisons between antiviral compounds in vivo.
Heterosubstituted
2',3'-dideoxynucleoside analogs, such as lamivudine (3TC) and 5-fluoro
3TC (FTC), differ from other nucleoside analog reverse transcriptase
(RT) inhibitors by having a carbon replaced by a sulfur in the 3'
position (11, 15, 16). Although 3TC is one of the most
commonly used nucleoside analogs in first-line combination therapy for
human immunodeficiency virus type 1 (HIV-1) infections (9),
3TC monotherapy results in the selection of preexisting 3TC-resistant
viral variants and a concomitant rebound in plasma viral load (13,
25). High-level resistance to 3TC is conferred by a single
mutation at codon 184 (from methionine to either valine or isoleucine)
in the catalytic domain of HIV-1 RT (8, 24, 32), and the
M184V substitution increases 50% inhibitory concentrations
(IC50s) of 3TC at least 1,000-fold (13, 31).
Concerns about the development of viral resistance to 3TC have spurred
the discovery of structurally related nucleosides with activity against
HIV-1 isolates containing common 3TC resistance mutations. The
nucleoside analog 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC, or BCH-10652)
is a racemic mixture of two relatively equipotent enantiomers with
antiviral activity against 3TC-resistant clinical HIV-1 isolates
(5, 11, 16), and it is currently in clinical development.
Although dOTC is structurally related to 3TC, it has an inversion of
the oxygen and sulfur in the furanosyl ring and is a mixture of
enantiomers with D-sugar [(
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Copyright © 2000, American Society for Microbiology. All rights reserved.
Antiviral Activity of
2'-Deoxy-3'-Oxa-4'-Thiocytidine (BCH-10652) against
Lamivudine-Resistant Human Immunodeficiency Virus Type 1 in SCID-hu
Thy/Liv Mice
ABSTRACT
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)dOTC] and
L-sugar [(+)dOTC] configurations, whereas 3TC is the
L-sugar racemate only (Fig.
1). In this study, we compared the
antiviral activities of 3TC and dOTC against the HIV-1 molecular clone
NL4-3 (1) and an NL4-3 clone containing the M184V mutation
in RT (NL4-3/M184V) in phytohemagglutinin-activated human peripheral
blood mononuclear cells (PBMCs) and in the SCID-hu Thy/Liv mouse model
of HIV-1 infection (2, 7, 17, 21, 26, 27).
View larger version (17K):
[in a new window]
FIG. 1.
Chemical structures of the enantiomers of dOTC and of
3TC.
Pooled human PBMCs from four to eight donors were inoculated in bulk at
a multiplicity of infection of 0.005 by adding 20,000 50% tissue
culture infective doses (TCID50s) of HIV-1 to 4 × 106 cells in 2 ml of RPMI 1640 supplemented with 10%
heat-inactivated fetal bovine serum, L-glutamine, and 5 U
of human lymphocyte interleukin-2 (IL-2) (Boehringer-Mannheim) per ml
for 2 h at 37°C. Cells were washed, and 100,000 cells in 50 µl
were added to triplicate wells of round-bottom 96-well plates. Wells
were treated with 200 µl of eight different concentrations of test
agent (in 10-fold increments) or with medium alone, and supernatants
were assayed at day 7 for HIV-1 gag p24 by enzyme-linked
immunosorbent assay (ELISA) in antibody-coated microplates (DuPont).
The IC50 is the concentration of test agent that was
calculated (by linear regression) to reduce p24 optical density values
by 50%. NL4-3/M184V was highly resistant to 3TC; the mean
IC50 for NL4-3/M184V was approximately 1,000-fold higher
than that for wild-type NL4-3 (Table 1).
In contrast to 3TC, dOTC had virtually identical mean IC50s
against the two viruses (9.6 µM for NL4-3/M184V versus 7.2 µM for
NL4-3). The M184V mutation in NL4-3 thus confers high-level resistance
to 3TC but causes essentially no increase in the IC50 of
dOTC. Despite the demonstrable activity of dOTC against NL4-3/M184V,
dOTC was 80-fold less potent than 3TC against wild-type NL4-3 in human
PBMCs (IC50s, 7.2 versus 0.09 µM). Parallel cellular
toxicity determinations in treated uninfected PBMCs incubated with
(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT)
(20) on day 7 yielded similar mean 50% cytotoxic
concentrations (CC50s) for both compounds (830 µM for 3TC
and 520 µM for dOTC).
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The efficacies of dOTC and 3TC against NL4-3 and NL4-3/M184V were evaluated in vivo in the SCID-hu Thy/Liv mouse model of HIV-1 infection. The human thymus implant in this model supports long-term differentiation of human lymphoid and myeloid cells (18, 22) and has been used to study the pathogenic effects of HIV-1 in vivo (3, 6, 7, 12, 14, 29, 30). The model has also been standardized for the preclinical evaluation of antiviral compounds against HIV-1 (10, 23, 28). By use of previously described procedures (23, 27), dOTC or 3TC in 0.5% carboxymethylcellulose was administered to SCID-hu Thy/Liv mice by oral gavage twice daily at various dosage levels, starting 24 h before direct injection of 1,000 TCID50s of either NL4-3 or NL4-3/M184V into each Thy/Liv implant. Each of four independent antiviral evaluations was performed in a cohort of mice implanted with thymus and liver from a single donor (with different cohorts made from different donors). Each dosing group comprised five to seven mice.
After 13 days of daily treatment (i.e., 12 days after virus
inoculation), implants were excised and dispersed into single-cell suspensions, and cells were lysed for quantitation of p24 by ELISA and
were also stained with antibodies to CD3, CD4, and CD8 for analysis of
T-cell subsets by flow cytometry. For quantitation of cell-associated
HIV-1 RNA by branched DNA assay, 5 × 106 cells were
disrupted with sterile disposable pestles and a cordless motor grinder
(Kontes, Vineland, N.J.) in 8 M guanidine HCl with 0.5% sodium
N-lauroylsarcosine. The RNA was extracted by adding 5 ml of
100% ethanol containing 20 µg of polyadenylic acid (Sigma) per ml,
and each sample was vortexed and pelleted at 12,000 × g for 20 min at 4°C. Supernatants were aspirated to remove DNA, and RNA pellets were washed with 5 ml of 70% ethanol, placed on dry
ice, and digested with reagents supplied by the manufacturer (Quantiplex HIV-1 RNA assay 2.0; Chiron Corporation, Emeryville, Calif.). The HIV-1 RNA load in the implant is expressed as copies per
106 implant thymocytes, and the log10 values
were used for the calculation of geometric means. The limit of
detection was typically 2.3 to 2.6 log10 RNA copies per
106 cells, and the lower-limit value was used for mean
calculation of implants with undetectable viral RNA. The Mann-Whitney U
test (StatView 5.0; Abacus Concepts, Berkeley, Calif.) was used for statistical analysis of p24 and viral RNA levels in implants, and
P values of 
0.05 were considered statistically
significant. The day of implant collection was chosen based on previous
studies of NL4-3 replication and thymocyte depletion kinetics in the
SCID-hu Thy/Liv model (23); p24 in implants normally reaches
half-maximum levels by day 12 in the absence of virus-induced thymocyte
depletion. A preliminary SCID-hu experiment with NL4-3/M184V indicated
that the mutant virus had replication kinetics in the human thymus similar to those of NL4-3 (data not shown), in contrast to the attenuated viral growth reported for M184V mutants in human PBMC cultures (19).
The first experiment was designed to evaluate the antiviral activity of
dOTC in mice with wild-type NL4-3-infected Thy/Liv implants. There were
statistically significant, dose-dependent reductions in implant p24 and
viral RNA levels in mice treated with dOTC at doses of 30, 90, and 200 mg/kg of body weight/day compared to levels in untreated mice (Fig.
2). Treatment with 200 mg of dOTC/kg/day
resulted in a 16-fold reduction in p24 and a 25-fold reduction in viral
RNA, and these reductions were comparable to those obtained in mice
treated with 3TC at 30 mg/kg/day in the same experiment. The in vivo
activity of dOTC therefore appears less potent than that of 3TC, as was
predicted by the IC50s obtained in NL4-3-infected PBMCs
(Table 1).
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In the second experiment, mice with NL4-3/M184V-infected implants were
treated with higher doses of either 3TC or dOTC to determine the level
of in vivo resistance conferred by the M184V mutation in RT. Treatment
with dOTC at 200 and 400 mg/kg/day caused 2- and 6-fold reductions in
p24 and 3- and 25-fold reductions in viral RNA, respectively, whereas
3TC at these doses had no detectable activity against the resistant
virus (Fig. 3). These data demonstrate
that dOTC has activity against 3TC-resistant HIV-1 in vivo.
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A direct comparison of the activities of 3TC and dOTC against NL4-3 and
NL4-3/M184V was performed in a third experiment with a large cohort
(n = 42) of SCID-hu Thy/Liv mice prepared with tissue
from a single donor. In mice with NL4-3-infected implants, 30 mg of
3TC/kg/day produced reductions in implant viral load that were
identical to those produced by dOTC at 200 mg/kg/day (Fig.
4), confirming the results we obtained in
the first experiment (Fig. 2). In contrast, the same doses of 3TC and
dOTC had no statistically significant activity against NL4-3/M184V.
Although 200 mg of dOTC/kg/day produced statistically significant
reductions in the p24 level in NL4-3/M184V-infected implants in the
second experiment (Fig. 3), that was not the case in the third
experiment, indicating that the M184V mutant is somewhat less sensitive
to dOTC than is wild-type NL4-3.
|
To confirm further the differential activity of 3TC and dOTC against
NL4-3 and NL4-3/M184V, a fourth experiment was performed in a single
SCID-hu cohort treated with 3TC or dOTC at the higher dosage level of
400 mg/kg/day. Treatment with high-dose dOTC reduced p24 to
undetectable levels and reduced viral RNA levels 630-fold in
NL4-3-infected implants but produced less-dramatic reductions (13-fold
for p24 and 25-fold for viral RNA) in NL4-3/M184V-infected implants
(Fig. 5).
|
Curiously, we observed statistically significantly higher viral loads in the NL4-3/M184V-infected implants of 3TC-treated mice than in those of untreated mice (Fig. 5). This paradoxical enhancement of NL4-3/M184V replication in the implants of 3TC-treated mice deserves further study and may be related to an in vitro phenomenon reported for zidovudine (AZT)-resistant HIV-1 in which AZT stimulated reverse transcription in cells infected with viruses containing the M41L or T215Y mutation in RT (4), although it has not been reported with 3TC-resistant HIV-1 grown in the presence of 3TC. The enhancement effect was not statistically significant with 3TC at 30 mg/kg/day (Fig. 4) but was significant in one of two experiments with mice treated with 400 mg/kg/day (compare Fig. 3 with Fig. 5).
In summary, dOTC had activity against wild-type NL4-3 both in human PBMCs and in the SCID-hu Thy/Liv model. Although dOTC was less potent than 3TC against NL4-3, dOTC inhibited replication of 3TC-resistant NL4-3/M184V at a dosage level (400 mg/kg/day) that was ineffective for 3TC. Treatment of mice with dOTC for 13 days caused no apparent toxicity and no significant weight loss, no reduction in implant cell numbers or viability (as assessed by forward- and side-scatter characteristics on the flow cytometer), and no perturbations in the percentages of different thymocyte subpopulations (data not shown). These data indicate that dOTC may be an effective agent against 3TC-resistant virus in humans. The experimental protocols also demonstrate the utility and flexibility of the SCID-hu Thy/Liv mouse model in direct comparisons of structurally related antiviral compounds in vivo and in the preclinical evaluation of drug resistance against HIV-1.
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ACKNOWLEDGMENTS |
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This work was supported by a contract from NIAID/NIH (N01-AI65309 to J. M. McCune). J. M. McCune is an Elizabeth Glaser Scientist supported by the Elizabeth Glaser Pediatric AIDS Foundation.
We thank Sam Lee and Bobby Benitez for expert technical assistance and Sandra Bridges of DAIDS/NIAID for scientific input.
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FOOTNOTES |
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* Corresponding author. Mailing address: Gladstone Institute of Virology and Immunology, P.O. Box 419100, San Francisco, CA 94141-9100. Phone: (415) 695-3813. Fax: (415) 826-8449. E-mail: cstoddart{at}gladstone.ucsf.edu.
Present address: Department of Experimental Oncology, European
Institute of Oncology, Milan, Italy.
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