Previous Article | Next Article 
Journal of Virology, October 2000, p. 9306-9312, Vol. 74, No. 19
Laboratoire d'Immunologie Cellulaire et
Tissulaire, UMR CNRS 7627,1 Laboratoire
de Virologie,3 and Département des
Maladies Infectieuses,4 Hôpital
Pitié-Salpêtrière, 75013 Paris, France, and
Max-Planck-Institut für Infektionsbiologie, D-10117
Berlin, Germany2
Received 28 January 2000/Accepted 26 June 2000
The impact of drug resistance mutations induced by nucleoside
reverse transcriptase (RT) inhibitors (NRTI) on cytotoxic T-lymphocyte (CTL) recognition of human immunodeficiency virus type 1 strain LAI
(HIV-1LAI) RT was addressed in 35 treated or untreated
patients. Two HIV-1LAI RT regions encompassing mutation
M41L, L74V, M184V, and T215Y/F were recognized in 75 and 83% mutated
and in 33 and 42% unmutated samples, respectively. A total of 41 new
CTL epitopes overlapping these mutations were predicted. Mutations
enhanced HLA-binding scores of 17 epitopes, decreased scores of 5, and had no effect in 19. Four predicted epitopes containing mutations 41, 74, and 184 were tested and recognized by CD8 cells from mutated or
unmutated samples, with frequencies up to 270 gamma interferon spot-forming cells per 106 peripheral blood mononuclear
cells. Therefore, RT mutations induced by NRTI can increase the
immunogenicity of RT for CTL and might allow a better immune control of
resistant viruses in vivo, suggesting that specific immune therapy
might help prevent these mutations.
Cytotoxic T lymphocytes (CTL)
specific for human immunodeficiency virus (HIV) or simian
immunodeficiency virus are considered the most efficient virus-specific
immune responses (4, 26, 29, 39). The strength and the
diversity of CTL responses (16, 54) have been proposed,
together with reverse transcriptase (RT) infidelity (7, 33,
37), as an important factor for virus variability at time of
asymptomatic disease and strong immune functions. Some viral mutations
can decrease immunogenicity by interfering with the intracellular
processing or with the HLA binding of viral peptides, thereby resulting
in a lack of CTL recognition (5, 11, 13, 14, 22, 30, 32,
34). In contrast, new HIV variants that do not interfere with
such processes can be immunogenic for specific new CTL clones
(16), a fact which contributes to some extent to determining
HIV variability (54).
The high level of HIV type 1 (HIV-1) RT sequence conservation among
different HIV isolates (25) makes RT one of the most frequent targets for CTL recognition; indeed, 80% of HIV-infected individuals have specific RT-specific CTL (17). Prolonged
antiviral mono- or bitherapy with nucleoside RT inhibitors (NRTI),
however, results in selection of HIV-1 strains containing mutations in the RT gene (36). These mutations often have an impact on
the enzymatic activity of RT and on the fitness of the virus (2, 45). These drug-induced mutations are highly standardized and characteristic of the various NRTI used (28, 38). Highly
active antiretroviral therapies (HAART) combining various drug regimens have decreased the occurrence of such mutations by reducing levels of
virus replication, but they concomitantly decrease the intensity of the
HIV-specific CTL responses (10, 15, 29). Currently viral
replication is efficiently controlled in only 50% of patients receiving HAART; frequency of treatment failures is increasing and
correlates with high levels of drug-induced mutations (56). In industrialized countries, approximately 15% of new cases of HIV
primary infection involve strains that show primary drug-induced mutations transmitted by treated individuals (3, 27, 55). The consequences of these mutations for RT recognition by CTL and the
ability of the host's RT-specific immune responses to help control
growth of resistant variants is not known.
To address this question and to evaluate whether fixed RT mutations
induced by nucleoside analogs might alter immune recognition, we
performed a prospective analysis of CTL responses directed against RT
drug-induced mutations in patients treated by NRTI in mono- or
bitherapy between 1991 and 1996, before the advent of protease
inhibitors, in order to avoid bias due to decreased CTL frequencies in
HAART-treated patients.
A total of 66 samples from 35 patients, either before (n = 29) or during (n = 37) antiretroviral therapy by
NRTI, were selected on the basis of positive CTL responses against the
whole HIV-1LAI Pol sequence. Polyclonal HIV-specific CTL
lines were generated by cocultures of patient peripheral blood
mononuclear cells (PBMC) autologous, irradiated phytohemagglutinin
(PHA)-stimulated cells, as described elsewhere (16). A
standard chromium release assay was performed against autologous
B-lymphoblastoid cell lines infected with recombinant vaccinia virus
expressing Pol and RT. We also tested recognition of two
HIV-1LAI RT truncated regions (RT-1 [1 to 143] and RT-2
[143 to 293]) encompassing the sites of NRTI-induced mutations as
described elsewhere (17). CTL responses were considered positive when the specific response exceeded the nonspecific response by 10% or more for at least two successive effector/target ratios. Regions RT-1 and RT-2 were recognized with similar frequencies (59%
for each in untreated samples; 49% for RT-1 and 46% for RT-2 in
treated samples), independently of their CD4 counts or viral loads
(data not shown).
We then analyzed patients PBMC for the presence of four major standard
mutations induced in vivo by nucleoside analogs at positions M41L and
L74V located in RT-1 and positions M184V and T215Y/F in RT-2. We used a
genotyping line probe assay (LiPA) for HIV-1 RT (Murex Diagnostics
S.A., Chatillon, France) according to manufacturer's instructions as
described by Descamps et al. (12). This assay simultaneously
detects the wild-type and drug-selected variants in codons 41, 69, 70, 74, 184, 214, and 215 (43), with specific oligonucleotide
probes immobilized on membrane-based strips. When comparing CTL
recognition of RT-1 and RT-2 with frequencies of mutations, we observed
RT-1-specific CTL in 5 out of 6 treated samples containing the M41L
and/or L74V mutations but in only 5 out of the 12 unmutated samples.
Similarly, RT-2 was recognized in six out of eight samples containing
mutations M184V and/or T215Y/F but in only three out of nine unmutated
samples (data not shown). In half of the cases, the wild-type and
mutated strains coexisted, but the LiPA method does not allow
quantification of the various clones. These results demonstrate that
CTL recognition of these RT regions is twice as frequent in samples
containing NRTI-induced mutations as in unmutated samples.
To analyze further the immunogenicity of the M41L, L74V, M184V, and
T215Y/F mutations, CTL recognition had to be studied at the epitope
level. Only few CTL epitopes surrounding sites of drug-induced
mutations have been described up to now: RT 33-41 and 33-43, 179-187, 180-189, and 209-220 (17, 18, 49-51) (Table 1). Therefore, we used first a
theoretical analysis to predict new RT epitopes around sites of
NRTI-induced mutations based on a computer scoring
(http://bimas.dcrt.nih.gov/molbio/hla_bind/) that allows the
location and ranking of peptides that contain binding motifs for HLA
class I molecules (31). For a given peptide, the best score
is obtained when it contains the correct dominant and auxiliary anchor
residues for a particular HLA molecule. The median score for 66 known,
published HIV CTL epitopes from the Los Alamos HIV molecular immunology
database was 15 (25th and 75th percentiles, 3 to 120) (6,
25). For example a known HIV-1LAI RT CTL epitope
(309-317) (48) had a predicted binding score to HLA-A0201 of
39. In the present study we used a cutoff of 10 for the HLA-binding
scores of our predicted epitopes.
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Immunogenicity of Mutations Induced by Nucleoside
Reverse Transcriptase Inhibitors for Human Immunodeficiency Virus
Type 1-Specific Cytotoxic T Cells
ABSTRACT
Top
Abstract
Text
References
TEXT
Top
Abstract
Text
References
TABLE 1.
Most important RT mutations induced by NRTI and known RT
CTL epitopes containing these mutationsa
We analyzed scores of binding of the HIV-1LAI RT sequences
around positions 41, 74, 184, and 215 to 19 patient HLA molecules from
our study group for which a prediction motif was available. We could
predict 41 new putative CTL epitopes surrounding the major mutations
M41L, L74V, M184V, and T215Y. We then compared the HLA-binding
capacities of the wild-type (LAI) or mutated RT sequences. Six epitopes
were predicted around each of the mutations M41L and L74V in the
context of nine distinct HLA molecules (Fig. 1A and B). Mutation M41L occurred at
anchor positions (p2 or p9) in three epitopes (32-41, 33-41, and 40-49)
and increased binding scores to 6 HLA molecules (Fig. 1A). Mutation
L74V affected the p2 anchor position in two RT epitopes (73-81 and
73-82) in the context of three HLA molecules but decreased the binding
scores to two of them (Fig. 1B). Mutation at position 184 was also
located in a highly immunogenic region since five predicted epitopes
surrounding mutation M184V were predicted in the context of 12 HLA
molecules (Fig. 1C). Mutation M184V affected anchor motif (p9) in only
one predicted epitope (RT 175-184) and induced a strong binding score increase in two out of three HLA molecules tested. The position 184 mutation slightly affected binding scores to only three HLA molecules.
In contrast, mutation T215Y occurred within a poorly immunogenic
region: only two epitopes could be predicted in the context of three
HLA molecules. Mutation T215Y increased the HLA-binding score
of peptide 206-215 to three HLA molecules only (Fig. 1D). Therefore, mutations M41L, L74V, and M184V occur in strongly
immunogenic regions that contain 11, 12, and 13 predicted CTL epitopes,
respectively, while mutation T215Y occurs in a poorly immunogenic
region that contains only 5 predicted epitopes.
|
Overall, NRTI-induced mutations increased the HLA-binding scores in 42% of the 41 predicted epitopes. In contrast, HLA binding scores were decreased in only 5 (12%) epitopes. Mutations 41, 74, and 215 affected peptide anchor positions, while mutation 184 affected mostly central amino acids in predicted epitopes. Altogether 21 epitopes had anchor positions affected; for 15 (71%) of these, the HLA-binding scores were increased. Mutation 184, which affected mostly the central amino acid positions of the predicted epitopes, decreased HLA-binding scores in only three combinations. These theoretical results suggest that the major mutations induced by NRTI rarely impair but rather improve at least in half of the cases the capacity of mutated candidate epitopes to bind HLA class I molecules.
We then tested whether such known or predicted epitopes were indeed
recognized by CD8 cells when affected by a drug-induced mutation.
We used an enzyme-linked spot (ELISPOT) assay for single-cell gamma interferon (IFN-
) release adapted from Dalod et al.
(10), using polyvinylidene difluoride-bottomed well plates
(Millipore, Molsheim, France) and two anti-human IFN- monoclonal
antibodies, the second being biotinylated (Diaclone, Besançon,
France). PBMC were added in triplicate wells at 105 and
5 × 104 cells per well in the presence of peptide,
PHA as a positive control, or medium alone. A panel of peptides was
synthesized according to the HIV-1 epitope sequences available at the
Los Alamos HIV molecular immunology database
(http://hiv-lanl.gov/immunology/advancedctl.html) or to the
predictive analysis described above (Syntem, Nîmes, France). We analyzed recognition of five epitopes affected by mutations
M41L, L74V, M184V, and T215Y in the context of the most frequent HLA
molecules in nine patients selected according to their treatment and
HLA type. As positive controls, known CTL epitopes from the HIV RT,
Env, or Nef and from cytomegalovirus (CMV) pp65 were recognized in the
context of the same HLA class I molecules, within ranges of frequencies
from 0 to 1,545 spot-forming cells (SFC) per 106 PBMC.
The effect of mutation M41L was evaluated in one HLA-B27 and four
HLA-A2 patients before and/or after receiving 3 zidovudine. The patient
201#5 sample harbored mutation M41L, which increased the HLA-A2-binding
score of this previously described epitope (33-41) (Fig. 1A). The
mutated but not the wild-type peptide was recognized after treatment in
this patient, with a frequency of 95 SFC per 106 PBMC (Fig.
2A). We evaluated the effect of mutation
L74V on recognition of the predicted epitope 73-82 in two HLA-A3
patients before and after treatment and found that neither of these
patients harbored mutations. The wild-type RT 73-82 peptide was
recognized both before and after treatment in patients 252#0 and 252#4,
with frequencies of 40 and 82 SFC per 106 PBMC,
respectively (Fig. 2B). The mutated peptide was not recognized. In that
case, the mutation theoretically decreased this epitope's binding
score to HLA-A3 (Fig. 1B). Two predicted epitopes surrounding mutation
M184V were tested in three patients. Both wild-type and mutated 175-184 peptides were recognized in the context of HLA-B51 in patient 246#1
before treatment, with frequencies of 51 and 100 SFC per
106 PBMC, respectively (Fig. 2D). Another peptide, RT
181-189, was tested in two HLA-A2 patients. Mutation 184 did not affect
significantly recognition of peptide 181-189 mutated or wild type (Fig.
2C), the calculated binding score for which was similarly unaffected (Fig. 1C). In patient 250#0, both wild-type and mutated peptides were
recognized with high frequencies of 214 to 270 SFC/106
PBMC. In a second HLA-A2 patient (201#5), no CTL could be detected against either wild-type or mutated peptide. Peptide 206-215, encompassing mutation T215Y, was tested in three patients before or
after receiving AZT. Only the patient 201#5 sample harbored the
mutation T215Y/F. Neither wild-type nor mutated peptides were recognized, however (Fig. 2A).
|
Therefore, all predicted epitopes that could be tested were recognized at least once, except around mutation T215Y. These new candidate epitopes surrounding NRTI mutations were recognized with frequencies of SFC ranging between 40 and 270 per 106 PBMC, similar to those observed for known HIV or even RT epitopes, except when surrounding the T215Y mutation, which appears to be located in a poorly immunogenic region.
Discussion. We demonstrated herein that mutations induced by mono- or bitherapy with NRTI, M41L, L74V, M184V, and T215Y/F, did not impair CTL recognition of the RT sites of drug-induced mutations in treated patients. On the contrary, the drug-induced mutations were associated with twofold more frequent recognition of the unmutated HIV-1LAI RT regions that encompass those mutations. The limited number of known CTL epitopes that surround these mutations prompted us to use a theoretical analysis to predict new CTL epitopes restricted by patient HLA molecules based on their HLA-binding capacity. Mutations M41L, L74V, and M184V occur in immunogenic regions containing multiple predicted epitopes binding to a number of HLA class I molecules. In contrast, mutation T215Y occurs in a region of poor immunogenicity that contains only five predicted epitopes. Mutations M41L, L74V, and T215Y, but not M184V, frequently involve dominant anchor motifs in these predicted epitopes. When the mutations involved dominant anchor motifs (for 21 predicted epitopes), the HLA-binding scores increased, in 15 cases (15/21 = 71%), correspondng to two-thirds of the cases. Overall, NRTI-induced mutations, whether they affected the anchor positions or not, augmented the HLA-binding scores for 42% of candidate epitopes whereas a decrease was predicted for only five epitopes, suggesting that these NRTI-induced mutations may facilitate CTL recognition of the predicted epitopes. These findings and predictions contrast with observations that for other HIV proteins, some HIV mutations affecting critical amino acid anchor positions result in partial escape of HIV-1 from CTL recognition (4, 14, 32). In addition, mutations sparing anchor motifs in CTL epitopes can also significantly alter peptide processing or CTL recognition (11, 21, 30). The findings presented here are in agreement with our previous report that most natural mutations occurring in HIV-1 Nef are immunogenic and stimulate new variant-specific CTL clones (16).
Here we demonstrated the in vivo CTL recognition of five predicted epitopes affected by mutations M41L, L74V, M184V, and T215Y in nine patients who beared frequent HLA molecules: A2, A3, B27, B51, and B62. All candidate epitopes were shown to be recognized at least once by CD8 T cells, except around mutation T215Y. The ELISPOT assay measures the frequencies of peptide-specific effector CD8 T cells that have been already primed and amplified in vivo and produce IFN- (1). The production of IFN- detected by ELISPOT assay has also been shown to be associated with cytolytic activity in Epstein-Barr virus infection (44). Our results
therefore indicate that the theoretically predicted epitopes that we
tested were efficiently processed in vivo and recognized by CD8 T cells in vivo. The frequencies observed ranged between 40 and 270 per 106 PBMC and were similar to those observed for other known
RT or HIV epitopes. The epitope-specific CD8 cell frequencies were in accordance with the mutation-induced predicted changes in HLA-binding scores, thus confirming the validity of the predictive model that we
used (31). Some discrepancies were observed, but we cannot exclude that the level of mutant expression in vivo might have been
insufficient to generate a specific CTL response. Alternatively, the
coexistence of other class I loci could have negatively selected the
appropriate CD8+ T-lymphocyte response. It is only in the
case of mutation T215Y, which is frequently observed within the
AZT-induced mutations (35, 56), that predicted epitopes
failed to be recognized, suggesting a poor immune control of this
region. Thus, both predictive model and ELISPOT analyses confirm the
poor immunogenicity of the RT region surrounding mutation 215. In
contrast, the high immunogenicity of regions surrounding mutations 41, 74, and 184 found in the context of multiple HLA class I molecules
together with the increasing or unchanged HLA-binding scores conferred by most mutations and their ex vivo detection by specific CD8 T cells
confirms our hypothesis that these NRTI-induced mutations do not alter
and might even improve the immune recognition of HIV-1 RT.
In conclusion, mutations induced by NRTI do not cause loss of CTL
recognition of the RT regions harboring the mutations. Moreover, our
data strongly suggest that some of these mutations induced by NRTI
might increase rather than decrease the immunogenicity of the
corresponding CTL epitopes and can be recognized in vivo by CD8 T
cells. Therefore, the persistence of these mutations over time might
reflect not an immune escape by lack of recognition but rather a strong
selective pressure of the drug. These mutations are known to induce
replication disadvantage and a loss in viral fitness (2, 8, 19,
40). We propose in addition that the enhanced CTL recognition of
the NRTI-induced variants might contribute to the relatively poor
growth capacity of mutated viruses in vivo. A larger study is in
progress in our laboratory to confirm these findings. At a time when
clinical benefits of antiretroviral therapy are clearly shown to depend
on the extent and durability of viral suppression (20), the
generation of specific immune responses to these mutated regions might
improve control of emerging drug-resistant mutations in HIV-1-treated
individuals. Similarly, the increasing frequencies of new
contaminations with mutated viruses should prompt design of vaccine
sequences taking those mutated epitopes into account. We propose that
both therapeutic immunization and preventive vaccine programs should
incorporate the RT-mutated immunogenic sequences described herein.
| |
ACKNOWLEDGMENTS |
|---|
This work was supported by the Agence Nationale de Recherches sur le SIDA (ANRS) and the Fondation pour la Recherche Medicale.
We thank the patients and clinicians of the IMMUNOCO cohort, without whom this work would not be possible, P. Debre for constant support in the study, ANRS for providing peptides and recombinant vaccinia viruses, M. Jung for help with RT sequence analysis, F. Hadida, O. Bonduelle, and J. C. Deschemin for CTL assays, K. Dott for vaccinia virus constructs, G. Jung for peptide synthesis, C. Dehay and M. Geuzoli for HLA typing, N. Profizi for advice in performing LiPA of HIV-1 RT from PBMC, and Dorian McIlroy and Lucile Mollet for reading the manuscript.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Laboratoire d'Immunologie Cellulaire et Tissulaire, UMR CNRS 7627, Hôpital Pitié-Salpêtrière, 83 Bd. de l'Hôpital, 75013 Paris, France. Phone: 33 1 42 17 74 03. Fax: 33 1 42 17 74 90. E-mail: brigitte.autran{at}ap-hop-paris.fr.
| |
REFERENCES |
|---|
|
Top
Abstract
Text
References
|
|---|
| 1. | Ahmed, R., and D. Gray. 1996. Immunological memory and protective immunity: understanding their relation. Science 272:54-60[Abstract]. |
| 2. | Back, N. K., M. Nijhuis, W. Keulen, C. A. Boucher, B. O. Oude Essink, A. B. van Kuilenburg, A. H. van Gennip, and B. Berkhout. 1996. Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme. EMBO J. 15:4040-4049[Medline]. |
| 3. |
Boden, D.,
A. Hurley,
L. Zhang,
Y. Cao,
Y. Guo,
E. Jones,
J. Tsay,
J. Ip,
C. Farthing,
K. Limoli,
N. Parkin, and M. Markowitz.
1999.
HIV-1 drug resistance in newly infected individuals.
JAMA
282:1135-1141 |
| 4. |
Borrow, P.,
H. Lewicki,
B. H. Hahn,
G. M. Shaw, and M. B. Oldstone.
1994.
Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection.
J. Virol.
68:6103-6110 |
| 5. | Borrow, P., H. Lewicki, X. Wei, M. S. Horwitz, N. Peffer, H. Meyers, J. A. Nelson, J. E. Gairin, B. H. Hahn, M. B. Oldstone, and G. M. Shaw. 1997. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat. Med. 3:205-211[CrossRef][Medline]. |
| 6. | Brander, C., and B. Walker. 1997. The HLA-class I restricted CTL response in HIV-1 infection: identification of optimal epitopes, p. IV50-IV60. In B. Korber, C. Brander, B. Walker, R. Koup, B. Haynes, and J. Moore (ed.), HIV-1 molecular immunology database, vol. 3. Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, N.Mex. |
| 7. | Coffin, J. M. 1992. Genetic diversity and evolution of retroviruses. Curr. Top. Microbiol. Immunol. 176:143-164[Medline]. |
| 8. | Coffin, J. M. 1995. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 267:483-489. |
| 9. | Culmann, B., E. Gomard, M. P. Kieny, B. Guy, F. Dreyfus, A. G. Saimot, D. Sereni, D. Sicard, and J. P. Levy. 1991. Six epitopes reacting with human cytotoxic CD8+ T cells in the central region of the HIV-1 NEF protein. J. Immunol. 146:1560-1565[Abstract]. |
| 10. | Dalod, M., M. Harzic, I. Pellegrin, B. Dumon, B. Hoen, D. Sereni, J. C. Deschemin, J. P. Levy, A. Venet, and E. Gomard. 1998. Evolution of cytotoxic T lymphocyte responses to human immunodeficiency virus type 1 in patients with symptomatic primary infection receiving antiretroviral triple therapy. J. Infect. Dis. 178:61-69[Medline]. |
| 11. | Del Val, M., H. J. Schlicht, T. Ruppert, M. J. Reddehase, and U. H. Koszinowski. 1991. Efficient processing of an antigenic sequence for presentation by MHC class I molecules depends on its neighboring residues in the protein. Cell 66:1145-1153[CrossRef][Medline]. |
| 12. |
Descamps, D.,
V. Calvez,
G. Collin,
A. Cecille,
C. Apetrei,
F. Damond,
C. Katlama,
S. Matheron,
J. M. Huraux, and F. Brun-Vezinet.
1998.
Line probe assay for detection of human immunodeficiency virus type 1 mutations conferring resistance to nucleoside inhibitors of reverse transcriptase: comparison with sequence analysis.
J. Clin. Microbiol.
36:2143-2145 |
| 13. | Evans, D. T., D. H. O'Connor, P. Jing, J. L. Dzuris, J. Sidney, J. da Silva, T. M. Allen, H. Horton, J. E. Venham, R. A. Rudersdorf, T. Vogel, C. D. Pauza, R. E. Bontrop, R. DeMars, A. Sette, A. L. Hughes, and D. I. Watkins. 1999. Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef. Nat. Med. 5:1270-1276[CrossRef][Medline]. |
| 14. | Goulder, P. J., R. E. Phillips, R. A. Colbert, S. McAdam, G. Ogg, M. A. Nowak, P. Giangrande, G. Luzzi, B. Morgan, A. Edwards, A. J. McMichael, and J. S. Rowland. 1997. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat. Med. 3:212-217[CrossRef][Medline]. |
| 15. |
Gray, C. M.,
J. Lawrence,
J. M. Schapiro,
J. D. Altman,
M. A. Winters,
M. Crompton,
M. Loi,
S. K. Kundu,
M. M. Davis, and T. C. Merigan.
1999.
Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy (HAART).
J. Immunol.
162:1780-1789 |
| 16. | Haas, G., U. Plikat, P. Debre, M. Lucchiari, C. Katlama, Y. Dudoit, O. Bonduelle, M. Bauer, H. G. Ihlenfeldt, G. Jung, B. Maier, A. Meyerhans, and B. Autran. 1996. Dynamics of viral variants in HIV-1 Nef and specific cytotoxic T lymphocytes in vivo. J. Immunol. 157:4212-4221[Abstract]. |
| 17. | Haas, G., A. Samri, E. Gomard, A. Hosmalin, J. Duntze, J. M. Bouley, H. G. Ihlenfeldt, C. Katlama, and B. Autran. 1998. Cytotoxic T-cell responses to HIV-1 reverse transcriptase, integrase and protease. AIDS 12:1427-1436[CrossRef][Medline]. |
| 18. | Harrer, E., T. Harrer, P. Barbosa, M. Feinberg, R. P. Johnson, S. Buchbinder, and B. D. Walker. 1996. Recognition of the highly conserved YMDD region in the human immunodeficiency virus type 1 reverse transcriptase by HLA-A2- restricted cytotoxic T lymphocytes from an asymptomatic long-term nonprogressor. J. Infect. Dis. 173:476-479[Medline]. |
| 19. |
Harrigan, P. R.,
S. Bloor, and B. A. Larder.
1998.
Relative replicative fitness of zidovudine-resistant human immunodeficiency virus type 1 isolates in vitro.
J. Virol.
72:3773-3778 |
| 20. |
Katzenstein, D. A.,
S. M. Hammer,
M. D. Hughes,
H. Gundacker,
J. B. Jackson,
S. Fiscus,
S. Rasheed,
T. Elbeik,
R. Reichman,
A. Japour,
T. C. Merigan, and M. S. Hirsch.
1996.
The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team.
N. Engl. J. Med.
335:1091-1098 |
| 21. | Klenerman, P., U. C. Meier, R. E. Phillips, and A. J. McMichael. 1995. The effects of natural altered peptide ligands on the whole blood cytotoxic T lymphocyte response to human immunodeficiency virus. Eur. J. Immunol. 25:1927-1931[Medline]. |
| 22. | Klenerman, P., J. S. Rowland, S. McAdam, J. Edwards, S. Daenke, D. Lalloo, B. Koppe, W. Rosenberg, D. Boyd, A. Edwards, et al. 1994. Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature 369:403-407[CrossRef][Medline]. |
| 23. | Koenig, S., T. R. Fuerst, L. V. Wood, R. M. Woods, J. A. Suzich, G. M. Jones, V. F. de la Cruz, R. J. Davey, S. Venkatesan, B. Moss, et al. 1990. Mapping the fine specificity of a cytolytic T cell response to HIV-1 nef protein. J. Immunol. 145:127-135[Abstract]. |
| 24. | Korbel, B., R. Koup, B. Walker, B. Haynes, J. Moore, and G. E. Myers (ed.). 1995. HIV molecular immunological database. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, N.Mex. |
| 25. | Korber, B. T., E. E. Allen, A. D. Farmer, and G. L. Myers. 1995. Heterogeneity of HIV-1 and HIV-2. AIDS 9(Suppl. A):S5-S18. |
| 26. |
Koup, R. A.,
J. T. Safrit,
Y. Cao,
C. A. Andrews,
G. McLeod,
W. Borkowsky,
C. Farthing, and D. D. Ho.
1994.
Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.
J. Virol.
68:4650-4655 |
| 27. |
Little, S. J.,
E. S. Daar,
R. T. D'Aquila,
P. H. Keiser,
E. Connick,
J. M. Whitcomb,
N. S. Hellmann,
C. J. Petropoulos,
L. Sutton,
J. A. Pitt,
E. S. Rosenberg,
R. A. Koup,
B. D. Walker, and D. D. Richman.
1999.
Reduced antiretroviral drug susceptibility among patients with primary HIV infection.
JAMA
282:1142-1149 |
| 28. | Mellors, J., B. Larder, and R. Schinazi. 1995. Mutations in HIV-1 reverse transcriptase and protease associated with drug resistance. Int. Antiviral News 3:8-13. |
| 29. |
Ogg, G. S.,
X. Jin,
S. Bonhoeffer,
P. R. Dunbar,
M. A. Nowak,
S. Monard,
J. P. Segal,
Y. Cao,
J. S. Rowland,
V. Cerundolo,
A. Hurley,
M. Markowitz,
D. D. Ho,
D. F. Nixon, and A. J. McMichael.
1998.
Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA.
Science
279:2103-2106 |
| 30. | Ossendorp, F., M. Eggers, A. Neisig, T. Ruppert, M. Groettrup, A. Sijts, E. Mengede, P. M. Kloetzel, J. Neefjes, U. Koszinowski, and C. Melief. 1996. A single residue exchange within a viral CTL epitope alters proteasome-mediated degradation resulting in lack of antigen presentation. Immunity 5:115-124[CrossRef][Medline]. |
| 31. | Parker, K. C., M. A. Bednarek, and J. E. Coligan. 1994. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J. Immunol. 152:163-175[Abstract]. |
| 32. | Phillips, R. E., J. S. Rowland, D. F. Nixon, F. M. Gotch, J. P. Edwards, A. O. Ogunlesi, J. G. Elvin, J. A. Rothbard, C. R. Bangham, C. R. Rizza, et al. 1991. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature 354:453-459[CrossRef][Medline]. |
| 33. |
Preston, B. D.,
B. J. Poiesz, and L. A. Loeb.
1988.
Fidelity of HIV-1 reverse transcriptase.
Science
242:1168-1171 |
| 34. |
Price, D. A.,
P. J. Goulder,
P. Klenerman,
A. K. Sewell,
P. J. Easterbrook,
M. Troop,
C. R. Bangham, and R. E. Phillips.
1997.
Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection.
Proc. Natl. Acad. Sci. USA
94:1890-1895 |
| 35. | Puchhammer, S. E., B. Schmied, C. W. Mandl, N. Vetter, and F. X. Heinz. 1999. Comparison of line probe assay (LIPA) and sequence analysis for detection of HIV-1 drug resistance. J. Med. Virol. 57:283-289[CrossRef][Medline]. |
| 36. | Richman, D. D. 1992. HIV drug resistance. AIDS Res. Hum. Retroviruses 8:1065-1071[Medline]. |
| 37. |
Roberts, J. D.,
K. Bebenek, and T. A. Kunkel.
1988.
The accuracy of reverse transcriptase from HIV-1.
Science
242:1171-1173 |
| 38. | Schinazi, R. F., B. A. Larder, and J. W. Mellors. 1999. Mutations in retroviral genes associated with drug resistance: 1999-2000. Int. Antiviral News 7:46-69. |
| 39. |
Schmitz, J. E.,
M. J. Kuroda,
S. Santra,
V. G. Sasseville,
M. A. Simon,
M. A. Lifton,
P. Racz,
R. K. Tenner,
M. Dalesandro,
B. J. Scallon,
J. Ghrayeb,
M. A. Forman,
D. C. Montefiori,
E. P. Rieber,
N. L. Letvin, and K. A. Reimann.
1999.
Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes.
Science
283:857-860 |
| 40. |
Sharma, P. L., and C. S. Crumpacker.
1999.
Decreased processivity of human immunodeficiency virus type 1 reverse transcriptase (RT) containing didanosine-selected mutation Leu74Val: a comparative analysis of RT variants Leu74Val and lamivudine-selected Met184Val.
J. Virol.
73:8448-8456 |
| 41. | Shiga, H., T. Shioda, H. Tomiyama, Y. Takamiya, S. Oka, S. Kimura, Y. Yamaguchi, T. Gojoubori, H. G. Rammensee, K. Miwa, and M. Takiguchi. 1996. Identification of multiple HIV-1 cytotoxic T-cell epitopes presented by human leukocyte antigen B35 molecules. AIDS 10:1075-1083[Medline]. |
| 42. | Sipsas, N. V., S. A. Kalams, A. Trocha, S. He, W. A. Blattner, B. D. Walker, and R. P. Johnson. 1997. Identification of type-specific cytotoxic T lymphocyte responses to homologous viral proteins in laboratory workers accidentally infected with HIV-1. J. Clin. Investig. 99:752-762[Medline]. |
| 43. | Stuyver, L., A. Wyseur, A. Rombout, J. Louwagie, T. Scarcez, C. Verhofstede, D. Rimland, R. F. Schinazi, and R. Rossau. 1997. Line probe assay for rapid detection of drug-selected mutations in the human immunodeficiency virus type 1 reverse transcriptase gene. Antimicrob. Agents Chemother. 41:284-291[Abstract]. |
| 44. |
Tan, L. C.,
N. Gudgeon,
N. E. Annels,
P. Hansasuta,
C. A. O'Callaghan,
J. S. Rowland,
A. J. McMichael,
A. B. Rickinson, and M. F. Callan.
1999.
A re-evaluation of the frequency of CD8+ T cells specific for EBV in healthy virus carriers.
J. Immunol.
162:1827-1835 |
| 45. |
Tisdale, M.,
S. D. Kemp,
N. R. Parry, and B. A. Larder.
1993.
Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase.
Proc. Natl. Acad. Sci. USA
90:5653-5636 |
| 46. | Tomiyama, H., K. Miwa, H. Shiga, Y. I. Moore, S. Oka, A. Iwamoto, Y. Kaneko, and M. Takiguchi. 1997. Evidence of presentation of multiple HIV-1 cytotoxic T lymphocyte epitopes by HLA-B*3501 molecules that are associated with the accelerated progression of AIDS. J. Immunol. 158:5026-5034[Abstract]. |
| 47. |
Tsomides, T. J.,
A. Aldovini,
R. P. Johnson,
B. D. Walker,
R. A. Young, and H. N. Eisen.
1994.
Naturally processed viral peptides recognized by cytotoxic T lymphocytes on cells chronically infected by human immunodeficiency virus type 1.
J. Exp. Med.
180:1283-1293 |
| 48. |
Tsomides, T. J.,
B. D. Walker, and H. N. Eisen.
1991.
An optimal viral peptide recognized by CD8+ T cells binds very tightly to the restricting class I major histocompatibility complex protein on intact cells but not to the purified class I protein.
Proc. Natl. Acad. Sci. USA
88:11276-11280 |
| 49. | van der Burg, S. H., M. R. Klein, O. Pontesilli, A. M. Holwerda, J. W. Drijfhout, W. M. Kast, F. Miedema, and C. J. Melief. 1997. HIV-1 reverse transcriptase-specific CTL against conserved epitopes do not protect against progression to AIDS. J. Immunol. 159:3648-3654[Abstract]. |
| 50. | van der Burg, S. H., M. R. Klein, C. J. van de Velde, W. M. Kast, F. Miedema, and C. J. Melief. 1995. Induction of a primary human cytotoxic T-lymphocyte response against a novel conserved epitope in a functional sequence of HIV-1 reverse transcriptase. AIDS 9:121-127[Medline]. |
| 51. | van der Burg, S. H., M. J. Visseren, R. M. Brandt, W. M. Kast, and C. J. Melief. 1996. Immunogenicity of peptides bound to MHC class I molecules depends on the MHC-peptide complex stability. J. Immunol. 156:3308-3314[Abstract]. |
| 52. |
Walker, B. D.,
C. Flexner,
L. K. Birch,
L. Fisher,
T. J. Paradis,
A. Aldovini,
R. Young,
B. Moss, and R. T. Schooley.
1989.
Long-term culture and fine specificity of human cytotoxic T-lymphocyte clones reactive with human immunodeficiency virus type 1.
Proc. Natl. Acad. Sci. USA
86:9514-9518 |
| 53. | Wills, M. R., A. J. Carmichael, K. Mynard, X. Jin, M. P. Weekes, B. Plachter, and J. G. Sissons. 1996. The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J. Virol. 70:7569-7579[Abstract]. |
| 54. | Wolinsky, S. M., B. T. Korber, A. U. Neumann, M. Daniels, K. J. Kunstman, A. J. Whetsell, M. R. Furtado, Y. Cao, D. D. Ho, and J. T. Safrit. 1996. Adaptive evolution of human immunodeficiency virus-type 1 during the natural course of infection. Science 272:537-542[Abstract]. |
| 55. | Yerly, S., L. Kaiser, E. Race, J. P. Bru, F. Clavel, and L. Perrin. 1999. Transmission of antiretroviral-drug-resistant HIV-1 variants. Lancet 354:729-733[CrossRef][Medline]. |
| 56. | Young, B., S. Johnson, M. Bahktiari, D. Shugarts, R. K. Young, M. Allen, R. N. Ramey, and D. R. Kuritzkes. 1998. Resistance mutations in protease and reverse transcriptase genes of human immunodeficiency virus type 1 isolates from patients with combination antiretroviral therapy failure. J. Infect. Dis. 178:1497-1501[CrossRef][Medline]. |
Journal of Virology, October 2000, p. 9306-9312, Vol. 74, No. 19
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Paredes, R., Sagar, M., Marconi, V. C., Hoh, R., Martin, J. N., Parkin, N. T., Petropoulos, C. J., Deeks, S. G., Kuritzkes, D. R.
(2009). In Vivo Fitness Cost of the M184V Mutation in Multidrug-Resistant Human Immunodeficiency Virus Type 1 in the Absence of Lamivudine. J. Virol.
83: 2038-2043
[Abstract] [Full Text] -
Perez, C. L., Larsen, M. V., Gustafsson, R., Norstrom, M. M., Atlas, A., Nixon, D. F., Nielsen, M., Lund, O., Karlsson, A. C.
(2008). Broadly Immunogenic HLA Class I Supertype-Restricted Elite CTL Epitopes Recognized in a Diverse Population Infected with Different HIV-1 Subtypes. J. Immunol.
180: 5092-5100
[Abstract] [Full Text] -
Cao, J., McNevin, J., McSweyn, M., Liu, Y., Mullins, J. I., McElrath, M. J.
(2008). Novel Cytotoxic T-Lymphocyte Escape Mutation by a Three-Amino-Acid Insertion in the Human Immunodeficiency Virus Type 1 p6Pol and p6Gag Late Domain Associated with Drug Resistance. J. Virol.
82: 495-502
[Abstract] [Full Text] -
Karlsson, A. C., Chapman, J. M., Heiken, B. D., Hoh, R., Kallas, E. G., Martin, J. N., Hecht, F. M., Deeks, S. G., Nixon, D. F.
(2007). Antiretroviral Drug Therapy Alters the Profile of Human Immunodeficiency Virus Type 1-Specific T-Cell Responses and Shifts the Immunodominant Cytotoxic T-Lymphocyte Response from Gag to Pol. J. Virol.
81: 11543-11548
[Abstract] [Full Text] -
Mueller, S. M., Schaetz, B., Eismann, K., Bergmann, S., Bauerle, M., Schmitt-Haendle, M., Walter, H., Schmidt, B., Korn, K., Sticht, H., Spriewald, B., Harrer, E. G., Harrer, T.
(2007). Dual Selection Pressure by Drugs and HLA Class I-Restricted Immune Responses on Human Immunodeficiency Virus Type 1 Protease. J. Virol.
81: 2887-2898
[Abstract] [Full Text] -
Samri, A., Durier, C., Urrutia, A., Sanchez, I., Gahery-Segard, H., Imbart, S., Sinet, M., Tartour, E., Aboulker, J.-P., Autran, B., Venet, A., the ANRS ELISpot Standardization Group,
(2006). Evaluation of the Interlaboratory Concordance in Quantification of Human Immunodeficiency Virus-Specific T Cells with a Gamma Interferon Enzyme-Linked Immunospot Assay. CVI
13: 684-697
[Abstract] [Full Text] -
Stratov, I., Dale, C. J., Chea, S., McCluskey, J., Kent, S. J.
(2005). Induction of T-Cell Immunity to Antiretroviral Drug-Resistant Human Immunodeficiency Virus Type 1. J. Virol.
79: 7728-7737
[Abstract] [Full Text] -
Mason, R. D., Bowmer, M. I., Howley, C. M., Gallant, M., Myers, J. C. E., Grant, M. D.
(2004). Antiretroviral Drug Resistance Mutations Sustain or Enhance CTL Recognition of Common HIV-1 Pol Epitopes. J. Immunol.
172: 7212-7219
[Abstract] [Full Text] -
Turner, D., Brenner, B., Wainberg, M. A.
(2003). Multiple Effects of the M184V Resistance Mutation in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1. CVI
10: 979-981
[Full Text] -
Karlsson, A. C., Deeks, S. G., Barbour, J. D., Heiken, B. D., Younger, S. R., Hoh, R., Lane, M., Sallberg, M., Ortiz, G. M., Demarest, J. F., Liegler, T., Grant, R. M., Martin, J. N., Nixon, D. F.
(2003). Dual Pressure from Antiretroviral Therapy and Cell-Mediated Immune Response on the Human Immunodeficiency Virus Type 1 Protease Gene. J. Virol.
77: 6743-6752
[Abstract] [Full Text] -
Matarrese, P., Gambardella, L., Cassone, A., Vella, S., Cauda, R., Malorni, W.
(2003). Mitochondrial Membrane Hyperpolarization Hijacks Activated T Lymphocytes Toward the Apoptotic-Prone Phenotype: Homeostatic Mechanisms of HIV Protease Inhibitors. J. Immunol.
170: 6006-6015
[Abstract] [Full Text] -
Spira, S., Wainberg, M. A., Loemba, H., Turner, D., Brenner, B. G.
(2003). Impact of clade diversity on HIV-1 virulence, antiretroviral drug sensitivity and drug resistance. J Antimicrob Chemother
51: 229-240
[Abstract] [Full Text] -
Jost, S., Bernard, M.-C., Kaiser, L., Yerly, S., Hirschel, B., Samri, A., Autran, B., Goh, L.-E., Perrin, L.
(2002). A Patient with HIV-1 Superinfection. NEJM
347: 731-736
[Full Text]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»