The High-Frequency Major Histocompatibility Comple
http://www.100md.com
病菌学杂志 2006年第10期
Wisconsin National Primate Research Center, University of Wisconsin—Madison, Madison, Wisconsin 53715
Department of Pathology and Laboratory Medicine, University of Wisconsin—Madison, Madison, Wisconsin 53715
Basic Research Program, Laboratory of Genomic Diversity, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702
and AIDS Vaccine Program/Basic Research Program, Science Applications International Corporation-Fredrick, Frederick, Maryland 21072
ABSTRACT
Particular HLA alleles are associated with reduced human immunodeficiency virus replication. It has been difficult, however, to characterize the immune correlates of viral control. An analysis of the influence of major histocompatibility complex class I alleles on viral control in 181 simian immunodeficiency virus SIVmac239-infected rhesus macaques revealed that Mamu-B17 was associated with a 26-fold reduction in plasma virus concentrations (P < 0.001). Mamu-B17 was also enriched 1,000-fold in a group of animals that controlled viral replication. Even after accounting for this group, Mamu-B17 was associated with an eightfold reduction in plasma virus concentrations (P < 0.001). Mamu-B17-positive macaques could, therefore, facilitate our understanding of the correlates of viral control.
TEXT
Major histocompatibility complex (MHC) class I alleles have been associated with the control of human immunodeficiency virus (HIV) replication (1, 2, 3, 5, 13). The protective benefit of the MHC class I alleles HLA-B27 and HLA-B57 is well established, and cellular immune responses restricted by these alleles have been characterized (7, 13). Unfortunately, correlating particular responses with the control of viral replication has been difficult. The dual obstacles of HIV variability and allelic diversity of the human MHC class I loci confound interpretation of immune correlates in the rare patients who control the virus. An animal model for understanding the basis of this HLA class I-associated control of viral replication would facilitate an investigation of the underlying immune correlates of control.
The MHC-defined Indian rhesus macaque infected with simian immunodeficiency virus (SIV) provides a tractable model system to discern the influence of MHC class I alleles on the replication of a pathogenic AIDS virus. Previous studies have reported associations between rhesus macaque MHC class I alleles and control of virus replication (9, 10, 11, 12). Here we investigate the effect of high-frequency MHC class I alleles in the Indian rhesus macaque on the control of viral replication after challenge with a clonal virus isolate.
High-frequency MHC class I allele associations with chronic-phase viral control. To investigate whether particular high-frequency MHC class I alleles are linked to the control of pathogenic SIVmac239 replication, we measured postchallenge plasma virus concentrations in 181 Indian rhesus macaques from two independent cohorts. Multiple chronic-phase plasma virus time points were measured for each animal, from 10 weeks postchallenge through the time of sacrifice (range, 10 to 320 weeks postchallenge). All animals were infected with the clonal isolate SIVmac239.
Remarkably, 13 animals maintained chronic-phase plasma virus concentrations that were 1,000-fold lower than those of the cohort geometric mean. This group was significantly enriched for four high-frequency MHC class I alleles: the closely linked Mamu-B17 and Mamu-B29 (P = 0.003), Mamu-A02 (P = 0.03), and Mamu-A11 (P = 0.03) (Table 1). Conversely, one allele, Mamu-B01, was significantly underrepresented in this group. Although Mamu-B01 was present in 60 of the 181 animals in the infected cohort, it was not present in any of the 13 "elite controllers" (P = 0.02) (Table 1). While 85% of the 181 animals had chronic-phase plasma virus concentrations within 2 log units of the cohort chronic-phase geometric mean of 457,000 viral RNA (vRNA) copies/ml, this group of elite controllers maintained plasma virus concentrations that were more than 3 log units lower (362 vRNA copies/ml) than the cohort chronic-phase geometric mean. In fact, the 13 elite controllers have maintained these plasma virus concentrations from week 10 postchallenge to the present (52 to 310 weeks postinfection). Interestingly, the percentage (7%) of macaques that controlled SIVmac239 replication to the lowest levels in this model system is very similar to the percentage (8%) of HIV-infected humans found to suppress their virus to comparable levels (6).
We performed independent statistical analyses for vaccinated and nonvaccinated animals for all alleles and found no significant differences between plasma virus concentrations of vaccinated and nonvaccinated animals of every genotype (data not shown). While 97/181 (54%) of the overall cohort received an experimental vaccine, 6/13 (46%) of the elite controllers received an experimental vaccine.
The most dramatic enrichment of the elite controller group was for animals positive for both Mamu-B17 (Mamu-B17+) and Mamu-B29 (Mamu-B29+). While 19% of the overall cohort was Mamu-B17+/Mamu-B29+, 69% of the elite controllers were positive for both of these alleles (P = 0.003). While Mamu-B17 binds at least 16 SIVmac239-derived peptides and thus restricts various SIV-specific cellular immune responses (8), there is no evidence to date that the closely linked (linkage R square value, 0.87) Mamu-B29 allele encodes a gene product that binds any SIVmac239-derived peptides.
Mamu-B17+/Mamu-B29+ animals exhibited a 26-fold decrease in geometric mean chronic-phase plasma virus concentrations, compared to the rest of the cohort (P < 0.001). The Mamu-B17+/Mamu-B29+ animals consisted of two discrete subgroups: the nine Mamu-B17+/Mamu-B29+ animals that controlled their chronic-phase plasma virus concentrations to below 1,000 vRNA copies/ml formed a separate distribution from the 25 Mamu-B17+/Mamu-B29+ animals with more typical chronic-phase plasma virus concentrations. We therefore analyzed the Mamu-B17+/Mamu-B29+ animals, taking into account the influence of the Mamu-B17+/Mamu-B29+ elite controller group (Fig. 1). When we accounted for these elite controller Mamu-B17+/Mamu-B29+ animals, we discovered that these two alleles were still associated with an eightfold reduction in geometric mean chronic-phase plasma virus concentrations (P < 0.001).
Previous reports have indicated an association between the expression of Mamu-A01 and a reduction in chronic-phase plasma virus concentrations in animals infected with SIVmac239 (9) and SIVmac251 (10, 12) and lower lymph node-associated virus concentrations in SHIV89.6P infection (14). Mamu-A01 was associated with only slightly decreased chronic-phase plasma virus concentrations in an expanded SIVmac239-infected cohort (11). Decreased chronic-phase plasma virus concentrations, however, were not observed in Mamu-A01+ cohorts infected with SIVsmE660, SHIV89.6P, or SHIVKU2 (12). In our further expanded cohorts, this allele was significantly associated with a threefold reduction in geometric mean plasma virus concentrations after we took into account vaccination and elite controller status (P = 0.006) (Fig. 1).
It is possible that genes closely linked to Mamu-B17 and Mamu-A01 might influence the ability of the virus to replicate in vivo. There were, however, no significant differences in acute-phase peak plasma virus concentrations in animals of all genotypes before the onset of cellular immune responses (Fig. 2). This suggests that the accentuated decline from acute-phase peak to chronic-phase plasma virus concentrations in Mamu-B17+ and Mamu-A01+ animals was not due to a differential intrinsic susceptibility of their CD4+ T cells to infection with pathogenic SIVmac239 or to the enhanced effect of some non-MHC class I host restriction factor.
These Mamu-B17+ animals promise to provide useful and clear-cut models for the understanding of the influence of particular MHC class I alleles on viral control. Because a comprehensive SIVmac239 epitope mapping study has been performed for Mamu-B17 (8), Mamu-B17+ animals provide a unique opportunity to analyze particular CD8+ T-cell specificities linked to successful control of viral replication. For example, we can ablate the SIV-specific CD8+ T-cell response in these Mamu-B17+ elite controllers with depleting antibodies. Additionally, since SIVmac239 has proven recalcitrant to effective neutralization by antibody responses, we can examine the effect of particular MHC class I-restricted cellular immune responses without the potentially confounding effects of neutralizing antibody.
A substantial proportion of captive Indian rhesus macaques express Mamu B17. Of the Indian rhesus macaques at the Wisconsin National Primate Research Center (WNPRC), approximately 16% are Mamu-B17+. Given the influence of this allele on the outcome of SIV infection, Mamu-B17+ animals should be removed from vaccine cohorts to avoid the attribution of Mamu-B17-associated control of viral replication to possible effects of vaccination. Simply balancing control and vaccine groups with these macaques is insufficient, because spontaneous control occurs in a sizeable subset of Mamu-B17+ animals. Until the precise determinants of this control are defined, the use of Mamu-B17+ animals should be avoided except for analysis of the causes underlying their exceptional viral control.
ACKNOWLEDGMENTS
We gratefully acknowledge Eva Rakasz, Kirsten Bomblies, and Matt Reynolds for helpful discussions, Jess Maxwell, Crystal Glidden, and Tim Jacoby for MHC typing, and Ron Desrosiers for SIVmac239 inocula.
This work was supported by NIH grants R01 AI052056-03 and R24 RR016038-05; NIH contract HHSN26620040008C/N 01-AI-40088; the WNPRC base grant 5P51 RR 000167; federal funds from the National Cancer Institute, National Institutes of Health, under contract no. NO1-CO-12400; and by the Intramural Research Program of the NIH, National NO1-CO-12400, Cancer Institute, Center for Cancer Research.
The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government.
REFERENCES
Carrington, M., and S. J. O'Brien. 2003. The influence of HLA genotype on AIDS. Annu. Rev. Med. 54:535-551.
Kaslow, R. A., M. Carrington, R. Apple, L. Park, A. Munoz, A. J. Saah, J. J. Goedert, C. Winkler, S. J. O'Brien, C. Rinaldo, R. Detels, W. Blattner, J. Phair, H. Erlich, and D. L. Mann. 1996. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat. Med. 2:405-411.
Kiepiela, P., A. J. Leslie, I. Honeyborne, D. Ramduth, C. Thobakgale, S. Chetty, P. Rathnavalu, C. Moore, K. J. Pfafferott, L. Hilton, P. Zimbwa, S. Moore, T. Allen, C. Brander, M. M. Addo, M. Altfeld, I. James, S. Mallal, M. Bunce, L. D. Barber, J. Szinger, C. Day, P. Klenerman, J. Mullins, B. Korber, H. M. Coovadia, B. D. Walker, and P. J. Goulder. 2004. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432:769-775.
Knapp, L. A., E. Lehmann, M. S. Piekarczyk, J. A. Urvater, and D. I. Watkins. 1997. A high frequency of Mamu-A01 in the rhesus macaque detected by polymerase chain reaction with sequence-specific primers and direct sequencing. Tissue Antigens 50:657-661.
McNeil, A. J., P. L. Yap, S. M. Gore, R. P. Brettle, M. McColl, R. Wyld, S. Davidson, R. Weightman, A. M. Richardson, and J. R. Robertson. 1996. Association of HLA types A1-B8-DR3 and B27 with rapid and slow progression of HIV disease. QJM 89:177-185.
Mellors, J. W., A. Munoz, J. V. Giorgi, J. B. Margolick, C. J. Tassoni, P. Gupta, L. A. Kingsley, J. A. Todd, A. J. Saah, R. Detels, J. P. Phair, and C. R. J. Rinaldo. 1997. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann. Intern. Med. 126:946-954.
Migueles, S. A., M. S. Sabbaghian, W. L. Shupert, M. P. Bettinotti, F. M. Marincola, L. Martino, C. W. Hallahan, S. M. Selig, D. Schwartz, J. Sullivan, and M. Connors. 2000. HLA B5701 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.
Mothe, B. R., J. Sidney, J. L. Dzuris, M. E. Liebl, S. Fuenger, D. I. Watkins, and A. Sette. 2002. Characterization of the peptide-binding specificity of Mamu-B17 and identification of Mamu-B17-restricted epitopes derived from simian immunodeficiency virus proteins. J. Immunol. 169:210-219.
Mothe, B. R., J. Weinfurter, C. Wang, W. Rehrauer, N. Wilson, T. M. Allen, D. B. Allison, and D. I. Watkins. 2003. Expression of the major histocompatibility complex class I molecule Mamu-A01 is associated with control of simian immunodeficiency virus SIVmac239 replication. J. Virol. 77:2736-2740.
Muhl, T., M. Krawczak, P. Ten Haaft, G. Hunsmann, and U. Sauermann. 2002. MHC class I alleles influence set-point viral load and survival time in simian immunodeficiency virus-infected rhesus monkeys. J. Immunol. 169:3438-3446.
O'Connor, D. H., B. R. Mothe, J. T. Weinfurter, S. Fuenger, W. M. Rehrauer, P. Jing, R. R. Rudersdorf, M. E. Liebl, K. Krebs, J. Vasquez, E. Dodds, J. Loffredo, S. Martin, A. B. McDermott, T. M. Allen, C. Wang, G. G. Doxiadis, D. C. Montefiori, A. Hughes, D. R. Burton, D. B. Allison, S. M. Wolinsky, R. Bontrop, L. J. Picker, and D. I. Watkins. 2003. Major histocompatibility complex class I alleles associated with slow simian immunodeficiency virus disease progression bind epitopes recognized by dominant acute-phase cytotoxic-T-lymphocyte responses. J. Virol. 77:9029-9040.
Pal, R., D. Venzon, N. L. Letvin, S. Santra, D. C. Montefiori, N. R. Miller, E. Tryniszewska, M. G. Lewis, T. C. VanCott, V. Hirsch, R. Woodward, A. Gibson, M. Grace, E. Dobratz, P. D. Markham, Z. Hel, J. Nacsa, M. Klein, J. Tartaglia, and G. Franchini. 2002. ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency. J. Virol. 76:292-302.
Saah, A. J., D. R. Hoover, S. Weng, M. Carrington, J. Mellors, C. R. J. Rinaldo, D. Mann, R. Apple, J. P. Phair, R. Detels, S. O'Brien, C. Enger, P. Johnson, and R. A. Kaslow. 1998. Association of HLA profiles with early plasma viral load, CD4+ cell count and rate of progression to AIDS following acute HIV-1 infection. Multicenter AIDS Cohort Study. AIDS 12:2107-2113.
Zhang, Z. Q., T. M. Fu, D. R. Casimiro, M. E. Davies, X. Liang, W. A. Schleif, L. Handt, L. Tussey, M. Chen, A. Tang, K. A. Wilson, W. L. Trigona, D. C. Freed, C. Y. Tan, M. Horton, E. A. Emini, and J. W. Shiver. 2002. Mamu-A01 allele-mediated attenuation of disease progression in simian-human immunodeficiency virus infection. J. Virol. 76:12845-12854.(Levi J. Yant, Thomas C. F)
Department of Pathology and Laboratory Medicine, University of Wisconsin—Madison, Madison, Wisconsin 53715
Basic Research Program, Laboratory of Genomic Diversity, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702
and AIDS Vaccine Program/Basic Research Program, Science Applications International Corporation-Fredrick, Frederick, Maryland 21072
ABSTRACT
Particular HLA alleles are associated with reduced human immunodeficiency virus replication. It has been difficult, however, to characterize the immune correlates of viral control. An analysis of the influence of major histocompatibility complex class I alleles on viral control in 181 simian immunodeficiency virus SIVmac239-infected rhesus macaques revealed that Mamu-B17 was associated with a 26-fold reduction in plasma virus concentrations (P < 0.001). Mamu-B17 was also enriched 1,000-fold in a group of animals that controlled viral replication. Even after accounting for this group, Mamu-B17 was associated with an eightfold reduction in plasma virus concentrations (P < 0.001). Mamu-B17-positive macaques could, therefore, facilitate our understanding of the correlates of viral control.
TEXT
Major histocompatibility complex (MHC) class I alleles have been associated with the control of human immunodeficiency virus (HIV) replication (1, 2, 3, 5, 13). The protective benefit of the MHC class I alleles HLA-B27 and HLA-B57 is well established, and cellular immune responses restricted by these alleles have been characterized (7, 13). Unfortunately, correlating particular responses with the control of viral replication has been difficult. The dual obstacles of HIV variability and allelic diversity of the human MHC class I loci confound interpretation of immune correlates in the rare patients who control the virus. An animal model for understanding the basis of this HLA class I-associated control of viral replication would facilitate an investigation of the underlying immune correlates of control.
The MHC-defined Indian rhesus macaque infected with simian immunodeficiency virus (SIV) provides a tractable model system to discern the influence of MHC class I alleles on the replication of a pathogenic AIDS virus. Previous studies have reported associations between rhesus macaque MHC class I alleles and control of virus replication (9, 10, 11, 12). Here we investigate the effect of high-frequency MHC class I alleles in the Indian rhesus macaque on the control of viral replication after challenge with a clonal virus isolate.
High-frequency MHC class I allele associations with chronic-phase viral control. To investigate whether particular high-frequency MHC class I alleles are linked to the control of pathogenic SIVmac239 replication, we measured postchallenge plasma virus concentrations in 181 Indian rhesus macaques from two independent cohorts. Multiple chronic-phase plasma virus time points were measured for each animal, from 10 weeks postchallenge through the time of sacrifice (range, 10 to 320 weeks postchallenge). All animals were infected with the clonal isolate SIVmac239.
Remarkably, 13 animals maintained chronic-phase plasma virus concentrations that were 1,000-fold lower than those of the cohort geometric mean. This group was significantly enriched for four high-frequency MHC class I alleles: the closely linked Mamu-B17 and Mamu-B29 (P = 0.003), Mamu-A02 (P = 0.03), and Mamu-A11 (P = 0.03) (Table 1). Conversely, one allele, Mamu-B01, was significantly underrepresented in this group. Although Mamu-B01 was present in 60 of the 181 animals in the infected cohort, it was not present in any of the 13 "elite controllers" (P = 0.02) (Table 1). While 85% of the 181 animals had chronic-phase plasma virus concentrations within 2 log units of the cohort chronic-phase geometric mean of 457,000 viral RNA (vRNA) copies/ml, this group of elite controllers maintained plasma virus concentrations that were more than 3 log units lower (362 vRNA copies/ml) than the cohort chronic-phase geometric mean. In fact, the 13 elite controllers have maintained these plasma virus concentrations from week 10 postchallenge to the present (52 to 310 weeks postinfection). Interestingly, the percentage (7%) of macaques that controlled SIVmac239 replication to the lowest levels in this model system is very similar to the percentage (8%) of HIV-infected humans found to suppress their virus to comparable levels (6).
We performed independent statistical analyses for vaccinated and nonvaccinated animals for all alleles and found no significant differences between plasma virus concentrations of vaccinated and nonvaccinated animals of every genotype (data not shown). While 97/181 (54%) of the overall cohort received an experimental vaccine, 6/13 (46%) of the elite controllers received an experimental vaccine.
The most dramatic enrichment of the elite controller group was for animals positive for both Mamu-B17 (Mamu-B17+) and Mamu-B29 (Mamu-B29+). While 19% of the overall cohort was Mamu-B17+/Mamu-B29+, 69% of the elite controllers were positive for both of these alleles (P = 0.003). While Mamu-B17 binds at least 16 SIVmac239-derived peptides and thus restricts various SIV-specific cellular immune responses (8), there is no evidence to date that the closely linked (linkage R square value, 0.87) Mamu-B29 allele encodes a gene product that binds any SIVmac239-derived peptides.
Mamu-B17+/Mamu-B29+ animals exhibited a 26-fold decrease in geometric mean chronic-phase plasma virus concentrations, compared to the rest of the cohort (P < 0.001). The Mamu-B17+/Mamu-B29+ animals consisted of two discrete subgroups: the nine Mamu-B17+/Mamu-B29+ animals that controlled their chronic-phase plasma virus concentrations to below 1,000 vRNA copies/ml formed a separate distribution from the 25 Mamu-B17+/Mamu-B29+ animals with more typical chronic-phase plasma virus concentrations. We therefore analyzed the Mamu-B17+/Mamu-B29+ animals, taking into account the influence of the Mamu-B17+/Mamu-B29+ elite controller group (Fig. 1). When we accounted for these elite controller Mamu-B17+/Mamu-B29+ animals, we discovered that these two alleles were still associated with an eightfold reduction in geometric mean chronic-phase plasma virus concentrations (P < 0.001).
Previous reports have indicated an association between the expression of Mamu-A01 and a reduction in chronic-phase plasma virus concentrations in animals infected with SIVmac239 (9) and SIVmac251 (10, 12) and lower lymph node-associated virus concentrations in SHIV89.6P infection (14). Mamu-A01 was associated with only slightly decreased chronic-phase plasma virus concentrations in an expanded SIVmac239-infected cohort (11). Decreased chronic-phase plasma virus concentrations, however, were not observed in Mamu-A01+ cohorts infected with SIVsmE660, SHIV89.6P, or SHIVKU2 (12). In our further expanded cohorts, this allele was significantly associated with a threefold reduction in geometric mean plasma virus concentrations after we took into account vaccination and elite controller status (P = 0.006) (Fig. 1).
It is possible that genes closely linked to Mamu-B17 and Mamu-A01 might influence the ability of the virus to replicate in vivo. There were, however, no significant differences in acute-phase peak plasma virus concentrations in animals of all genotypes before the onset of cellular immune responses (Fig. 2). This suggests that the accentuated decline from acute-phase peak to chronic-phase plasma virus concentrations in Mamu-B17+ and Mamu-A01+ animals was not due to a differential intrinsic susceptibility of their CD4+ T cells to infection with pathogenic SIVmac239 or to the enhanced effect of some non-MHC class I host restriction factor.
These Mamu-B17+ animals promise to provide useful and clear-cut models for the understanding of the influence of particular MHC class I alleles on viral control. Because a comprehensive SIVmac239 epitope mapping study has been performed for Mamu-B17 (8), Mamu-B17+ animals provide a unique opportunity to analyze particular CD8+ T-cell specificities linked to successful control of viral replication. For example, we can ablate the SIV-specific CD8+ T-cell response in these Mamu-B17+ elite controllers with depleting antibodies. Additionally, since SIVmac239 has proven recalcitrant to effective neutralization by antibody responses, we can examine the effect of particular MHC class I-restricted cellular immune responses without the potentially confounding effects of neutralizing antibody.
A substantial proportion of captive Indian rhesus macaques express Mamu B17. Of the Indian rhesus macaques at the Wisconsin National Primate Research Center (WNPRC), approximately 16% are Mamu-B17+. Given the influence of this allele on the outcome of SIV infection, Mamu-B17+ animals should be removed from vaccine cohorts to avoid the attribution of Mamu-B17-associated control of viral replication to possible effects of vaccination. Simply balancing control and vaccine groups with these macaques is insufficient, because spontaneous control occurs in a sizeable subset of Mamu-B17+ animals. Until the precise determinants of this control are defined, the use of Mamu-B17+ animals should be avoided except for analysis of the causes underlying their exceptional viral control.
ACKNOWLEDGMENTS
We gratefully acknowledge Eva Rakasz, Kirsten Bomblies, and Matt Reynolds for helpful discussions, Jess Maxwell, Crystal Glidden, and Tim Jacoby for MHC typing, and Ron Desrosiers for SIVmac239 inocula.
This work was supported by NIH grants R01 AI052056-03 and R24 RR016038-05; NIH contract HHSN26620040008C/N 01-AI-40088; the WNPRC base grant 5P51 RR 000167; federal funds from the National Cancer Institute, National Institutes of Health, under contract no. NO1-CO-12400; and by the Intramural Research Program of the NIH, National NO1-CO-12400, Cancer Institute, Center for Cancer Research.
The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government.
REFERENCES
Carrington, M., and S. J. O'Brien. 2003. The influence of HLA genotype on AIDS. Annu. Rev. Med. 54:535-551.
Kaslow, R. A., M. Carrington, R. Apple, L. Park, A. Munoz, A. J. Saah, J. J. Goedert, C. Winkler, S. J. O'Brien, C. Rinaldo, R. Detels, W. Blattner, J. Phair, H. Erlich, and D. L. Mann. 1996. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat. Med. 2:405-411.
Kiepiela, P., A. J. Leslie, I. Honeyborne, D. Ramduth, C. Thobakgale, S. Chetty, P. Rathnavalu, C. Moore, K. J. Pfafferott, L. Hilton, P. Zimbwa, S. Moore, T. Allen, C. Brander, M. M. Addo, M. Altfeld, I. James, S. Mallal, M. Bunce, L. D. Barber, J. Szinger, C. Day, P. Klenerman, J. Mullins, B. Korber, H. M. Coovadia, B. D. Walker, and P. J. Goulder. 2004. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432:769-775.
Knapp, L. A., E. Lehmann, M. S. Piekarczyk, J. A. Urvater, and D. I. Watkins. 1997. A high frequency of Mamu-A01 in the rhesus macaque detected by polymerase chain reaction with sequence-specific primers and direct sequencing. Tissue Antigens 50:657-661.
McNeil, A. J., P. L. Yap, S. M. Gore, R. P. Brettle, M. McColl, R. Wyld, S. Davidson, R. Weightman, A. M. Richardson, and J. R. Robertson. 1996. Association of HLA types A1-B8-DR3 and B27 with rapid and slow progression of HIV disease. QJM 89:177-185.
Mellors, J. W., A. Munoz, J. V. Giorgi, J. B. Margolick, C. J. Tassoni, P. Gupta, L. A. Kingsley, J. A. Todd, A. J. Saah, R. Detels, J. P. Phair, and C. R. J. Rinaldo. 1997. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann. Intern. Med. 126:946-954.
Migueles, S. A., M. S. Sabbaghian, W. L. Shupert, M. P. Bettinotti, F. M. Marincola, L. Martino, C. W. Hallahan, S. M. Selig, D. Schwartz, J. Sullivan, and M. Connors. 2000. HLA B5701 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.
Mothe, B. R., J. Sidney, J. L. Dzuris, M. E. Liebl, S. Fuenger, D. I. Watkins, and A. Sette. 2002. Characterization of the peptide-binding specificity of Mamu-B17 and identification of Mamu-B17-restricted epitopes derived from simian immunodeficiency virus proteins. J. Immunol. 169:210-219.
Mothe, B. R., J. Weinfurter, C. Wang, W. Rehrauer, N. Wilson, T. M. Allen, D. B. Allison, and D. I. Watkins. 2003. Expression of the major histocompatibility complex class I molecule Mamu-A01 is associated with control of simian immunodeficiency virus SIVmac239 replication. J. Virol. 77:2736-2740.
Muhl, T., M. Krawczak, P. Ten Haaft, G. Hunsmann, and U. Sauermann. 2002. MHC class I alleles influence set-point viral load and survival time in simian immunodeficiency virus-infected rhesus monkeys. J. Immunol. 169:3438-3446.
O'Connor, D. H., B. R. Mothe, J. T. Weinfurter, S. Fuenger, W. M. Rehrauer, P. Jing, R. R. Rudersdorf, M. E. Liebl, K. Krebs, J. Vasquez, E. Dodds, J. Loffredo, S. Martin, A. B. McDermott, T. M. Allen, C. Wang, G. G. Doxiadis, D. C. Montefiori, A. Hughes, D. R. Burton, D. B. Allison, S. M. Wolinsky, R. Bontrop, L. J. Picker, and D. I. Watkins. 2003. Major histocompatibility complex class I alleles associated with slow simian immunodeficiency virus disease progression bind epitopes recognized by dominant acute-phase cytotoxic-T-lymphocyte responses. J. Virol. 77:9029-9040.
Pal, R., D. Venzon, N. L. Letvin, S. Santra, D. C. Montefiori, N. R. Miller, E. Tryniszewska, M. G. Lewis, T. C. VanCott, V. Hirsch, R. Woodward, A. Gibson, M. Grace, E. Dobratz, P. D. Markham, Z. Hel, J. Nacsa, M. Klein, J. Tartaglia, and G. Franchini. 2002. ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency. J. Virol. 76:292-302.
Saah, A. J., D. R. Hoover, S. Weng, M. Carrington, J. Mellors, C. R. J. Rinaldo, D. Mann, R. Apple, J. P. Phair, R. Detels, S. O'Brien, C. Enger, P. Johnson, and R. A. Kaslow. 1998. Association of HLA profiles with early plasma viral load, CD4+ cell count and rate of progression to AIDS following acute HIV-1 infection. Multicenter AIDS Cohort Study. AIDS 12:2107-2113.
Zhang, Z. Q., T. M. Fu, D. R. Casimiro, M. E. Davies, X. Liang, W. A. Schleif, L. Handt, L. Tussey, M. Chen, A. Tang, K. A. Wilson, W. L. Trigona, D. C. Freed, C. Y. Tan, M. Horton, E. A. Emini, and J. W. Shiver. 2002. Mamu-A01 allele-mediated attenuation of disease progression in simian-human immunodeficiency virus infection. J. Virol. 76:12845-12854.(Levi J. Yant, Thomas C. F)