High-Potency Human Immunodeficiency Virus Vaccinat
http://www.100md.com
病菌学杂志 2005年第15期
Department of Haematology, Prince of Wales Hospital, and Centre for Vascular Research, University of New South Wales, Kensington NSW 2052, Australia
Merck Research Laboratories, West Point, Pennsylvania 19486
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico 87545
ABSTRACT
CD8+ T lymphocytes are thought to play an important role in the control of acute and chronic human immunodeficiency virus infections. However, there is a significant delay between infection and the first observed increase in virus-specific CD8+ T-cell numbers. Prior to this time, viral kinetics are not significantly different between controls and vaccinees. Surprisingly, higher initial virus-specific CD8+ T-cell numbers lead to a longer delay prior to initial CD8+ T-cell expansion, and slower CD8+ T-cell increases. Nevertheless, higher initial CD8+ T-cell numbers were associated with reduced peak and chronic viral loads and reduced CD4+ T-cell depletion.
TEXT
Virus-specific CD8+ T lymphocytes are important in the control of acute and chronic viral infections, and CD8+ T-cell-inducing vaccines are being developed for human immunodeficiency virus (HIV) and other infectious diseases (2, 4, 9). However, there is little understanding of the kinetics of CD8+ T-cell responses and their effects on pathogen growth and disease outcome. Virus-specific CD8+ T cells appear to prevent neither initial viral growth nor the establishment of chronic infection in animal models of HIV, although they do appear able to reduce viral loads in chronic infection (2, 4, 7, 9). We recently reported that a 10-day delay between infection and the initial increase in virus-specific CD8+ T-cell numbers in blood allowed uncontrolled early viral growth in DNA-vaccinated, simian-human immunodeficiency virus-challenged macaques (7). However, in that study, the level of vaccine-induced virus-specific CD8+ T cells prior to infection was modest (mean, 3.8 ± 4.2 cells μl–1). Here we analyze the results of two vaccination-challenge studies utilizing Mamu-A01+ macaques vaccinated with a variety of regimens and challenged with 50 50% monkey infectious doses of SHIV-89.6P at either 6 weeks (study A) or 12 weeks (study B) after boosting (9). CD8+ T cells specific for the Mamu-A01-restricted SIV gag p11CM epitope (residues 181 through 189) (p11CM+ T cells) were quantitated by using major histocompatibility complex class I-peptide tetramers. The initial number of p11CM+ T cells (on day –1 [study A] or –7 [study B] prior to challenge) ranged from undetectable (<0.01%) to 158 cells μl–1. This range of p11CM+ T cells allowed us to correlate the initial p11CM+ T-cell number against immune and viral kinetic parameters.
Impact of initial number of vaccine-induced p11CM+ T cells on p11CM+ T-cell kinetics. The first question we addressed was whether inducing higher p11CM+ T-cell numbers could overcome the observed delay in virus-specific CD8+ T-cell expansion (1, 7). Following infection, the number of p11CM+ T cells was not significantly increased compared to preinfection levels until day 14 for study B and day 15 for study A, and at these times, the numbers of p11CM+ T cells were 10-fold higher than preinfection levels (P values of 0.0039 and <0.0001, respectively [paired Wilcoxon]). The time p11CM+ T-cell expansion starts, ton, was estimated by finding when the T-cell growth curve, assumed to be exponential with intersects the initial p11CM+ T-cell number prior to infection, T0 (Fig. 1a). If the observed number of p11CM+ T cells before infection is T0, the growth rate of p11CM+ T cells (calculated by linear regression of the natural-log transformed data) is g and the y intercept of this regression line is b, then the time when expansion commenced (ton) is as follows: ton = (lnT0 – b)/g. The viral load at this time was calculated by linear interpolation of the log-transformed viral load data (using the two data points immediately before and after ton).
A higher preinfection p11CM+ T-cell number was associated with a greater delay in the time of initial p11CM+ T-cell expansion (r = 0.68, P = 0.0011 [Spearman]) (Fig. 2a). If the delay is due to the time taken for the level of antigen or number of infected cells to reach a certain threshold in order to activate CD8+ T cells, it is possible that the longer delay may be due to better viral control (i.e., slower viral growth leads to a longer delay until the threshold level is reached). To examine this, we calculated the viral load at ton, the time when p11CM+ T-cell expansion was estimated to commence (Fig. 1b). Higher initial p11CM+ T-cell numbers were associated with higher viral loads at ton (r = 0.54, P = 0.014) (Fig. 2c), contrary to the idea of a strict viral threshold. In addition, the growth rate of p11CM+ T cells was negatively correlated with the initial number of these cells (r = –0.58, P = 0.0075) (Fig. 2b). Thus, the higher the initial number of p11CM+ T cells, the greater the delay before their initial expansion and the more slowly they increased.
The initial number of p11CM+ T cells was a poor predictor of their peak number during acute infection (r = 0.15, P = 0.53) (Fig. 2e). Closer examination of the relationship between initial and peak p11CM+ T-cell numbers suggests that the peak number of p11CM+ T cells increases with larger initial numbers but only up to an initial level of 2 cells μl–1. However, for initial numbers between 2 and 158 cells μl–1, a similar peak number (600 cells μl–1) was achieved, suggesting that larger initial numbers beyond 2 cells μl–1 had little effect on the peak levels reached.
Following the peak in p11CM+ T-cell responses around day 20, most cells die, leaving a small pool of long-lived "memory" cells (Fig. 1a). The mean decay rate in the vaccinees was 0.32 ± 0.14 day–1 (equivalent to a half-life of 2.2 days). This decay rate was negatively correlated with the initial p11CM+ T-cell number (r = –0.47, P = 0.037) (Fig. 2d). To estimate the efficiency of memory formation after the peak CD8+ T-cell response, we calculated the number of specific CD8+ T cells remaining at 6 weeks as a proportion of those cells at the peak of the response. Higher p11CM+ T-cell numbers before infection were found to be a significant predictor of a higher proportion of peak cells remaining at 6 weeks (r = 0.47, P = 0.038) (Fig. 2f). Thus, although high initial p11CM+ T-cell numbers did not contribute to higher peak p11CM+ T-cell numbers, they did lead to a higher number of memory p11CM+ T cells. This suggests that a high initial number of memory cells from vaccination contributed to better memory retention during the resolution phase of primary infection, perhaps due to the better preservation of CD4+ T-cell help (5, 11).
Impact of initial p11CM+ T-cell number on viral kinetics. In our previous study, we found that vaccination had no significant effect on viral load prior to day 10 of infection (7). In the present study, the preinfection p11CM+ T-cell number was not correlated with viral load at day 10 (r = –0.22, P = 0.27 [Spearman]) (Fig. 3a), nor was there any correlation between the number of p11CM+ T cells preinfection and the initial viral growth rate (estimated by linear regression of the natural log-transformed viral load data) (r = –0.24, P = 0.24) (Fig. 3b). However, higher preinfection p11CM+ T-cell numbers were significantly associated with lower peak viral loads (r = –0.67, P = 0.0002) (Fig. 3c).
The mean postpeak decay rate of virus in acute infection was 0.82 ± 0.18 day–1 (half-life of 20.3 h). There was no correlation between viral decay rate and either preinfection p11CM+ T-cell number (r = 0.30, P = 0.13) (Fig. 3d) or peak p11CM+ T-cell number (r = 0.14, P = 0.50). Thus, as we have previously observed (7), high virus-specific CD8+ T-cell numbers did not appear to affect the postpeak decay rate of virus in acute infection. However, viral decay continued for longer and to lower levels in animals with a higher initial p11CM+ T-cell number. Long-term viral loads (18 weeks) were inversely correlated with initial p11CM+ T-cell numbers (r = –0.64, P = 0.0004) (Fig. 3e).
SHIV-89.6P mediates early and rapid CD4+ T-cell depletion in na?ve animals. We calculated the level of CD4+ T-cell depletion as follows: [(initial CD4+ T-cell number) – (CD4+ T cells at time t)]/(initial CD4+ T-cell number), where the initial number was determined at day –1 or –7. Initial p11CM+ T-cell number was inversely correlated with the level of CD4+ depletion both early after infection, one week after peak in viral load (r = –0.66, P = 0.0003) (Fig. 3f), and late, day 122 to 129 (r = –0.74, P < 0.0001).
Implications for vaccine design. The delay in CD8+ T-cell control of virus following infection allows for uncontrolled early viral growth and the establishment of chronic infection (7). One might speculate that extremely potent vaccination regimens could overcome this delay and mediate sterilizing immunity to infection. Now, we report that higher initial virus-specific CD8+ T-cell numbers led to longer delays before the initial expansion of these cells and slower growth once expansion commenced. However, higher initial virus-specific CD8+ T-cell numbers led to higher numbers of memory CD8+ T cells, reduced peak viral loads, and improved long-term viral control.
Since these animals were primed with whole antigens, they make CD8+, CD4+, and antibody responses to multiple epitopes, and we cannot exclude the possibility of the contributions of these other factors to the observed correlations between p11CM+ T-cell numbers and outcome. Other important factors not analyzed are responses against different epitopes and the functional status of the virus-specific CD8+ T cells. However, it is unlikely that targeting of other (subdominant) epitopes will be more successful at mediating early viral control, as we have previously shown that these T cells are also delayed and grow more slowly than the dominant response (7). In addition, others have reported similar delays for functionally capable virus-specific CD8+ T cells (1).
There is no clear consensus on the type of immune response required to control HIV infection. Kinetic analysis of the effects of antibody (12) and CD8+ T cells (1) on virus provides insights into the possibilities and limitations of these responses. CD8+ T-cell-inducing vaccines appear unable to mediate sterilizing immunity but may mediate long-term viral control and improved clinical outcome for infected individuals. Such disease-modifying vaccines may also contribute to the control of the HIV epidemic (6, 10). Additional hurdles to effective vaccination may also be encountered for natural HIV infection, due to the antigenic variation of the virus. Optimal T-cell responses may need to be more broadly targeted, both to cover the range of viral strains present in the community and to reduce the risk of immune escape within the individual (3, 8). Thus, a consideration of quantitative and qualitative aspects of the CD8+ T cells response to virus is crucial, since a thorough understanding of the interplay between cytotoxic T lymphocytes and virus can lead to a more rational vaccine design process.
ACKNOWLEDGMENTS
Portions of this work were done under the auspices of the U.S. Department of Energy under contract W-7405-ENG-36 and supported by the James S. McDonnell Foundation 21st Century Research Award/Studying Complex Systems (M.P.D.) and National Institutes of Health grants AI28433 and RR06555 (A.S.P.).
REFERENCES
Abdel-Motal, U. M., J. Gillis, K. Manson, M. Wyand, D. Montefiori, K. Stefano-Cole, R. C. Montelaro, J. D. Altman, and R. P. Johnson. 2005. Kinetics of expansion of SIV Gag-specific CD8+ T lymphocytes following challenge of vaccinated macaques. Virology 333:226-238.
Amara, R. R., F. Villinger, J. D. Altman, S. L. Lydy, S. P. O'Neil, S. I. Staprans, D. C. Montefiori, Y. Xu, J. G. Herndon, L. S. Wyatt, M. A. Candido, N. L. Kozyr, P. L. Earl, J. M. Smith, H. L. Ma, B. D. Grimm, M. L. Hulsey, J. Miller, H. M. McClure, J. M. McNicholl, B. Moss, and H. L. Robinson. 2001. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292:69-74.
Barouch, D. H., J. Kunstman, M. J. Kuroda, J. E. Schmitz, S. Santra, F. W. Peyerl, G. R. Krivulka, K. Beaudry, M. A. Lifton, D. A. Gorgone, D. C. Montefiori, M. G. Lewis, S. M. Wolinsky, and N. L. Letvin. 2002. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415:335-339.
Barouch, D. H., S. Santra, J. E. Schmitz, M. J. Kuroda, T. M. Fu, W. Wagner, M. Bilska, A. Craiu, X. X. Zheng, G. R. Krivulka, K. Beaudry, M. A. Lifton, C. E. Nickerson, W. L. Trigona, K. Punt, D. C. Freed, L. M. Guan, S. Dubey, D. Casimiro, A. Simon, M. E. Davies, M. Chastain, T. B. Strom, R. S. Gelman, D. C. Montefiori, et al. 2000. Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 290:486-492.
Belz, G. T., D. Wodarz, G. Diaz, M. A. Nowak, and P. C. Doherty. 2002. Compromised influenza virus-specific CD8+-T-cell memory in CD4+-T-cell-deficient mice. J. Virol. 76:12388-12393.
Davenport, M. P., R. M. Ribeiro, D. L. Chao, and A. S. Perelson. 2004. Predicting the impact of a nonsterilizing vaccine against human immunodeficiency virus. J. Virol. 78:11340-11351.
Davenport, M. P., R. M. Ribeiro, and A. S. Perelson. 2004. Kinetics of virus specific CD8+ T cells and the control of human immunodeficiency virus infection. J. Virol. 78:10096-10103.
Goulder, P. J. R., 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 S. Rowland-Jones. 1997. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat. Med. 3:212-217.
Shiver, J. W., T. M. Fu, L. Chen, D. R. Casimiro, M. E. Davies, R. K. Evans, Z. Q. Zhang, A. J. Simon, W. L. Trigona, S. A. Dubey, L. Huang, V. A. Harris, R. S. Long, X. Liang, L. Handt, W. A. Schleif, L. Zhu, D. C. Freed, N. V. Persaud, L. Guan, K. S. Punt, A. Tang, M. Chen, K. A. Wilson, K. B. Collins, G. J. Heidecker, V. R. Fernandez, H. C. Perry, J. G. Joyce, K. M. Grimm, J. C. Cook, P. M. Keller, D. S. Kresock, H. Mach, R. D. Troutman, L. A. Isopi, D. M. Williams, Z. Xu, K. E. Bohannon, D. B. Volkin, D. C. Montefiori, A. Miura, G. R. Krivulka, M. A. Lifton, M. J. Kuroda, J. E. Schmitz, N. L. Letvin, M. J. Caulfield, A. J. Bett, R. Youil, D. C. Kaslow, and E. A. Emini. 2002. Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 415:331-335.
Smith, R. J., and S. M. Blower. 2004. Could disease-modifying HIV vaccines cause population-level perversity? Lancet Infect. Dis. 4:636-639.
Sun, J. C., M. A. Williams, and M. J. Bevan. 2004. CD4(+) T cells are required for the maintenance, not programming, of memory CD8(+) T cells after acute infection. Nat. Immunol. 5:927-933.
Zhang, L., R. M. Ribeiro, J. R. Mascola, M. G. Lewis, G. Stiegler, H. Katinger, A. S. Perelson, and M. P. Davenport. 2004. Effects of antibody on viral kinetics in simian/human immunodeficiency virus infection: implications for vaccination. J. Virol. 78:5520-5522.(Miles P. Davenport, Lei Z)
Merck Research Laboratories, West Point, Pennsylvania 19486
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico 87545
ABSTRACT
CD8+ T lymphocytes are thought to play an important role in the control of acute and chronic human immunodeficiency virus infections. However, there is a significant delay between infection and the first observed increase in virus-specific CD8+ T-cell numbers. Prior to this time, viral kinetics are not significantly different between controls and vaccinees. Surprisingly, higher initial virus-specific CD8+ T-cell numbers lead to a longer delay prior to initial CD8+ T-cell expansion, and slower CD8+ T-cell increases. Nevertheless, higher initial CD8+ T-cell numbers were associated with reduced peak and chronic viral loads and reduced CD4+ T-cell depletion.
TEXT
Virus-specific CD8+ T lymphocytes are important in the control of acute and chronic viral infections, and CD8+ T-cell-inducing vaccines are being developed for human immunodeficiency virus (HIV) and other infectious diseases (2, 4, 9). However, there is little understanding of the kinetics of CD8+ T-cell responses and their effects on pathogen growth and disease outcome. Virus-specific CD8+ T cells appear to prevent neither initial viral growth nor the establishment of chronic infection in animal models of HIV, although they do appear able to reduce viral loads in chronic infection (2, 4, 7, 9). We recently reported that a 10-day delay between infection and the initial increase in virus-specific CD8+ T-cell numbers in blood allowed uncontrolled early viral growth in DNA-vaccinated, simian-human immunodeficiency virus-challenged macaques (7). However, in that study, the level of vaccine-induced virus-specific CD8+ T cells prior to infection was modest (mean, 3.8 ± 4.2 cells μl–1). Here we analyze the results of two vaccination-challenge studies utilizing Mamu-A01+ macaques vaccinated with a variety of regimens and challenged with 50 50% monkey infectious doses of SHIV-89.6P at either 6 weeks (study A) or 12 weeks (study B) after boosting (9). CD8+ T cells specific for the Mamu-A01-restricted SIV gag p11CM epitope (residues 181 through 189) (p11CM+ T cells) were quantitated by using major histocompatibility complex class I-peptide tetramers. The initial number of p11CM+ T cells (on day –1 [study A] or –7 [study B] prior to challenge) ranged from undetectable (<0.01%) to 158 cells μl–1. This range of p11CM+ T cells allowed us to correlate the initial p11CM+ T-cell number against immune and viral kinetic parameters.
Impact of initial number of vaccine-induced p11CM+ T cells on p11CM+ T-cell kinetics. The first question we addressed was whether inducing higher p11CM+ T-cell numbers could overcome the observed delay in virus-specific CD8+ T-cell expansion (1, 7). Following infection, the number of p11CM+ T cells was not significantly increased compared to preinfection levels until day 14 for study B and day 15 for study A, and at these times, the numbers of p11CM+ T cells were 10-fold higher than preinfection levels (P values of 0.0039 and <0.0001, respectively [paired Wilcoxon]). The time p11CM+ T-cell expansion starts, ton, was estimated by finding when the T-cell growth curve, assumed to be exponential with intersects the initial p11CM+ T-cell number prior to infection, T0 (Fig. 1a). If the observed number of p11CM+ T cells before infection is T0, the growth rate of p11CM+ T cells (calculated by linear regression of the natural-log transformed data) is g and the y intercept of this regression line is b, then the time when expansion commenced (ton) is as follows: ton = (lnT0 – b)/g. The viral load at this time was calculated by linear interpolation of the log-transformed viral load data (using the two data points immediately before and after ton).
A higher preinfection p11CM+ T-cell number was associated with a greater delay in the time of initial p11CM+ T-cell expansion (r = 0.68, P = 0.0011 [Spearman]) (Fig. 2a). If the delay is due to the time taken for the level of antigen or number of infected cells to reach a certain threshold in order to activate CD8+ T cells, it is possible that the longer delay may be due to better viral control (i.e., slower viral growth leads to a longer delay until the threshold level is reached). To examine this, we calculated the viral load at ton, the time when p11CM+ T-cell expansion was estimated to commence (Fig. 1b). Higher initial p11CM+ T-cell numbers were associated with higher viral loads at ton (r = 0.54, P = 0.014) (Fig. 2c), contrary to the idea of a strict viral threshold. In addition, the growth rate of p11CM+ T cells was negatively correlated with the initial number of these cells (r = –0.58, P = 0.0075) (Fig. 2b). Thus, the higher the initial number of p11CM+ T cells, the greater the delay before their initial expansion and the more slowly they increased.
The initial number of p11CM+ T cells was a poor predictor of their peak number during acute infection (r = 0.15, P = 0.53) (Fig. 2e). Closer examination of the relationship between initial and peak p11CM+ T-cell numbers suggests that the peak number of p11CM+ T cells increases with larger initial numbers but only up to an initial level of 2 cells μl–1. However, for initial numbers between 2 and 158 cells μl–1, a similar peak number (600 cells μl–1) was achieved, suggesting that larger initial numbers beyond 2 cells μl–1 had little effect on the peak levels reached.
Following the peak in p11CM+ T-cell responses around day 20, most cells die, leaving a small pool of long-lived "memory" cells (Fig. 1a). The mean decay rate in the vaccinees was 0.32 ± 0.14 day–1 (equivalent to a half-life of 2.2 days). This decay rate was negatively correlated with the initial p11CM+ T-cell number (r = –0.47, P = 0.037) (Fig. 2d). To estimate the efficiency of memory formation after the peak CD8+ T-cell response, we calculated the number of specific CD8+ T cells remaining at 6 weeks as a proportion of those cells at the peak of the response. Higher p11CM+ T-cell numbers before infection were found to be a significant predictor of a higher proportion of peak cells remaining at 6 weeks (r = 0.47, P = 0.038) (Fig. 2f). Thus, although high initial p11CM+ T-cell numbers did not contribute to higher peak p11CM+ T-cell numbers, they did lead to a higher number of memory p11CM+ T cells. This suggests that a high initial number of memory cells from vaccination contributed to better memory retention during the resolution phase of primary infection, perhaps due to the better preservation of CD4+ T-cell help (5, 11).
Impact of initial p11CM+ T-cell number on viral kinetics. In our previous study, we found that vaccination had no significant effect on viral load prior to day 10 of infection (7). In the present study, the preinfection p11CM+ T-cell number was not correlated with viral load at day 10 (r = –0.22, P = 0.27 [Spearman]) (Fig. 3a), nor was there any correlation between the number of p11CM+ T cells preinfection and the initial viral growth rate (estimated by linear regression of the natural log-transformed viral load data) (r = –0.24, P = 0.24) (Fig. 3b). However, higher preinfection p11CM+ T-cell numbers were significantly associated with lower peak viral loads (r = –0.67, P = 0.0002) (Fig. 3c).
The mean postpeak decay rate of virus in acute infection was 0.82 ± 0.18 day–1 (half-life of 20.3 h). There was no correlation between viral decay rate and either preinfection p11CM+ T-cell number (r = 0.30, P = 0.13) (Fig. 3d) or peak p11CM+ T-cell number (r = 0.14, P = 0.50). Thus, as we have previously observed (7), high virus-specific CD8+ T-cell numbers did not appear to affect the postpeak decay rate of virus in acute infection. However, viral decay continued for longer and to lower levels in animals with a higher initial p11CM+ T-cell number. Long-term viral loads (18 weeks) were inversely correlated with initial p11CM+ T-cell numbers (r = –0.64, P = 0.0004) (Fig. 3e).
SHIV-89.6P mediates early and rapid CD4+ T-cell depletion in na?ve animals. We calculated the level of CD4+ T-cell depletion as follows: [(initial CD4+ T-cell number) – (CD4+ T cells at time t)]/(initial CD4+ T-cell number), where the initial number was determined at day –1 or –7. Initial p11CM+ T-cell number was inversely correlated with the level of CD4+ depletion both early after infection, one week after peak in viral load (r = –0.66, P = 0.0003) (Fig. 3f), and late, day 122 to 129 (r = –0.74, P < 0.0001).
Implications for vaccine design. The delay in CD8+ T-cell control of virus following infection allows for uncontrolled early viral growth and the establishment of chronic infection (7). One might speculate that extremely potent vaccination regimens could overcome this delay and mediate sterilizing immunity to infection. Now, we report that higher initial virus-specific CD8+ T-cell numbers led to longer delays before the initial expansion of these cells and slower growth once expansion commenced. However, higher initial virus-specific CD8+ T-cell numbers led to higher numbers of memory CD8+ T cells, reduced peak viral loads, and improved long-term viral control.
Since these animals were primed with whole antigens, they make CD8+, CD4+, and antibody responses to multiple epitopes, and we cannot exclude the possibility of the contributions of these other factors to the observed correlations between p11CM+ T-cell numbers and outcome. Other important factors not analyzed are responses against different epitopes and the functional status of the virus-specific CD8+ T cells. However, it is unlikely that targeting of other (subdominant) epitopes will be more successful at mediating early viral control, as we have previously shown that these T cells are also delayed and grow more slowly than the dominant response (7). In addition, others have reported similar delays for functionally capable virus-specific CD8+ T cells (1).
There is no clear consensus on the type of immune response required to control HIV infection. Kinetic analysis of the effects of antibody (12) and CD8+ T cells (1) on virus provides insights into the possibilities and limitations of these responses. CD8+ T-cell-inducing vaccines appear unable to mediate sterilizing immunity but may mediate long-term viral control and improved clinical outcome for infected individuals. Such disease-modifying vaccines may also contribute to the control of the HIV epidemic (6, 10). Additional hurdles to effective vaccination may also be encountered for natural HIV infection, due to the antigenic variation of the virus. Optimal T-cell responses may need to be more broadly targeted, both to cover the range of viral strains present in the community and to reduce the risk of immune escape within the individual (3, 8). Thus, a consideration of quantitative and qualitative aspects of the CD8+ T cells response to virus is crucial, since a thorough understanding of the interplay between cytotoxic T lymphocytes and virus can lead to a more rational vaccine design process.
ACKNOWLEDGMENTS
Portions of this work were done under the auspices of the U.S. Department of Energy under contract W-7405-ENG-36 and supported by the James S. McDonnell Foundation 21st Century Research Award/Studying Complex Systems (M.P.D.) and National Institutes of Health grants AI28433 and RR06555 (A.S.P.).
REFERENCES
Abdel-Motal, U. M., J. Gillis, K. Manson, M. Wyand, D. Montefiori, K. Stefano-Cole, R. C. Montelaro, J. D. Altman, and R. P. Johnson. 2005. Kinetics of expansion of SIV Gag-specific CD8+ T lymphocytes following challenge of vaccinated macaques. Virology 333:226-238.
Amara, R. R., F. Villinger, J. D. Altman, S. L. Lydy, S. P. O'Neil, S. I. Staprans, D. C. Montefiori, Y. Xu, J. G. Herndon, L. S. Wyatt, M. A. Candido, N. L. Kozyr, P. L. Earl, J. M. Smith, H. L. Ma, B. D. Grimm, M. L. Hulsey, J. Miller, H. M. McClure, J. M. McNicholl, B. Moss, and H. L. Robinson. 2001. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292:69-74.
Barouch, D. H., J. Kunstman, M. J. Kuroda, J. E. Schmitz, S. Santra, F. W. Peyerl, G. R. Krivulka, K. Beaudry, M. A. Lifton, D. A. Gorgone, D. C. Montefiori, M. G. Lewis, S. M. Wolinsky, and N. L. Letvin. 2002. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415:335-339.
Barouch, D. H., S. Santra, J. E. Schmitz, M. J. Kuroda, T. M. Fu, W. Wagner, M. Bilska, A. Craiu, X. X. Zheng, G. R. Krivulka, K. Beaudry, M. A. Lifton, C. E. Nickerson, W. L. Trigona, K. Punt, D. C. Freed, L. M. Guan, S. Dubey, D. Casimiro, A. Simon, M. E. Davies, M. Chastain, T. B. Strom, R. S. Gelman, D. C. Montefiori, et al. 2000. Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 290:486-492.
Belz, G. T., D. Wodarz, G. Diaz, M. A. Nowak, and P. C. Doherty. 2002. Compromised influenza virus-specific CD8+-T-cell memory in CD4+-T-cell-deficient mice. J. Virol. 76:12388-12393.
Davenport, M. P., R. M. Ribeiro, D. L. Chao, and A. S. Perelson. 2004. Predicting the impact of a nonsterilizing vaccine against human immunodeficiency virus. J. Virol. 78:11340-11351.
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