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The Journal of Immunology, 2000, 164: 6015-6019.
Copyright © 2000 by The American Association of Immunologists

Simian Immunodeficiency Virus (SIV)-Specific CTL Are Present in Large Numbers in Livers of SIV-Infected Rhesus Monkeys1

Jörn E. Schmitz2,3,*, Marcelo J. Kuroda3,*, Ronald S. Veazey{dagger}, Aruna Seth*, Wesley M. Taylor{dagger}, Christine E. Nickerson*, Michelle A. Lifton*, Peter J. Dailey{ddagger}, Meryl A. Forman§, Paul Racz, Klara Tenner-Racz and Norman L. Letvin*

* Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; {dagger} New England Regional Primate Research Center, Harvard Medical School, Southborough, MA 01772; {ddagger} Bayer Diagnostics, Nucleic Acid Diagnostics, Emeryville, CA 94608; § Beckman Coulter, Miami, FL 33116; and Department of Pathology, Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The immunopathogenesis of AIDS-associated hepatitis was explored in the SIV/rhesus monkey model. The livers of SIV-infected monkeys showed a mild hepatitis, with a predominantly CD8+ T lymphocyte infiltration in the periportal fields and sinusoids. These liver-associated CD8+ T cells were comprised of a high percentage of SIV-specific CTL as defined by MHC class I/Gag peptide tetramer binding and Gag peptide epitope-specific lytic activity. There was insufficient viral replication in these livers to account for attracting this large number of functional virus-specific CTL to the liver. There was also no evidence that the predominant population of CTL were functionally end-stage cells trapped in the liver and destined to undergo apoptotic cell death in that organ. Interestingly, we noted that liver tetramer-binding cells showed an increased expression of CD62L, an adhesion molecule usually only rarely expressed on tetramer-binding cells. This observation suggests that the expression of specific adhesion molecules by CTL might facilitate the capture of these cells in the liver. These results demonstrate that functional SIV-specific CD8+ T cells are present in large numbers in the liver of chronically SIV-infected monkeys. Thus, the liver may be a trap for virus-specific cytotoxic T cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Hepatitis is a common clinical manifestation of a number of viral infections. While some hepatitis-inducing viruses, such as hepatitis A and B viruses, infect hepatic parenchymal cells, others, such as EBV, cytomegalovirus, measles virus, and rubella virus, do not. The pathogenesis of the benign hepatitides associated with infection by this latter group of viruses remains unclear (1).

Hepatitis associated with HIV-1 is being seen with increasing frequency as this virus becomes more prevalent in diverse human populations. While HIV-1 does not infect hepatocytes, systemic infection with this virus is often accompanied by lymphocytic infiltration and bile duct proliferation in the liver (2, 3, 4). These pathogenic manifestations can be of mild or moderate severity. The etiology of this clinical process is not understood.

The immunopathogenesis of HIV-1-associated hepatitis would be difficult to explore in HIV-1-infected humans because such studies would require frequent invasive procedures to obtain the requisite tissue samples. However, the SIV/macaque (SIVmac)4 model of AIDS is ideally suited for such an investigation. SIVmac-infected rhesus monkeys develop a spectrum of disease manifestations virtually indistinguishable from that seen in HIV-1-infected humans (5). Moreover, immunologic tools are now available that allow precise and sophisticated analyses of virus-specific CD8+ T lymphocyte responses in these infected monkeys (6, 7, 8).

The present studies were done to characterize the immunologic basis of the hepatitis associated with SIVmac infection of rhesus monkeys. Using the MHC class I/peptide tetramer technology to define dominant SIVmac epitope-specific CTL in liver-associated CD8+ T cell populations, the central role of virus-specific CTL in this process is demonstrated.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Animals and viruses

EDTA-anticoagulated blood samples and lymphocytes isolated from liver were obtained from euthanized rhesus monkeys (Macaca mulatta) infected with uncloned SIVmac strain 251 for >12 mo. Liver biopsies were performed by standard fine needle biopsy on five healthy rhesus monkeys. All rhesus monkeys used in this study were Mamu-A*01+ as determined both by PCR-based MHC class I typing and by functional CTL assays as previously described (6, 7, 8). These animals were maintained in accordance with the guidelines of the Committee on Animals for the Harvard Medical School and the "Guide for the Care and Use of Laboratory Animals" (National Research Council, National Academic Press, Washington, DC, 1996).

Staining and phenotypic analysis of p11C, C-M-specific CD8+ T lymphocytes

Soluble tetrameric Mamu-A*01/p11C, C-M complex was made as previously described (5). The tetramer was produced by mixing biotinylated Mamu-A*01/p11C, C-M complex with PE-labeled ExtrAvidin (Sigma, St. Louis, MO) or Alexa 488-labeled NeutrAvidin (Molecular Probes, Eugene, OR) at a 4:1 molar ratio. The mAbs used for this study were directly coupled to FITC, PE-Texas red (ECD), or allophycocyanin (APC). The following mAbs were used: anti-CD8{alpha}(Leu2a)-FITC (Becton Dickinson, San Jose, CA); anti-CD8{alpha}ß(2ST8-5H7)-ECD, anti-CD11a(25.3.1)-PE, anti-CD28(4B10)-PE, anti-CD45RA(2H4)-PE, anti-CD49d(HP2/1)-PE, and anti-HLA-DR(I3)-PE (Beckman Coulter, Miami, FL); and anti-CD95(DX2)-PE (Caltag, Burlingame, CA). The mAb FN18, which recognizes rhesus monkey CD3, a gift from Dr. D. M. Neville Jr. (National Institutes of Health, Bethesda, MD), was directly coupled to APC. The mAb ACT-1, which recognizes the integrin molecule {alpha}4ß7, was obtained from Mike Briskin (LeukoSite, Cambridge, MA) and coupled to PE. Annexin V coupled to FITC (Beckman Coulter) was used to determine apoptotic lymphocytes. The three reagents Alexa 488-coupled tetrameric Mamu-A*01/p11C, C-M complex, anti-CD8{alpha}ß-ECD, and anti-rhesus monkey CD3-APC were used either with anti-CD11a-PE, anti-CD28-PE, anti-CD45RA-PE, anti-CD49d-PE, anti-CD95-PE, or anti-HLA-DR-PE to perform four-color flow cytometric analyses. The PE-coupled tetrameric Mamu-A*01/p11C, C-M complex was used with anti-CD8{alpha}-FITC in conjunction with anti-CD8{alpha}ß-ECD and anti-rhesus monkey CD3-APC. Alexa 488- or PE-coupled tetrameric Mamu-A*01/p11C, C-M complex (0.5 µg) was used in conjunction with the directly labeled mAbs to stain either 100 µl of fresh whole blood or 5 x 105 single cells isolated from liver or 5 x 105 lymphocytes isolated by density gradient centrifugation over Ficoll-Hypaque following in vitro culture. Samples were analyzed on a Coulter EPICS Elite ESP as described previously (5, 6, 7). Data presentation was performed using WinMDI software version 2.8 (Joseph Trotter, La Jolla, CA) and Microsoft PowerPoint 97 (Microsoft, Redmond, WA).

Cytotoxicity assay

Autologous B-lymphoblastoid cell lines were used as target cells and were incubated with 5 µg/ml of p11C, C-M (CTPYDINQM) or the negative control peptide p11B (ALSEGCTPYDIN) for 90 min during 51Cr labeling. For effector cells, PBMC or single cells isolated from the liver of four monkeys chronically infected with SIVmac were cultured for 3 days in the presence of 1 µg/ml of the peptide p11C, C-M at a density of 3 x 106 cells/ml and then maintained for another 7–11 days in medium supplemented with recombinant human IL-2 (20 U/ml) (provided by Hoffman-La Roche, Nutley, NJ). PBMC or liver lymphocytes were centrifuged over Ficoll-Hypaque (Ficopaque; Pharmacia, Piscataway, NJ) and assessed as effector cells either when freshly isolated or after in vitro culture as described above in a standard 51Cr release assay using U-bottom microtiter plates containing 104 target cells with effector cells at different E:T ratios. All wells were established and assayed in duplicate. Plates were incubated in a humidified incubator at 37°C for 4 h. Specific release was calculated as [(experimental release - spontaneous release)/(maximum release - spontaneous release)] x 100. Spontaneous release was <20% of maximal release with detergent (1% Triton X-100; Sigma) in all assays.

Branched DNA quantitation of SIV RNA

SIV RNA was quantitated by a branched DNA signal amplification assay (9). The target probes were designed to hybridize with the pol region of the SIVmac group of virus strains, including SIVmac 251, SIVmac239, and SIVmne. SIV RNA was quantified per 1 ml EDTA plasma by comparison with a standard curve produced by purified, quantified, in vitro-transcribed SIVmac239 pol RNA. The lower quantitation limit of this assay was 1500 SIV RNA equivalents per sample.

In situ hybridization

An 35S-labeled, single-stranded, antisense RNA probe (Lofstrand Laboratories, Gaithersburg, MD) was used. The hybridization was done on frozen sections as previously described (10). The sections were examined with a microscope equipped with epiluminescent illumination (Axiophot; Carl Zeiss, Jena, Germany). Cells were considered positive for viral gene expression if the grain count was more than six times higher than the background count.

Immunohistochemistry

Identification of CD8+ lymphocytes in liver sections was performed on snap-frozen liver specimens that were sectioned (6 µm) on a cryostat and fixed in 2% paraformaldehyde at room temperature for 15 min. Sections were rinsed in PBS and incubated with a mixture of anti-CD8 Abs (Leu-2a, Becton Dickinson, Heidelberg, Germany and C8/144B, Dakopatts, Hamburg, Germany). Binding of the primary Abs was visualized by the alkaline phosphatase anti-alkaline phosphatase technique using New Fuchsin (Chroma, Koengen, Germany) as the chromogen. Sections were counterstained with hematoxylin and mounted.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
To begin exploring the immunopathogenesis of lymphocyte-mediated liver pathology in SIVmac-infected rhesus monkeys, biopsies were obtained from five healthy animals. Cell staining and flow cytometric analysis of lymphocytes isolated from these biopsies demonstrated that ~90% of the liver-associated T cells were CD8+ (Fig. 1Go). Immunohistologic studies of these liver specimens showed that the CD8+ T cells were seldom found in the periportal regions or hepatic sinusoids (Fig. 2Go, c and d). These findings are consistent with previous demonstrations that CD8+ T lymphocytes accumulate in livers of healthy humans (11). A similarly performed analysis of liver-associated lymphocytes in four chronically SIVmac-infected rhesus monkeys demonstrated increased numbers of CD8+ T cells, with infiltration predominately into the periportal regions (Fig. 2Go, a and b). The biopsy specimens that were evaluated demonstrated no evidence of the opportunistic infections or tumors that can occur in the setting of chronic SIVmac infection.



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  		FIGURE 1. Percent of T lymphocytes that are CD8+ in the peripheral blood and liver of healthy and SIVmac-infected rhesus monkeys. The percent CD8+ T cells in PBL and lymphocytes isolated from liver biopsies from five healthy and four chronically SIVmac-infected rhesus monkeys were determined by cell staining and flow cytometric analysis. The median values and ranges of percent CD8+ T cells are indicated.

 


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  		FIGURE 2. Distribution of CD8+ T lymphocytes in livers of healthy and SIVmac-infected rhesus monkeys. The CD8+ lymphocytes are stained red. a, Periportal region in liver of an SIVmac-infected rhesus monkey. b, Sinusoidal area in liver of the same SIVmac-infected rhesus monkey. c, Periportal region in liver of a healthy, uninfected rhesus monkey. d, Sinusoidal area in a liver of the same healthy rhesus monkey. Liver specimens were obtained following sacrifice of the SIVmac-infected rhesus monkey 575–91 (a and b) and by needle biopsy from the healthy rhesus monkey 93–98 (c and d). (Original magnifications, x40).

 
These SIVmac-infected rhesus monkeys shared the MHC class I allele Mamu-A*01, an allele that is associated with a dominant Gag p11C, C-M epitope-specific CTL response to this virus. This allowed use of the tetrameric MHC class I/peptide complex staining technique to detect SIVmac Gag p11C-specific cells in the CD8+ T lymphocyte populations isolated from these infected monkeys. Tetramer binding was evaluated on simultaneously sampled liver-associated and peripheral blood lymphocytes of these SIVmac-infected monkeys, gating on CD8{alpha}ß+CD3+ T cells as previously described (5, 6, 7). Interestingly, consistently higher percentages of tetramer-binding CD8+T cells were detected in the livers than in the peripheral bloods of the animals (Fig. 3Go).



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  		FIGURE 3. Percent tetramer-binding CD8+ T lymphocytes in PBL and liver of four chronically SIVmac-infected, Mamu-A*01+ rhesus monkeys. CD8+ T lymphocytes are cells gated on CD8{alpha}ß+ CD3+ T cells.

 
A relatively high percent of liver-associated CD8+ T lymphocytes are virus-specific effector cells in the setting of a number of virus infections in humans and mice (11, 12, 13). To determine whether the liver-associated CD8+ T lymphocytes from these infected monkeys had SIVmac-specific functional CTL activity, 51Cr release assays were performed using as effector cells freshly isolated or Gag peptide-stimulated lymphocytes from peripheral blood and liver. SIVmac Gag epitope-specific functional CTL activity was detected in liver-associated lymphocytes from the infected animals both in freshly isolated and peptide-stimulated cells (Table IGo). These results suggest that liver-associated tetramer-binding CD8+ T lymphocytes include both activated SIVmac-specific effector and memory CTL populations. Moreover, consistent with the tetramer staining data, cytotoxic activity was more readily demonstrated in the liver-associated lymphocytes than in the PBL. To determine whether the lymphocytes infiltrating the livers would exhibit an increased expression of proinflammatory cytokines, we performed immmunohistochemical analyses of liver sections from healthy and SIVmac-infected animals. Significant expression of TNF-{alpha} or IFN-{gamma} was not detected (data not shown).


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  		Table I. Freshly isolated and peptide-stimulated CD8+ T cells in the livers of SIVmac-infected rhesus monkeys exhibit Gag-specific CTL activity

 
Studies were then initiated to determine why SIVmac-specific CTL were selectively increased in number in the livers of the infected monkeys. One possible explanation for this observation is that CTL traffic to the liver to control particularly high levels of local replication of virus. To assess this possibility, assays were performed on liver sections to detect viral RNA by in situ hybridization techniques. High levels of systemic SIVmac replication were detected in these monkeys. Viral RNA in plasma ranged from 1 x 105 to 5 x 106 copies/ml in three of the four animals. Only one animal had copy numbers below the limit of detection of the assay employed in these studies (1.5 x 103/ml). SIVmac RNA was also readily detected by in situ hybridization in various organs, including ileal Peyers patches, in two of these four monkeys (Fig. 4Go). However, SIVmac replication could not be demonstrated in the liver tissue (Fig. 4Go). Some investigators have suggested that hepatic Kupffer cells, being of the monocyte/macrophage lineage, could be a site of HIV-1/SIV virus replication (14). However, these studies have shown that the frequency of infection of these cells is low, even during the final stages of clinical AIDS (14). Therefore, there was no evidence suggesting that CTL were being attracted to the liver to contain high levels of local viral replication in these SIVmac-infected monkeys.



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  		FIGURE 4. Detection of SIVmac RNA by in situ hybridization in the liver (left) and ileum (right) of the SIVmac-infected rhesus monkey 3KI. The in situ hybridization signals for SIVmac viral RNA are shown by blue staining. Original magnifications, x40 (left) and x20 (right).

 
It has also been suggested that the large numbers of virus-specific CD8+ T lymphocytes that accumulate in the liver in the setting of various systemic viral infections are end-stage cells that are trapped and will eventually be eliminated by apoptosis (13, 15, 16). To determine whether this might explain the large number of SIVmac Gag-specific CD8+ T lymphocytes in the livers of the infected rhesus monkeys, we performed staining of the tetramer+CD8+ T cells with annexin V to detect cells that are committed to die. We found that >90% of the tetramer+CD8+ T cells did not bind annexin V (Fig. 5Go). Therefore, although the percentages of annexin V+ tetramer-binding CD8+ T cells were higher in liver (range, 0.5–9%) than in peripheral blood (range, 0–4%), these results suggested that the predominant populations of liver-associated tetramer-binding CD8+ T lymphocytes in SIVmac-infected monkeys were viable. Therefore, these liver-associated CTL were not simply apoptotic, end-stage cells.



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  		FIGURE 5. Annexin V-negative tetramer-binding CD8+ T lymphocytes in peripheral blood and liver of four chronically SIVmac-infected, Mamu-A*01+ rhesus monkeys.

 
Finally, to investigate why CD8+ CTL were present in increased numbers in the livers of these monkeys, phenotypic analyses of the hepatic tetramer-binding CD8+ T cells were performed. A high expression of activation-associated molecules (CD11a and CD49d) was apparent on these cells (data not shown). These findings are consistent with the previously demonstrated expression of activation-associated molecules on tetramer-binding CD8+ T lymphocytes in a variety of anatomic compartments of SIVmac-infected rhesus monkeys (8). Importantly, however, an increased expression of the CD62L molecule was also apparent on tetramer-binding CD8+ T cells in the liver (Fig. 6Go).



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  		FIGURE 6. Expression of CD62L on tetramer-binding CD8+ T cells in PBL and liver of four chronically SIVmac-infected, Mamu-A*01+ rhesus monkeys. CD8+ T lymphocytes are cells gated on CD8{alpha}ß+ CD3+ T cells.

 
CD62L, L-selectin, is expressed on naive T lymphocytes in peripheral blood. This molecule mediates the adhesion of these cells to high endothelial venules, a process that initiates their migration from blood to the lymphatic tissue and parenchymal tissues (17). CD62L expression is then down-regulated as these trafficking naive T lymphocytes are activated and become effector or memory cells. We have previously shown that tetramer-binding CD8+ T lymphocytes in the peripheral blood and lymph nodes express very little CD62L, consistent with our expectation for Ag-committed memory or effector lymphocytes (8). Therefore, the findings of high levels of CD62L on the tetramer-binding CD8+ T lymphocytes in the liver of these monkeys is surprising.

Although we clearly can demonstrate that livers of SIV-infected rhesus monkeys contain a high percent of SIV Gag-specific CD8+ T cells in the periportal infiltrations, we have no evidence that would immediately explain this finding. However, previous investigations in other animal models have shown similar findings. A selective binding of activated CD8+ T cells has been demonstrated in normal livers of mice (17). Activated T cells accumulate in the periportal fields in livers of rats (18). The expression of CD62L by the liver-associated, SIVmac-specific CTL could explain how these cells might be trapped as they enter the liver from the blood stream. More likely, however, lymphocytes that accumulate in livers probably express a variety of adhesion molecules that contribute to this homing (19). One such molecule, the integrin {alpha}4ß7, which has previously been shown to mediate binding of lymphocytes to gut tissues (20), was only weakly expressed on tetramer-binding lymphocytes in the liver. However, this molecule was expressed to high levels on tetramer-binding lymphocytes in peripheral blood (data not shown). Therefore, it is unlikely that this molecule is involved in the selective enrichment of tetramer-binding lymphocytes in the liver. The limited number of available mAbs that bind to rhesus monkey adhesion molecules makes an in-depth evaluation of this possibility difficult.

It is also possible that virus-specific CTL expand in number in the liver because the environment is conducive to their local proliferation. Finally, the finding that a modestly higher percent of the tetramer-binding CD8+ T lymphocytes in the liver are annexin V binding as compared with PBL indicates that a larger fraction of these cells is apoptotic. This observation suggests the possibility that at least some of the concentration of SIVmac-specific CTL in the liver may be explained by the fact that the organ acts as a repository for dying cells.

Our recent observations showed that the increased accumulation of tetramer-binding lymphocytes in the liver is exceptionally high in comparison with other gut tissues, which showed either a similar or a lower percent of tetramer-binding lymphocytes (J. E. Schmitz, M. J. Kuroda, R. S. Veazey, D. B. Levy, A. Seth, K. G. Mansfield, C. E. Nickerson, M. A. Lifton, P. J. Dailey, M. A. Forman et al., unpublished observation). Whatever the reason for the accumulation of CD8+ CTL in the livers of these monkeys, their presence could certainly contribute to the pathogenesis of their hepatitis. SIVmac does not itself infect hepatocytes nor should it cause hepatic cell dysfunction. However, local release of cytokines by these CD8+ T lymphocytes or interaction of the CD95 (APO-1/Fas) receptor with its ligand (21) might lead to hepatocyte dysfunction. A similar immunopathogenic process may also underlie the mild to moderate hepatitis associated with infections by other viruses such as EBV and CMV.


   Acknowledgments
 
We thank William A. Charini and Carol A. Lord for MHC class I typing of the monkeys used in this study, Lisa Franz for assistance in preparation of this manuscript, Casey Wingfield for SIV RNA analysis, and Gudrun Großschupff and Birgit Raschdorf for performing in situ hybridizations.


   Footnotes
 
1 This work was supported by National Institutes of Health Grants AI-20729 and RR00168, the German Ministry of Education and Research, Bonn, Germany (BMBF, Grant 01 KI-97146), and the Koerber Foundation, Hamburg, Germany. Back

2 Address correspondence to and reprint requests to Dr. Jörn E. Schmitz, Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, RE-113, P.O. Box 15732, Boston, MA 02215. Back

3 J.E.S. and M.J.K. contributed equally to this work. Back

4 Abbreviations used in this paper: SIVmac, SIV/macaque; ECD, PE-Texas red; APC, allophycocyanin. Back

Received for publication October 27, 1999. Accepted for publication March 14, 2000.


   References
Top
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 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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J. Baig, D. B. Levy, P. F. McKay, J. E. Schmitz, S. Santra, R. A. Subbramanian, M. J. Kuroda, M. A. Lifton, D. A. Gorgone, L. S. Wyatt, et al.
Elicitation of Simian Immunodeficiency Virus-Specific Cytotoxic T Lymphocytes in Mucosal Compartments of Rhesus Monkeys by Systemic Vaccination
J. Virol., October 11, 2002; 76(22): 11484 - 11490.
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B. R. Mothe, J. Sidney, J. L. Dzuris, M. E. Liebl, S. Fuenger, D. I. Watkins, and A. Sette
Characterization of the Peptide-Binding Specificity of Mamu-B*17 and Identification of Mamu-B*17-Restricted Epitopes Derived from Simian Immunodeficiency Virus Proteins
J. Immunol., July 1, 2002; 169(1): 210 - 219.
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L. Zhang, P. J. Dailey, A. Gettie, J. Blanchard, and D. D. Ho
The Liver Is a Major Organ for Clearing Simian Immunodeficiency Virus in Rhesus Monkeys
J. Virol., April 16, 2002; 76(10): 5271 - 5273.
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J. E. Schmitz, R. S. Veazey, M. J. Kuroda, D. B. Levy, A. Seth, K. G. Mansfield, C. E. Nickerson, M. A. Lifton, X. Alvarez, A. A. Lackner, et al.
Simian immunodeficiency virus (SIV)-specific cytotoxic T lymphocytes in gastrointestinal tissues of chronically SIV-infected rhesus monkeys
Blood, December 15, 2001; 98(13): 3757 - 3761.
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Z. Hel, J. Nacsa, B. Kelsall, W.-P. Tsai, N. Letvin, R. W. Parks, E. Tryniszewska, L. Picker, M. G. Lewis, Y. Edghill-Smith, et al.
Impairment of Gag-Specific CD8+ T-Cell Function in Mucosal and Systemic Compartments of Simian Immunodeficiency Virus mac251- and Simian-Human Immunodeficiency Virus KU2-Infected Macaques
J. Virol., December 1, 2001; 75(23): 11483 - 11495.
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R. S. Veazey, M.-C. Gauduin, K. G. Mansfield, I. C. Tham, J. D. Altman, J. D. Lifson, A. A. Lackner, and R. P. Johnson
Emergence and Kinetics of Simian Immunodeficiency Virus-Specific CD8+ T Cells in the Intestines of Macaques during Primary Infection
J. Virol., November 1, 2001; 75(21): 10515 - 10519.
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R. A. Kaslow, C. Rivers, J. Tang, T. J. Bender, P. A. Goepfert, R. El Habib, K. Weinhold, M. J. Mulligan, and the NIAID Aids Vaccine Evaluation Group
Polymorphisms in HLA Class I Genes Associated with both Favorable Prognosis of Human Immunodeficiency Virus (HIV) Type 1 Infection and Positive Cytotoxic T-Lymphocyte Responses to ALVAC-HIV Recombinant Canarypox Vaccines
J. Virol., September 15, 2001; 75(18): 8681 - 8689.
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