Previous Article | Next Article 
Journal of Virology, January 1999, p. 797-800, Vol. 73, No. 1
Institute of Molecular Medicine,
Received 12 June 1998/Accepted 1 October 1998
Little is known of the changes in human immunodeficiency virus type
1 (HIV-1)-specific effector cytotoxic T lymphocytes (CTL) after potent
antiretroviral therapy. Using HLA/peptide tetrameric complexes, we show
that after starting treatment, there are early rapid fluctuations in
the HIV-1-specific CTL response which last 1 to 2 weeks. These
fluctuations are followed by an exponential decay (median half-life, 45 days) of HIV-1-specific CTL which continues while viremia remains
undetectable. These data have implications for the immunological
control of drug-resistant virus.
Combination antiretroviral
therapy induces significant changes in the total CD8+
T-cell count (3, 4, 11) which are accompanied by a decrease in the expression of markers associated with cell activation (HLA-DR and CD38) (3). In the absence of detectable viremia, the
frequency of HIV-specific CD8+ T cells is significantly
lower at 6 months than at pretrial levels (16), but it is
not known whether this loss occurs in the first few days of treatment
or over a longer time course. It is also unclear whether the loss
is preceded by a transient increase, as observed in some studies
of total CD8+ cell changes (3). Through
frequent sample time points, we used HLA-peptide tetrameric complexes
to characterize the detailed kinetics of the human immunodeficiency
virus (HIV)-specific cytotoxic T-lymphocyte (CTL) response after potent
antiretroviral therapy in eight treated individuals.
HLA-A*0201 and HLA-B*3501 tetramers were synthesized as previously
described (2) with the immunodominant peptides SLYNTVATL (HIV type 1 [HIV-1] Gag 77-85) (17) and
ILKEPVHGV (HIV-1 Pol 476-84) (21) for A*0201 and
DPNPQEVVL (HIV-1 Env 77-85) (19) for B*3501. HLA
heavy chain was expressed in Escherichia coli with an
engineered C-terminal signal sequence containing a biotinylation site for the enzyme BirA. The 3' primer used for HLA B*3501 was GGAGTGGGAC TCTACCCTC GGTCCTAGG
GACGTAGTA TAAGACCTA CGTGTCTTT
TACCACACC TTAGTAGCA ATTCGAATAGTGT.
After refolding of heavy chain, Tetramer binding is known to correlate well with functional activity
including uncultured peptide-specific cytolysis (16) and
gamma interferon production (14). Weaker positive
correlations exist between tetramer binding and limiting-dilution
analyses (precursor frequency analyses) which quantify those CTL able
to survive and divide during a period of expansion in vitro.
Limiting-dilution analyses generate frequencies of antigen-specific CTL
1 to 2 logs less than those obtained by tetramer binding
(14), and so the overwhelming majority of circulating CTL
measured by the tetramers are believed to be effector CTL (CTLe) that
have more limited proliferative potential. This is consistent with
previous studies showing a similar discrepancy between estimates of
circulating CTL activity and limiting-dilution analyses (8,
13). The lower limit of detection of antigen-specific CTL using
the HLA tetramers is 0.02% of CD8+ cells, based on the
staining of HIV-negative peripheral-blood mononuclear cells
(16). The staining is highly specific, such that CTL clones
and lines directed to different epitope peptides bound to the
same HLA molecule do not stain (5). Tetramer staining was
performed on cryopreserved samples that had been frozen in a
controlled-rate facility to maximize cell viability (routinely greater
than 95%). Staining of fresh and cryopreserved specimens revealed no difference in the fluorescence intensity or frequency of
antigen-specific CTL.
Two-thirds of A*0201-positive individuals recognize the
p17Gag 77-85 epitope (SLYNTVATL), and most of the remainder
respond to the Pol 476-84 epitope (ILKEPVHGV) (9).
Therefore, if both responses are measured concurrently, virtually all
individuals will have quantifiable responses (9, 16).
Furthermore, levels of CTLe to these epitopes have previously been
shown to be potentially important, as the frequency of CTLe inversely
correlates with the plasma viral RNA load, consistent with a role in
the control of plasma viremia (16).
Eight patients with HLA-A*0201 or B*3501 were treated with zidovudine
(600 mg daily), lamivudine (300 mg daily), and a protease inhibitor
(ritonavir [1,200 mg daily], nelfinavir [2,250 mg daily], or
indinavir [2,400 mg daily]). All patients showed a fall in plasma
viral RNA load to below the limit of detection throughout the study.
Three patients were treated within 120 days of infection, and five
patients were treated during the chronic asymptomatic phase. Prior to
initiation of therapy, the CD4 counts ranged from 219 to 564 cells/µl
(mean, 357 cells/µl), the CD8 counts ranged from 303 to 2,275 cells/µl (mean, 945 cells/µl), and the plasma RNA viral loads
(bDNA; lower limit of detection, 500 copies/ml) ranged from 1,420 to
197,300 copies/ml (mean, 46,327 copies/ml). Patients were HLA typed by
using allele-specific PCR.
HIV-specific CTLe frequencies were observed in eight individuals after
starting treatment with combination therapy. Seven of these individuals
were known to be HLA A*0201 positive, and one was B*3501 positive. Of
the seven HLA A*0201-positive individuals, all 7 had identifiable
A2Gag-specific CTLe and six had A2Pol-specific CTLe prior to starting
therapy. Patients B, D, and E were all treated within 120 days of the
onset of symptoms, and patients A, C, and F to H were chronically
infected individuals. Figure 1 (A to H)
documents the changes, from all patients, in the percentage of
CD8+ T cells staining with each tetramer for 6 months after
initiating treatment. Prior to treatment, the percentage of
CD8+ T cells staining with the tetramer ranged from 0.07 to
2.73% (mean, 0.501%; median, 0.2%), whereas after 6 months of
treatment the percentages ranged from 0 to 1.64% (mean, 0.17%;
median, 0.04%). Two members of the study cohort (patients G and H) had
levels of CTLe quantified on more than one occasion prior to treatment, confirming that in the preceding days or weeks, the CTLe response was
relatively stable in the absence of therapy. We have also observed
longitudinal CTLe responses in many untreated chronically infected
individuals who were not included in the current study and found that
large fluctuations do not typically occur in the HIV-specific CTLe
response over 6 months or more (5a, 10a). This is consistent
with previous studies showing that levels of circulating
antigen-specific CTL can be maintained for prolonged periods in the
absence of treatment (13, 22).
Through frequent sampling in six HLA-A*0201-positive individuals (Fig.
1A to F), we were able to examine the detailed changes of the
HIV-specific CTLe in the first 1 to 2 weeks after starting treatment.
Large fluctuations in the A2Gag- and A2Pol-specific CTLe were observed
during the first 2 weeks of therapy. In the majority of individuals,
the fluctuations were composed of an initial fall in the first 5 to 7 days, followed by a rebound increase to levels sometimes above those
obtained prior to treatment. We reasoned that several factors may have
contributed to the early rapid fluctuations in the level of
HIV-specific CTLe observed after starting treatment, including effects
secondary to changes in the CD4+ T-cell population or
redistribution between blood and tissues.
The early rapid fluctuations were then followed by a slower decline
phase. Four individuals (patients A, B, G, and H) had pretreatment
HIV-specific CTLe levels sufficiently high to allow monitoring of the
decay of the CTLe for several months. Figure 2 documents the decay of HIV-specific
CTLe in these individuals, which followed an exponential pattern with a
median half-life of 45 days (mean, 80 days; range, 40 to 200 days). One
individual (patient H) had very high levels of B35Env-specific CTL
(2.7% of CD8+ T cells) prior to starting treatment. We
were therefore able to observe the CTL decline in this individual to 20 months on therapy and confirmed that the decay half-life continued to
remain constant (Fig. 3A to C). Given the
prolonged decay time course, the CTLe fall is unlikely to be explained
by redistribution from peripheral blood but instead is more consistent
with a real loss of such activated effector CTL. The removal of
antigenic drive secondary to the fall in viral replication seems the
likely cause for the loss of HIV-specific CTLe, but it is also possible
that the drugs might interfere with the presentation of antigen per se
or that they are toxic to the CD8+ T-cell population.
However, the increases in the total CD8+ T-cell number
observed in some studies (4, 11) argue that such effects are
minimal. All eight individuals had suppression of viremia to below the
limit of detection for the duration of the study. It is important to
undertake similar analyses of treated individuals who have had
incomplete suppression of viral replication in order to further
delineate the causes of the loss of HIV-specific CTLe. Loss of
HIV-specific CTLe occurred in all individuals, regardless of the stage
of infection. However, none of the patients were treated prior to
seroconversion, which has been shown to be important for the protection
of HIV-specific CD4+ T-cell responses (18).
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Decay Kinetics of Human Immunodeficiency Virus-Specific Effector
Cytotoxic T Lymphocytes after Combination Antiretroviral
Therapy
ABSTRACT
Top
Abstract
Text
References
TEXT
Top
Abstract
Text
References
2-microglobulin, and peptide,
the complex was biotinylated by BirA (Avidity) in the presence of
ATP-Mg2+ (Sigma). Following purification by gel
filtration and ion-exchange chromatography, tetramer formation was
induced by the addition of streptavidin. Use of fluorescently
labeled streptavidin (Extravidin-PE, Sigma) allowed the tetramer to be
used for staining of antigen-specific CD8+ T cells.
View larger version (22K):
[in a new window]
FIG. 1.
Changes in HIV-specific CTLe frequencies in eight
individuals (A to H). The percentages of CD8+ T cells
staining with A2Gag ( 
), A2Pol (
), and B35Env (
) are
represented on the y axes and the x axes show the
number of days after starting treatment. Patients G and H had high
frequencies of HIV-specific CTL prior to treatment and therefore have
larger-scaled axes than patients A to F. Note that for patients C and
F, the first on-therapy time point measured was 1 day after treatment
started.
View larger version (20K):
[in a new window]
FIG. 2.
Late exponential decay of HIV-specific CTLe responses in
four individuals. The patients and epitopes are identified on the
right. Two responses were monitored in patient A, while one response
was monitored in patients B, G, and H. The median half-life of the
decay was 45 days.
View larger version (47K):
[in a new window]
FIG. 3.
(A) Serial flow cytometry profiles of one individual
after starting treatment with potent antiretrovirals. The
CD8+ T-cell population is illustrated with CD38 expression
along the x axes and B35Env tetramer staining along the
y axes. The time after treatment and percentage of
CD8+ T cells staining with the tetramer are documented in
the top right-hand corner of each graph. The percentage of
CD8+ T cells staining with the tetramer and the intensity
with which the tetramer-positive cells stain with anti-CD38 antibodies
declined after treatment started. (B) Changes in the percentage of
CD8+ T cells staining with the B35Env tetramer to 600 days
after treatment started. The decay half-life remained constant
throughout the course of the study. (C) Decay in the staining of
tetramer-positive cells with anti-CD38 antibodies. In the absence of
detectable viremia, staining with anti-CD38 antibodies declined in
intensity.
In order to address the question of whether there was continued cell activation during the decay phase, we analyzed the cell surface phenotype of the tetramer-positive cells from all individuals. CD38 is a cell surface glycoprotein with multiple proposed functions, including a role in adhesion, signalling, and NAD hydrolase activity (20). Intense staining with anti-CD38 antibodies is also known to be a marker of T-cell activation when there is a transient increase in cell surface CD38 (20). The proportion of CD8+ T cells expressing CD38 increases progressively during the course of infection with HIV (7), and the intensity with which CD8+ T cells stain with CD38 correlates with plasma viremia (12). Expression of CD38 by the total CD8+ T-cell population declines during antiretroviral treatment, but it remains unclear whether the same is true of HIV-specific CTL (3). During the HIV-specific CTLe decay phase observed after starting treatment, tetramer-positive CTL from all individuals decreased their expression of cell surface CD38 consistent with the loss of their antigenic stimulus and minimal ongoing cell activation. Figure 3A and C shows the decay of cell surface CD38 expression in one individual (patient H). Such a decrease in CD38 expression argues that the exponential loss of HIV-specific CTL reflects the true half-life of these effector CTL in vivo, although it is possible that the net decay phase is apparently slowed by the ongoing proliferation of a small number of HIV-specific clones. Whether such prolonged survival is dependent on antigen persistence (1) is unknown, but it is important to compare the CTLe decay rate in individuals with late emergence of drug-resistant virus. Therefore, we conclude that the half-life of HIV-specific effector CTL is less than or equal to 45 days in vivo.
In all treated individuals, levels of HIV-specific CTLe fell while viral RNA remained undetectable. This may partly explain why virus can rapidly rise when drug-resistant strains emerge (15). The basic reproductive ratio is defined as the number of secondarily infected cells generated by one infected cell placed into an environment of susceptible cells. This is partially dependent on the host immune system, with an effective response helping to maintain potentially resistant virus in a state where the basic reproductive ratio is less than 1. The eventual loss of circulating HIV-specific CTLe activity may weaken such control, leading to the development of resistance. Significant infection of susceptible target cells by drug-resistant virus may occur before memory CTL can proliferate sufficiently to contribute effectively to the overall circulating CTL activity (6). However, it is necessary to study the effects of antiretroviral therapy on the HIV-specific memory CTL response to determine whether a similar loss occurs. Such a loss of memory CTL might be expected to further delay the response to potential drug-resistant virus. An implication of this study is that boosting of HIV-specific CTLe by posttreatment vaccination or immunotherapy with cytokines may be an important adjunct to antiretroviral therapy (10). Such strategies could provide a means to maintain effective immunological control of potentially resistant virus.
| |
ACKNOWLEDGMENTS |
|---|
The assistance of the nursing staff at the Rockefeller Hospital, and that of Jenny Jin and Jia Song in the processing of peripheral blood mononuclear cell samples, is gratefully acknowledged.
This work was supported by NIH U01AI41534 and General Clinical Research Center grant MO1-RR00102. G.S.O., S.L.R.-J., and A.J.M. are funded by the MRC UK. S.B. and M.A.N. are supported by the Wellcome Trust.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Institute of Molecular Medicine, Nuffield Department of Medicine, Oxford OX3 9DS, United Kingdom. Phone: 44 1865 222336. Fax: 44 1865 222502. E-mail: andrew.mcmichael{at}ndm.ox.ac.uk.
| |
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. |
Altman, J.,
P. A. H. Moss,
P. Goulder, et al.
1996.
Direct visualization and phenotypic analysis of virus-specific T lymphocytes in HIV-infected individuals.
Science
274:94-96 |
| 3. |
Autran, B.,
G. Carcelain,
T. S. Li, et al.
1997.
Positive effects of combined antiretroviral therapy on CD4+ homeostasis and function in advanced HIV disease.
Science
277:112-116 |
| 4. | Carr, A., S. Emery, A. Kelleher, et al. 1996. CD8+ lymphocyte responses to antiretroviral therapy of HIV infection. J. Acquired Immune Defic. Syndr. Hum. Retrovirol. 13:320-326[Medline]. |
| 5. | Dorrell, L., T. Dong, G. S. Ogg, et al. Distinct recognition of non-clade B human immunodeficiency virus type 1 epitopes by cytotoxic T lymphocytes generated from donors infected in Africa. J. Virol., in press. |
| 5a. | Dyer, W. B., G. S. Ogg, M. A. Demoitie, X. Jin, A. F. Geczy, S. L. Rowland-Jones, A. J. McMichael, D. F. Nixon, J. S. Sullivan. 1999. Strong human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte activity in Sydney Blood Bank Cohort patients infected with nef-defective HIV type 1. 73:436-443. |
| 6. | Ehl, S., P. Klenerman, P. Aichele, et al. 1997. A functional and kinetic comparison of antiviral effector and memory cytotoxic T lymphocyte populations in vivo and in vitro. Eur. J. Immunol. 27:3404-3413[Medline]. |
| 7. | Giorgi, J., and R. Detels. 1989. T cell subset alterations in HIV-infected homosexual men: NIAID Multicenter AIDS Cohort Study. Clin. Immunol. Immunopathol. 52:10-18[Medline]. |
| 8. |
Gotch, F. M.,
D. F. Nixon,
N. Alp, et al.
1990.
High frequency of memory and effector gag specific cytotoxic T lymphocytes in HIV seropositive individuals.
Int. Immunol.
2:707-711 |
| 9. |
Goulder, P. J. R.,
A. K. Sewell,
D. G. Lalloo, et al.
1997.
Patterns of Immunodominance in HIV-1-specific cytotoxic T lymphocyte responses in two human histocompatibility leukocyte antigen (HLA)-identical siblings with HLA-A*0201 are influenced by epitope mutation.
J. Exp. Med.
185:1423-1433 |
| 10. |
Ho, D. D.
1998.
Towards HIV eradication or remission: the task ahead.
Science
280:1866 |
| 10a. | Jin, X., et al. Unpublished data. |
| 11. | Kelleher, A. D., A. Carr, J. Zaunders, and D. A. Cooper. 1996. Alterations in the immune response of human immunodeficiency virus (HIV)-infected subjects treated with an HIV-specific protease inhibitor, ritonavir. J. Infect. Dis. 173:321-329[Medline]. |
| 12. | Liu, Z., W. Cumberland, L. Hultin, et al. 1997. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J. Acquired Immune Defic. Syndr. Hum. Retrovirol. 16:83-92[Medline]. |
| 13. |
Moss, P. A. H.,
S. L. Rowland-Jones,
P. M. Frodsham, et al.
1995.
Persistent high frequency of human immunodeficiency virus-specific cytotoxic T cells in peripheral blood of infected donors.
Proc. Natl. Acad. Sci. USA
92:5773-5777 |
| 14. | Murali-Krishna, K., J. D. Altman, M. Suresh, et al. 1998. Counting antigen-specific CD8 T cells: a re-evaluation of bystander activation during viral infection. Immunity 8:177-187[Medline]. |
| 15. | Nowak, M. A., S. Bonhoeffer, G. M. Shaw, and R. M. May. 1997. Antiviral drug treatment: dynamics of resistance in free virus and infected cell populations. J. Theor. Biol. 184:203-217[Medline]. |
| 16. |
Ogg, G.,
X. Jin,
S. Bonhoeffer, et al.
1998.
Quantitation of HIV-specific CTL and plasma load of viral RNA.
Science
279:2103-2106 |
| 17. | Parker, K. C., M. A. Bednarek, L. K. Hull, et al. 1992. Sequence motifs important for peptide binding to the human MHC class I molecule, HLA-A2. J. Immunol. 149:3580-3587[Abstract]. |
| 18. |
Rosenberg, E. S.,
J. M. Billingsley,
A. M. Caliendo, et al.
1997.
Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.
Science
278:1447-1450 |
| 19. | Shiga, H., T. Shioda, H. Tomiyama, et al. 1996. Identification of multiple HIV-1 cytotoxic T-cell epitopes presented by human leukocyte antigen B35 molecules. AIDS 10:1075-1083[Medline]. |
| 20. | Shubinsky, G., and M. Schlesinger. 1997. The CD38 lymphocyte differentiation marker: new insight into its ectoenzymatic activity and its role as a signal transducer. Immunity 7:315-324[Medline]. |
| 21. |
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 |
| 22. |
Wilson, J. D. K.,
G. S. Ogg,
R. L. Allen, et al.
1998.
Oligoclonal expansions of CD8+ T cells in chronic HIV infection are antigen-specific.
J. Exp. Med.
188:785-790 |
Journal of Virology, January 1999, p. 797-800, Vol. 73, No. 1
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Wick, W. D., Gilbert, P. B., Yang, O. O.
(2009). Predicting the Impact of Blocking Human Immunodeficiency Virus Type 1 Nef In Vivo. J. Virol.
83: 2349-2356
[Abstract] [Full Text] -
(2008). Decay dynamics of HIV-1 depend on the inhibited stages of the viral life cycle. Proc. Natl. Acad. Sci. USA
105: 4832-4837
-
Critchfield, J. W., Lemongello, D., Walker, D. H., Garcia, J. C., Asmuth, D. M., Pollard, R. B., Shacklett, B. L.
(2007). Multifunctional Human Immunodeficiency Virus (HIV) Gag-Specific CD8+ T-Cell Responses in Rectal Mucosa and Peripheral Blood Mononuclear Cells during Chronic HIV Type 1 Infection. J. Virol.
81: 5460-5471
[Abstract] [Full Text] -
Andrews, N. P., Pack, C. D., Vezys, V., Barber, G. N., Lukacher, A. E.
(2007). Early Virus-Associated Bystander Events Affect the Fitness of the CD8 T Cell Response to Persistent Virus Infection. J. Immunol.
178: 7267-7275
[Abstract] [Full Text] -
Dorrell, L., Yang, H., Ondondo, B., Dong, T., di Gleria, K., Suttill, A., Conlon, C., Brown, D., Williams, P., Bowness, P., Goonetilleke, N., Rostron, T., Rowland-Jones, S., Hanke, T., McMichael, A.
(2006). Expansion and Diversification of Virus-Specific T Cells following Immunization of Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Individuals with a Recombinant Modified Vaccinia Virus Ankara/HIV-1 Gag Vaccine.. J. Virol.
80: 4705-4716
[Abstract] [Full Text] -
Yu, Q., Yue, F. Y., Gu, X. X., Schwartz, H., Kovacs, C. M., Ostrowski, M. A.
(2006). OX40 Ligation of CD4+ T Cells Enhances Virus-Specific CD8+ T Cell Memory Responses Independently of IL-2 and CD4+ T Regulatory Cell Inhibition. J. Immunol.
176: 2486-2495
[Abstract] [Full Text] -
Rouzine, I. M., Sergeev, R. A., Glushtsov, A. I.
(2006). Two types of cytotoxic lymphocyte regulation explain kinetics of immune response to human immunodeficiency virus. Proc. Natl. Acad. Sci. USA
103: 666-671
[Abstract] [Full Text] -
Seth, N., Kaufmann, D., Lahey, T., Rosenberg, E. S., Wucherpfennig, K. W.
(2005). Expansion and Contraction of HIV-Specific CD4 T Cells with Short Bursts of Viremia, but Physical Loss of the Majority of These Cells with Sustained Viral Replication. J. Immunol.
175: 6948-6958
[Abstract] [Full Text] -
Lauer, G. M., Lucas, M., Timm, J., Ouchi, K., Kim, A. Y., Day, C. L., zur Wiesch, J. S., Paranhos-Baccala, G., Sheridan, I., Casson, D. R., Reiser, M., Gandhi, R. T., Li, B., Allen, T. M., Chung, R. T., Klenerman, P., Walker, B. D.
(2005). Full-Breadth Analysis of CD8+ T-Cell Responses in Acute Hepatitis C Virus Infection and Early Therapy. J. Virol.
79: 12979-12988
[Abstract] [Full Text] -
Mondal, D., Williams, C. A., Ali, M., Eilers, M., Agrawal, K. C.
(2005). The HIV-1 Tat Protein Selectively Enhances CXCR4 and Inhibits CCR5 Expression in Megakaryocytic K562 Cells. Exp. Biol. Med.
230: 631-644
[Abstract] [Full Text] -
Koibuchi, T., Allen, T. M., Lichterfeld, M., Mui, S. K., O'Sullivan, K. M., Trocha, A., Kalams, S. A., Johnson, R. P., Walker, B. D.
(2005). Limited Sequence Evolution within Persistently Targeted CD8 Epitopes in Chronic Human Immunodeficiency Virus Type 1 Infection. J. Virol.
79: 8171-8181
[Abstract] [Full Text] -
Chakraborty, R., Morel, A.-S., Sutton, J. K., Appay, V., Ripley, R. M., Dong, T., Rostron, T., Ogola, S., Palakudy, T., Musoke, R., D'Agostino, A., Ritter, M., Rowland-Jones, S. L.
(2005). Correlates of Delayed Disease Progression in HIV-1-Infected Kenyan Children. J. Immunol.
174: 8191-8199
[Abstract] [Full Text] -
Ibarrondo, F. J., Anton, P. A., Fuerst, M., Ng, H. L., Wong, J. T., Matud, J., Elliott, J., Shih, R., Hausner, M. A., Price, C., Hultin, L. E., Hultin, P. M., Jamieson, B. D., Yang, O. O.
(2005). Parallel Human Immunodeficiency Virus Type 1-Specific CD8+ T-Lymphocyte Responses in Blood and Mucosa during Chronic Infection. J. Virol.
79: 4289-4297
[Abstract] [Full Text] -
Casazza, J. P., Betts, M. R., Hill, B. J., Brenchley, J. M., Price, D. A., Douek, D. C., Koup, R. A.
(2005). Immunologic Pressure within Class I-Restricted Cognate Human Immunodeficiency Virus Epitopes during Highly Active Antiretroviral Therapy. J. Virol.
79: 3653-3663
[Abstract] [Full Text] -
Kim, A. Y., Lauer, G. M., Ouchi, K., Addo, M. M., Lucas, M., Wiesch, J. S. z., Timm, J., Boczanowski, M., Duncan, J. E., Wurcel, A. G., Casson, D., Chung, R. T., Draenert, R., Klenerman, P., Walker, B. D.
(2005). The magnitude and breadth of hepatitis C virus-specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1. Blood
105: 1170-1178
[Abstract] [Full Text] -
Davenport, M. P., Ribeiro, R. M., Chao, D. L., Perelson, A. S.
(2004). Predicting the Impact of a Nonsterilizing Vaccine against Human Immunodeficiency Virus. J. Virol.
78: 11340-11351
[Abstract] [Full Text] -
Autran, B., Carcelain, G., Combadiere, B., Debre, P.
(2004). Therapeutic Vaccines for Chronic Infections. Science
305: 205-208
[Abstract] [Full Text] -
Shacklett, B. L., Cox, C. A., Quigley, M. F., Kreis, C., Stollman, N. H., Jacobson, M. A., Andersson, J., Sandberg, J. K., Nixon, D. F.
(2004). Abundant Expression of Granzyme A, but Not Perforin, in Granules of CD8+ T Cells in GALT: Implications for Immune Control of HIV-1 Infection. J. Immunol.
173: 641-648
[Abstract] [Full Text] -
Kinloch-de Loes, S.
(2004). Role of therapeutic vaccines in the control of HIV-1. J Antimicrob Chemother
53: 562-566
[Abstract] [Full Text] -
Feeney, M. E., Draenert, R., Roosevelt, K. A., Pelton, S. I., McIntosh, K., Burchett, S. K., Mao, C., Walker, B. D., Goulder, P. J. R.
(2003). Reconstitution of Virus-Specific CD4 Proliferative Responses in Pediatric HIV-1 Infection. J. Immunol.
171: 6968-6975
[Abstract] [Full Text] -
Alter, G., Hatzakis, G., Tsoukas, C. M., Pelley, K., Rouleau, D., LeBlanc, R., Baril, J.-G., Dion, H., Lefebvre, E., Thomas, R., Cote, P., Lapointe, N., Routy, J.-P., Sekaly, R.-P., Conway, B., Bernard, N. F.
(2003). Longitudinal Assessment of Changes in HIV-Specific Effector Activity in HIV-Infected Patients Starting Highly Active Antiretroviral Therapy in Primary Infection. J. Immunol.
171: 477-488
[Abstract] [Full Text] -
Shacklett, B. L., Cox, C. A., Sandberg, J. K., Stollman, N. H., Jacobson, M. A., Nixon, D. F.
(2003). Trafficking of Human Immunodeficiency Virus Type 1-Specific CD8+ T Cells to Gut-Associated Lymphoid Tissue during Chronic Infection. J. Virol.
77: 5621-5631
[Abstract] [Full Text] -
Spetz, A.-L., Sorensen, A. S., Walther-Jallow, L., Wahren, B., Andersson, J., Holmgren, L., Hinkula, J.
(2002). Induction of HIV-1-Specific Immunity After Vaccination with Apoptotic HIV-1/Murine Leukemia Virus-Infected Cells. J. Immunol.
169: 5771-5779
[Abstract] [Full Text] -
Tryniszewska, E., Nacsa, J., Lewis, M. G., Silvera, P., Montefiori, D., Venzon, D., Hel, Z., Parks, R. W., Moniuszko, M., Tartaglia, J., Smith, K. A., Franchini, G.
(2002). Vaccination of Macaques with Long-Standing SIVmac251 Infection Lowers the Viral Set Point After Cessation of Antiretroviral Therapy. J. Immunol.
169: 5347-5357
[Abstract] [Full Text] -
Constantin, C. M., Bonney, E. E., Altman, J. D., Strickland, O. L.
(2002). Major Histocompatibility Complex (MHC) Tetramer Technology: An Evaluation. Biol Res Nurs
4: 115-127
[Abstract] -
Oxenius, A., McLean, A. R., Fischer, M., Price, D. A., Dawson, S. J., Hafner, R., Schneider, C., Joller, H., Hirschel, B., Phillips, R. E., Weber, R., Gunthard, H. F.
(2002). Human Immunodeficiency Virus-Specific CD8+ T-Cell Responses Do Not Predict Viral Growth and Clearance Rates during Structured Intermittent Antiretroviral Therapy. J. Virol.
76: 10169-10176
[Abstract] [Full Text] -
Tomiyama, H., Akari, H., Adachi, A., Takiguchi, M.
(2002). Different Effects of Nef-Mediated HLA Class I Down-Regulation on Human Immunodeficiency Virus Type 1-Specific CD8+ T-Cell Cytolytic Activity and Cytokine Production. J. Virol.
76: 7535-7543
[Abstract] [Full Text] -
Davenport, M. P., Fazou, C., McMichael, A. J., Callan, M. F. C.
(2002). Clonal Selection, Clonal Senescence, and Clonal Succession: The Evolution of the T Cell Response to Infection with a Persistent Virus. J. Immunol.
168: 3309-3317
[Abstract] [Full Text] -
Ortiz, G. M., Hu, J., Goldwitz, J. A., Chandwani, R., Larsson, M., Bhardwaj, N., Bonhoeffer, S., Ramratnam, B., Zhang, L., Markowitz, M. M., Nixon, D. F.
(2002). Residual Viral Replication during Antiretroviral Therapy Boosts Human Immunodeficiency Virus Type 1-Specific CD8+ T-Cell Responses in Subjects Treated Early after Infection. J. Virol.
76: 411-415
[Abstract] [Full Text] -
Betts, M. R., Ambrozak, D. R., Douek, D. C., Bonhoeffer, S., Brenchley, J. M., Casazza, J. P., Koup, R. A., Picker, L. J.
(2001). Analysis of Total Human Immunodeficiency Virus (HIV)-Specific CD4+ and CD8+ T-Cell Responses: Relationship to Viral Load in Untreated HIV Infection. J. Virol.
75: 11983-11991
[Abstract] [Full Text] -
Pathan, A. A., Wilkinson, K. A., Klenerman, P., McShane, H., Davidson, R. N., Pasvol, G., Hill, A. V. S., Lalvani, A.
(2001). Direct Ex Vivo Analysis of Antigen-Specific IFN-{gamma}-Secreting CD4 T Cells in Mycobacterium tuberculosis-Infected Individuals: Associations with Clinical Disease State and Effect of Treatment. J. Immunol.
167: 5217-5225
[Abstract] [Full Text] -
Ortiz, G. M., Wellons, M., Brancato, J., Vo, H. T. T., Zinn, R. L., Clarkson, D. E., Van Loon, K., Bonhoeffer, S., Miralles, G. D., Montefiori, D., Bartlett, J. A., Nixon, D. F.
(2001). Structured antiretroviral treatment interruptions in chronically HIV-1-infected subjects. Proc. Natl. Acad. Sci. USA
10.1073/pnas.221452198v1
[Abstract] [Full Text] -
Lisziewicz, J., Gabrilovich, D. I., Varga, G., Xu, J., Greenberg, P. D., Arya, S. K., Bosch, M., Behr, J.-P., Lori, F.
(2001). Induction of Potent Human Immunodeficiency Virus Type 1-Specific T-Cell-Restricted Immunity by Genetically Modified Dendritic Cells. J. Virol.
75: 7621-7628
[Abstract] [Full Text] -
Casazza, J. P., Betts, M. R., Picker, L. J., Koup, R. A.
(2001). Decay Kinetics of Human Immunodeficiency Virus-Specific CD8+ T Cells in Peripheral Blood after Initiation of Highly Active Antiretroviral Therapy. J. Virol.
75: 6508-6516
[Abstract] [Full Text] -
De Paoli, P.
(2001). Immunological Effects of Interleukin-2 Therapy in Human Immunodeficiency Virus-Positive Subjects. CVI
8: 671-677
[Full Text] -
Hogan, C. M., Hammer, S. M.
(2001). Host Determinants in HIV Infection and Disease: Part 2: Genetic Factors and Implications for Antiretroviral Therapeutics. ANN INTERN MED
134: 978-996
[Abstract] [Full Text] -
McBreen, S., Imlach, S., Shirafuji, T., Scott, G. R., Leen, C., Bell, J. E., Simmonds, P.
(2001). Infection of the CD45RA+ (Naive) Subset of Peripheral CD8+ Lymphocytes by Human Immunodeficiency Virus Type 1 In Vivo. J. Virol.
75: 4091-4102
[Abstract] [Full Text] -
Altfeld, M. A., Livingston, B., Reshamwala, N., Nguyen, P. T., Addo, M. M., Shea, A., Newman, M., Fikes, J., Sidney, J., Wentworth, P., Chesnut, R., Eldridge, R. L., Rosenberg, E. S., Robbins, G. K., Brander, C., Sax, P. E., Boswell, S., Flynn, T., Buchbinder, S., Goulder, P. J. R., Walker, B. D., Sette, A., Kalams, S. A.
(2001). Identification of Novel HLA-A2-Restricted Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Epitopes Predicted by the HLA-A2 Supertype Peptide-Binding Motif. J. Virol.
75: 1301-1311
[Abstract] [Full Text] -
Altfeld, M., Rosenberg, E. S., Shankarappa, R., Mukherjee, J. S., Hecht, F. M., Eldridge, R. L., Addo, M. M., Poon, S. H., Phillips, M. N., Robbins, G. K., Sax, P. E., Boswell, S., Kahn, J. O., Brander, C., Goulder, P. J.R., Levy, J. A., Mullins, J. I., Walker, B. D.
(2001). Cellular Immune Responses and Viral Diversity in Individuals Treated during Acute and Early HIV-1 Infection. JEM
193: 169-180
[Abstract] [Full Text] -
Carcelain, G., Tubiana, R., Samri, A., Calvez, V., Delaugerre, C., Agut, H., Katlama, C., Autran, B.
(2001). Transient Mobilization of Human Immunodeficiency Virus (HIV)-Specific CD4 T-Helper Cells Fails To Control Virus Rebounds during Intermittent Antiretroviral Therapy in Chronic HIV Type 1 Infection. J. Virol.
75: 234-241
[Abstract] [Full Text] -
Ostrowski, M. A., Justement, S. J., Ehler, L., Mizell, S. B., Lui, S., Mican, J., Walker, B. D., Thomas, E. K., Seder, R., Fauci, A. S.
(2000). The Role of CD4+ T Cell Help and CD40 Ligand in the In Vitro Expansion of HIV-1-Specific Memory Cytotoxic CD8+ T Cell Responses. J. Immunol.
165: 6133-6141
[Abstract] [Full Text] -
Betts, M. R., Casazza, J. P., Patterson, B. A., Waldrop, S., Trigona, W., Fu, T.-M., Kern, F., Picker, L. J., Koup, R. A.
(2000). Putative Immunodominant Human Immunodeficiency Virus-Specific CD8+ T-Cell Responses Cannot Be Predicted by Major Histocompatibility Complex Class I Haplotype. J. Virol.
74: 9144-9151
[Abstract] [Full Text] -
Dela Cruz, C. S., Tan, R., Rowland-Jones, S. L., Barber, B. H.
(2000). Creating HIV-1 reverse transcriptase cytotoxic T lymphocyte target structures by HLA-A2 heavy chain modifications. Int Immunol
12: 1293-1302
[Abstract] [Full Text] -
Trimble, L. A., Shankar, P., Patterson, M., Daily, J. P., Lieberman, J.
(2000). Human Immunodeficiency Virus-Specific Circulating CD8 T Lymphocytes Have Down-Modulated CD3zeta and CD28, Key Signaling Molecules for T-Cell Activation. J. Virol.
74: 7320-7330
[Abstract] [Full Text] -
Mollet, L., Li, T.-S., Samri, A., Tournay, C., Tubiana, R., Calvez, V., Debre, P., Katlama, C., Autran, B.
(2000). Dynamics of HIV-Specific CD8+ T Lymphocytes with Changes in Viral Load. J. Immunol.
165: 1692-1704
[Abstract] [Full Text] -
Wodarz, D., Nowak, M. A.
(2000). HIV therapy: Managing resistance. Proc. Natl. Acad. Sci. USA
97: 8193-8195
[Full Text] -
Gea-Banacloche, J. C., Migueles, S. A., Martino, L., Shupert, W. L., McNeil, A. C., Sabbaghian, M. S., Ehler, L., Prussin, C., Stevens, R., Lambert, L., Altman, J., Hallahan, C. W., de Quiros, J. C. L. B., Connors, M.
(2000). Maintenance of Large Numbers of Virus-Specific CD8+ T Cells in HIV-Infected Progressors and Long-Term Nonprogressors. J. Immunol.
165: 1082-1092
[Abstract] [Full Text] -
Appay, V., Nixon, D. F., Donahoe, S. M., Gillespie, G. M.A., Dong, T., King, A., Ogg, G. S., Spiegel, H. M.L., Conlon, C., Spina, C. A., Havlir, D. V., Richman, D. D., Waters, A., Easterbrook, P., McMichael, A. J., Rowland-Jones, S. L.
(2000). HIV-Specific Cd8+ T Cells Produce Antiviral Cytokines but Are Impaired in Cytolytic Function. JEM
192: 63-76
[Abstract] [Full Text] -
Fleury, S., Rizzardi, G. P., Chapuis, A., Tambussi, G., Knabenhans, C., Simeoni, E., Meuwly, J.-Y., Corpataux, J.-M., Lazzarin, A., Miedema, F., Pantaleo, G.
(2000). Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA
97: 5393-5398
[Abstract] [Full Text] -
Rinaldo, C. R. Jr., Huang, X.-L., Fan, Z., Margolick, J. B., Borowski, L., Hoji, A., Kalinyak, C., McMahon, D. K., Riddler, S. A., Hildebrand, W. H., Day, R. B., Mellors, J. W.
(2000). Anti-Human Immunodeficiency Virus Type 1 (HIV-1) CD8+ T-Lymphocyte Reactivity during Combination Antiretroviral Therapy in HIV-1-Infected Patients with Advanced Immunodeficiency. J. Virol.
74: 4127-4138
[Abstract] [Full Text] -
Oxenius, A., Price, D. A., Easterbrook, P. J., O'Callaghan, C. A., Kelleher, A. D., Whelan, J. A., Sontag, G., Sewell, A. K., Phillips, R. E.
(2000). Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc. Natl. Acad. Sci. USA
97: 3382-3387
[Abstract] [Full Text] -
Soudeyns, H., Campi, G., Rizzardi, G. P., Lenge, C., Demarest, J. F., Tambussi, G., Lazzarin, A., Kaufmann, D., Casorati, G., Corey, L., Pantaleo, G.
(2000). Initiation of antiretroviral therapy during primary HIV-1 infection induces rapid stabilization of the T-cell receptor beta chain repertoire and reduces the level of T-cell oligoclonality. Blood
95: 1743-1751
[Abstract] [Full Text] -
Spiegel, H. M. L., Ogg, G. S., DeFalcon, E., Sheehy, M. E., Monard, S., Haslett, P. A. J., Gillespie, G., Donahoe, S. M., Pollack, H., Borkowsky, W., McMichael, A. J., Nixon, D. F.
(2000). Human Immunodeficiency Virus Type 1- and Cytomegalovirus-Specific Cytotoxic T Lymphocytes Can Persist at High Frequency for Prolonged Periods in the Absence of Circulating Peripheral CD4+ T Cells. J. Virol.
74: 1018-1022
[Abstract] [Full Text] -
D'Aquila, R., Walker, B.
(1999). Exploring the Benefits and Limits of Highly Active Antiretroviral Therapy. JAMA
282: 1668-1669
[Full Text] -
Ogg, G. S., Kostense, S., Klein, M. R., Jurriaans, S., Hamann, D., McMichael, A. J., Miedema, F.
(1999). Longitudinal Phenotypic Analysis of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Lymphocytes: Correlation with Disease Progression. J. Virol.
73: 9153-9160
[Abstract] [Full Text] -
Lukacher, A. E., Moser, J. M., Hadley, A., Altman, J. D.
(1999). Visualization of Polyoma Virus-Specific CD8+ T Cells In Vivo During Infection and Tumor Rejection. J. Immunol.
163: 3369-3378
[Abstract] [Full Text] -
Kalams, S. A., Buchbinder, S. P., Rosenberg, E. S., Billingsley, J. M., Colbert, D. S., Jones, N. G., Shea, A. K., Trocha, A. K., Walker, B. D.
(1999). Association between Virus-Specific Cytotoxic T-Lymphocyte and Helper Responses in Human Immunodeficiency Virus Type 1 Infection. J. Virol.
73: 6715-6720
[Abstract] [Full Text] -
Kalams, S. A., Goulder, P. J., Shea, A. K., Jones, N. G., Trocha, A. K., Ogg, G. S., Walker, B. D.
(1999). Levels of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Effector and Memory Responses Decline after Suppression of Viremia with Highly Active Antiretroviral Therapy. J. Virol.
73: 6721-6728
[Abstract] [Full Text] -
Migueles, S. A., Sabbaghian, M. S., Shupert, W. L., Bettinotti, M. P., Marincola, F. M., Martino, L., Hallahan, C. W., Selig, S. M., Schwartz, D., Sullivan, J., Connors, M.
(2000). HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc. Natl. Acad. Sci. USA
97: 2709-2714
[Abstract] [Full Text] -
Ortiz, G. M., Wellons, M., Brancato, J., Vo, H. T. T., Zinn, R. L., Clarkson, D. E., Van Loon, K., Bonhoeffer, S., Miralles, G. D., Montefiori, D., Bartlett, J. A., Nixon, D. F.
(2001). Structured antiretroviral treatment interruptions in chronically HIV-1-infected subjects. Proc. Natl. Acad. Sci. USA
98: 13288-13293
[Abstract] [Full Text] -
Fraser, C., Ferguson, N. M., Anderson, R. M.
(2001). Quantification of intrinsic residual viral replication in treated HIV-infected patients. Proc. Natl. Acad. Sci. USA
98: 15167-15172
[Abstract] [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»