The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Balla-Jhagjhoorsingh, S. S.
Right arrow Articles by Heeney, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Balla-Jhagjhoorsingh, S. S.
Right arrow Articles by Heeney, J. L.
The Journal of Immunology, 1999, 162: 2308-2314.
Copyright © 1999 by The American Association of Immunologists

Conserved CTL Epitopes Shared Between HIV-Infected Human Long-Term Survivors and Chimpanzees1

Sunita S. Balla-Jhagjhoorsingh, Gerrit Koopman, Petra Mooij, Tom G. M. Haaksma, Vera J. P. Teeuwsen, Ronald E. Bontrop and Jonathan L. Heeney2

Departments of Virology and Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Certain HIV-1 infected humans that do not progress to AIDS have been documented to share particular MHC class I alleles that appear to correlate with long-term survival. HIV-1-infected chimpanzees are relatively resistant to progression to AIDS. Out of a group of 10 chimpanzees with CTL activity and nonprogressive HIV-1 infection, 2 animals with prominent cytolytic CD3+CD8+ T cell responses to HIV-1 Ags were studied in detail. Characterization of these CTL revealed that they contained the granzymes A and B, T cell intracellular Ag-1, and perforin and induced calcium-dependent cytolysis that correlated with the presence of apoptotic nuclei in target cells. These CTL responses were directed against two gagpeptides, which were found to be identical to previously described epitopes recognized in the context of HLA-B27 and HLA-B57 molecules. The latter two restriction elements occur with increased frequency in human long-term survivor cohorts. Phylogenetic comparisons revealed that the chimpanzee restriction elements, Patr-B*02and -B*03, described here do not show any obvious similarity with the HLA-B*27 and -B*57 alleles, suggesting that CTL responses to HIV-1 in distinct primate species may be controlled by different types of HLA-B-like molecules. The CTL responses in these two chimpanzees are directed, however, against highly conserved epitopes mapping across the majority of HIV-1 clades.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Most untreated HIV-1-infected humans develop high virus loads and declining CD4+ T cell numbers within 5–10 yr after infection 1 . In contrast to these progressors, a small group of long-term survivors (LTS)3 do not develop evidence of progression to AIDS despite the fact that they are known to be infected for >17 yr 2, 3, 4, 5 . In addition, so called exposed seronegative individuals appear to be protected against HIV infection despite several years of unprotected sex with HIV-infected partners 6, 7, 8, 9 .

As possible mechanisms of resistance to AIDS, several hypotheses have been put forward. In a few defined cases resistance has been documented to be due to defective HIV-1 viruses 10, 11 . Similarly, in a small percentage of LTS, mutations in chemokine coreceptors have been identified as genetic factors of host resistance 12, 13, 14, 15, 16 . In terms of host immune responses, the elimination of infected cells by cytotoxic immune responses is of importance to establish control of the intracellular stages of viral infections 17, 18, 19 . It has been documented that certain CTL responses may be protective in the case of HIV-1-infected individuals by reducing viral loads 20, 21, 22, 23 . The beneficial role of CD8+ CTL in LTS is indirectly supported by the finding that certain MHC class I alleles, especially HLA-B*27 and -B*57, are found with increased frequencies in various LTS cohorts 24, 25, 26 . The corresponding HIV-1 epitopes that are presented by these particular HLA molecules and recognized by CTL have been mapped 3, 5, 24, 27, 28, 29 .

AIDS can be induced in various macaque species after infection with HIV-2-related SIV, naturally carried by Sooty mangabeys 30, 31 . Similar to humans, CTL responses directed against lentivirus-specific Ags have been reported in macaques 32, 33, 34, 35 . A particular MHC class I allele has been correlated with long-term survival in SIV-infected rhesus macaques 36, 37 . Furthermore a correlation of certain MHC alleles and particular opportunistic infections after the onset of AIDS in macaques has been documented 38 . In addition to humans, chimpanzees are one of the few species susceptible to persistent infection with HIV-1. Worldwide, >150 chimpanzees have been infected with divergent HIV-1 isolates including infection by uncultured clinical samples directly from AIDS patients 39 . To date there has been only one reported case of a chimpanzee that developed AIDS after infection with several HIV-1 strains 40 . In chimpanzees the CCR5 HIV-1 coreceptor is intact and infected animals do not have the mutations associated with resistance to AIDS in humans 41 . Additionally, most chimpanzees have been experimentally infected with defined viral inoculums, and deletions in viral genes such as nef have in most cases been ruled out 42 . The majority of HIV-1-infected chimpanzees do not show signs of disease progression and in this regard resemble the status in LTS.

Cytotoxic T cell activity has been occasionally observed in chimpanzees after HIV-1 infection or immunizations 43, 44, 45 . However, to date detailed characterization of HIV-1-specific CTL responses in chimpanzees is lacking. In this study we set out to determine the phenotype and specificity of the CTL responses in two HIV-1-infected chimpanzees in our cohort.


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

From a cohort of 10 chronically HIV-1-infected and 3 HIV-1-negative chimpanzees (Pan troglodytes verus), 2 HIV-1-infected chimpanzees (Ch-La and Ch-Ze) were studied in detail. All of the HIV-1-infected chimpanzees in this cohort have been extensively studied in a long-term follow-up for evidence of progression to AIDS. None of these infected animals showed signs of lymphadenopathy, a decline in CD4+ T cell numbers, elevated virus load, increased activation or apoptosis markers, anemia, and/or thrombocytopenia 39, 46, 47 . The two animals described in detail in this report were part of a group of six chimpanzees who were all infected i.v. on the same day with the same dose and strain of HIV-1 as part of a larger vaccine efficacy study 48 . Ch-La had served as a naive control and Ch-Ze had been immunized with rgp120 but subsequently became infected 49 . In that study the presence of CTL was not determined. Ch-La and Ch-Ze were tested 5 yr later and were the first animals found in time in our cohort with positive cytolytic responses and thus chosen for further study. The eight remaining HIV-1-infected animals as well as the three HIV-1 negative chimpanzees served as controls. These animals were MHC typed and lacked the Patr-B*02 or -B*03 molecules.

Virus-specific CTL activities

Effector cells were generated from Lymphocyte Separation Medium (Organon Teknica Corporation, Durham, NC) density gradient isolated PBMC. Ag-specific cytotoxic effector cells from PBMC were activated by coculture with autologous PHA (5 µg/ml, Sigma, St. Louis, MO) stimulated, IL-2 (ADP 901, Medical Research Council, Hertfordshire, U.K.) expanded and peptide pulsed T cell blasts as stimulator cells. To prepare stimulator cells the T cell blasts were incubated with overlapping peptide pools (2.5 µg/ml per peptide) spanning the gag protein (22 peptides) for 3 h at 37°C and 5% CO2. Overlapping peptides spanning the gag of HIV-1SF2 were obtained from MRC AIDS Reagent project (ADP 788, MRC) and consisted of 22 20-mers overlapping by 10 amino acids spanning gag amino acid residues 135–364. Peptides 1 and 2 covered the residues 135–164 and peptides 13 and 14 covered the residues 252–284. For more detailed epitope mapping, a panel of custom 9-mer peptides overlapping the specific epitopes were used (Quality Control Biochemicals, Hopkinton, MA). After incubation, stimulator cells were irradiated with 30 Gray. Stimulator cells and 15 x 106 freshly isolated PBMC were cocultured at a ratio of 0.5–1:1 in 3 ml RPMI 1640 (Life Technologies, Paisley, Scotland) supplemented with L-glutamine (2 mM, Life Technologies), penicillin (100 U/ml, Biochemie, Vienna, Austria), streptomycin (0, 2 mg/ml, Biochemie), and 10% FCS (Life Technologies). After 48 h these cultures were supplemented with IL-2 at a concentration of 20 U/ml. Cultures were regularly fed with culture medium containing IL-2 during the coculture period. After 8 days, cocultures were harvested, enriched for vital cells by lymphocyte separation medium density gradient centrifugation, and restimulated with autologous stimulator cells. After 48 h restimulated cultures were supplemented with IL-2. Cytotoxicity was tested at day 16. Before assaying cytotoxic effector cells, dead cells were removed by lymphocyte separation medium density gradient centrifugation. To enrich cell cultures for CD8+ cells, CD4+ cells were depleted after the first stimulation by incubation with magnetic beads coupled to anti-CD4 Abs (Dynabeads M450, Dynal, Oslo, Norway) for 60 min on ice. Rosetted cells were depleted on a magnetic separator (MPC-6, Dynal). The phenotype of cytolytic T cell lines was assessed by triple color flow cytometry analysis (FACSort, Becton Dickinson, Mountain View, CA), using FITC-labeled anti-CD8 (Becton Dickinson); phycoerythin-labeled anti-CD4 and phycoerythin Cy5-labeled anti-CD3 (Becton Dickinson). The CD8+ cells were stimulated again before testing in the chromium release assay. Specific cytolytic T cell lines were maintained by periodic restimulation with irradiated autologous stimulator cells and PHA-stimulated human PBMC.

Cytotoxicity assay

Target cells were autologous EBV B-lymphoblastoid cell line labeled with 150 µCi Na2CrO4 (Amersham International, Buckinghamshire, U.K.) for 1 h, then pulsed with pools of peptides at a concentration of 25 µg/ml for 1 h at 37°C, followed by a 16 h incubation period with the same peptides at a concentration of 2.5 µg/ml. Unpulsed B-lymphoblastoid cell lines were used as controls. Subsequently, target cells were washed and plated at 5 x 103 cells per well in 96-well U-shaped plates (Costar, Cambridge, MA) together with effector cells at three E:T ratios. After 5 h incubation at 37°C supernatants were harvested and {gamma} counted in a {gamma} counter (Cobra 5, Packard). Percentages of specific 51Cr release were calculated as 100 x (experimental release - spontaneous release)/(maximum release - spontaneous release). All experimental values were determined in duplicate or triplicate and maximum and spontaneous releases were performed in quadruplicate. Responses of 10% or more above specific lysis of control unpulsed targets, were scored as positive.

Immunocytochemistry

The granzymes A and B (GrA and GrB), the RNA binding protein T cell intracellular Ag-1 (TIA-1), and perforin expression on CD8+ and CD4+ T cells was studied using a double-staining technique. Cytospin preparations were fixed in 4% buffered formalin for 9 min, washed in PBS, and preincubated with normal goat serum (10% in PBS). Subsequently, the slides were incubated with anti-GrA (GA11) or -GrB (GB11), both kindly provided by Dr. E. Hack (CLB, Amsterdam, The Netherlands), anti-TIA-1 (Coulter, Hialeah, FL) or antiperforin mAb (T Cell Diagnostics, Woburn, MA), secondary biotinylated Ab (goat anti-mouse, Dako, Glostrup, Denmark), a streptavidine-biotin-alkaline phosphatase complex (Dako), normal mouse serum (5% in PBS, Jackson ImmunoResearch Laboratories, West Grove, PA), FITC-labeled CD8 (DK25) or CD4 (OKT4), peroxidase-labeled rabbit anti-FITC (Dako), and peroxidase-labeled swine anti-rabbit (Dako). All incubation steps were performed at room temperature for 30 min. Endogenous peroxidases were blocked with 0.1% NaN3 plus 0.3% H2O2 in PBS after the incubation with the first Ab AP activity was detected with naphthol-AS-MX phosphate (Sigma), and Fast Blue BB (Sigma) in 0.1 M Tris-HCl, pH 8.5 (20 min in the dark), yielding a blue color. HRP activity was detected using H2O2 (0.03%) and 3-amino-9-ethylcarbazole (Sigma) yielding a red color.

For detection of apoptosis during CTL-mediated killing, cytospin preparations of CTL incubated with peptide pulsed autologous B cell target cells cultured for 5 h were prepared and stained subsequently with anti-CD20 mAb (L26, Dako), FITC-labeled goat anti-mouse Ab (Dako) and ethidium bromide (100 µg/ml in PBS; Sigma).

MHC class I typing, restriction, and epitope mapping

Chimpanzees were initially typed for their Patr class I Ags by means of serological methods 50 . The corresponding Patr class I nucleotide sequences were determined based on the method described by Ennis et al. 51 . The correlation of serotypes and nucleotide sequences was established based on performing extensive segregation studies 52 . The Patr class I alleles (Patr-B*02 and -B*03) that are relevant for this study have been published previously 53, 54 . These restriction elements were identified by testing cytotoxic reactivity of CTL of Ch-La and Ch-Ze on a panel of allogeneic Patr-A, -B, and -C locus-typed cells.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Detection of gag-specific CTL in HIV-1-infected chimpanzees

Of the 10 chimpanzees in our HIV-1-infected cohort, 6 chimpanzees were challenged with HIV-1 in 1990 49 . In that study the presence of CTL were not determined. PBMC from these animals were tested 5 years later for the presence of gag and env-specific CTL responses. Persistent Ag-specific cytolytic activity was first detected in two animals against different gag epitopes suggesting the existence of at least two CTL epitopes (Fig. 1Go). The strong gag-specific CTL responses in these two infected animals (Ch-La and Ch-Ze) were selected for further study and characterized in detail. Env-specific CTL were not detected. As controls, cells from chimpanzees lacking the Patr-B*02 and -B*03 molecules were also tested for the ability to recognize the epitopes described in this study in a CTL assay. Cells from three HIV-1 negative control chimpanzees as well as eight HIV-1-infected chimpanzees were stimulated according to the same stimulation protocol with pooled peptides. Taking these 11 animals into account, we have never detected false positive responses in these chimpanzees to the specific epitopes. Cytolytic responses were observed to distinct pooled peptides, but these have not yet been characterized to the epitope level (data not shown).



View larger version (28K):
[in this window]
[in a new window]
  		FIGURE 1. CTL epitope mapping of (A) Ch-La and (B) Ch-Ze on 20-mer peptides with a 10-mer overlap at an E:T ratio of 5:1. Custom made 9-mer peptides were used for a more detailed epitope mapping. The first bar represents the specific lysis for a pool of all 22 gag peptides; the next six bars represent the specific lysis for smaller pools of the gag peptides, whereas single 20-mer peptides of the reacting pool are depicted in the next three bars for Ch-La (A) or the next four bars for Ch-Ze (B). The actual peptide reactivity is seen in the last two bars.

 
CTL epitope mapping

CTL of Ch-La were found to recognize a pool of peptides 1–3 of HIV-1 gag (Fig. 1GoA). After testing individual peptides it was found that only peptides 1 and 2 were recognized. This suggested that the actual epitope that was recognized was located in the overlapping region of these two peptides (VHQAISPRTL). To test this assumption, two novel peptides were synthesized and target cells were pulsed with these 9-mer peptides. Target cells loaded with VHQAISPRT were not affected whereas HQAISPRTL (HIV-1 gag amino acid residues 146–154) loaded target cells were lysed by the effector cells.

CTL of Ch-Ze were found to react with a pool of peptides 11–14 of the same HIV-1 gag preparation mentioned earlier (Fig. 1GoB). More in detail, only peptides 13 and 14 were recognized mapping to the following 10-mer (KRWIILGLNK). To define the fine specificity of the epitope, target cells were pulsed with the relevant 9-mer peptides. These subsequent studies demonstrated that target cells with KRWIILGLN (HIV-1 gag amino acid residues 265–273) were lysed whereas targets loaded with the RWIILGLNK oligopeptide were not lysed by the effector cells.

Phenotypic characterization of CTL and their killing mechanism

The phenotype of the effector cells was characterized by FACS analysis to determine the cell surface markers. The bulk culture contained CD3+CD4+ T cells, CD3-CD8+ as an indication of NK cells and CD3+CD8+ cells as an indication of CTL. After enrichment for CD8+ cells using magnetic beads, the CTL culture from Ch-Ze was found to consist of 95% CD3+CD8+ T cells and 3% CD4+ T cells (Fig. 2Go). These cells were then stimulated again before testing. The cells maintained the same phenotype during the culture period. Similar data were found for the culture of Ch-La and these results were consistent over time.



View larger version (33K):
[in this window]
[in a new window]
  		FIGURE 2. FACS scattergrams of the cell culture of Ch-Ze after the first stimulation after CD8 cell purification using magnetic beads. Cultured cells were stained with phycoerythin-labeled anti-CD4, FITC-labeled anti-CD8 and RPE-Cy5-labeled anti-CD3 mAbs. Percentage of the different cell populations in culture are depicted in the quadrants.

 
To establish that these chimpanzee CD3+CD8+ T cells used the same cytolytic machinery as human CTL, the effector cells were incubated with peptide-labeled target cells according to standardized procedures. The autologous B cell targets were found to have fragmented apoptotic nuclei as was determined by staining the B cells with FITC-labeled anti-CD20 in combination with propidium iodide for detection of B and T cell nuclei. Further analysis revealed that the CD8+ T cells were positive for TIA-1 (Fig. 3GoA). This was in contrast to the CD4+ T cells present in the same cultures that were, as expected, negative for these markers (Fig. 3GoB). The same was seen for the other contents of the cytotoxic granules GrA, GrB, and perforin. Cytolytic responses were also tested for calcium dependency in medium containing 1.5 M EDTA, which was found to completely inhibit these specific chimpanzee CTL responses. Thus, the CTL activity observed in these chimpanzees is caused by CD3+CD8+ T cells carrying GrA, GrB, TIA-1, and perforin that use a calcium-dependent pathway resulting in apoptosis of target cells and therefore resembles human CTL 55 .



View larger version (138K):
[in this window]
[in a new window]
  		FIGURE 3. Analysis of Ch-La PBMC in culture after two rounds of stimulation. The cells were double stained for (A) CD8 and TIA-1 and (B) CD4 and TIA-1. Original magnification was x60.

 
Characterization of MHC restriction elements

The involvement of MHC class I restriction elements was determined for both chimpanzees using a mAb W6/32 (anti-MHC class I molecules). By FACS analysis the binding of the Ab W6/32 on the surface of the target cells was found to be optimal in the 1:100 dilution. As can be seen in the dose-response curve, a 1:100 dilution of the supernatant stock of Ab W6/32 resulted in complete inhibition of the Ag-specific functional cytolytic response (Fig. 4Go).



View larger version (33K):
[in this window]
[in a new window]
  		FIGURE 4. Inhibition of the cytolytic response of CTL from Ch-Ze at an E:T ratio of 2.5:1. Several dilutions of the anti-MHC class I Ab W6/32 were added to the peptide-pulsed autologous target cells for 30 min at 37°C. Then the target cells were added to the effector cells of Ch-Ze in a 51Cr release assay.

 
To elucidate which MHC class I molecules were functioning as restriction elements, an allogeneic B cell panel typed for the different Patr molecules was used as target cells. This panel of chimpanzee cells was selected based on the presence of known MHC class I and II nucleotide sequences. The autologous and (partly) matched allogeneic target cells were pulsed with the relevant gag peptides and subsequently tested with the effector cells of Ch-La and Ch-Ze (Table IGo). The target cells that are lysed are expected to share the same Patr allele that functions as restriction element. As expected, CTL from Ch-La effectively lysed autologous target cells and also cells from Ch-Ro, Ch-Wo, and Ch-Ka (Table IGo). All these cells share the Patr-B*02 and -C*05 molecules. To distinguish which of these two restriction elements are used, Ch-Su and Ch-Pe were selected that are positive for the Patr-C*05 molecules and lack Patr-B*02 Ags. These target cells were not lysed, indicating that the selected CTL from Ch-La recognize the gag epitope HQAISPRTL in the context of Patr-B*02 molecules. The same procedure was used to elucidate the restriction element of the CTL from Ch-Ze. The CTL from Ch-Ze recognized its autologous target cells as well as the allogeneic target cells from Ch-Fr, Ch-Qu, Ch-Na, and Ch-Ph (Table IGo). Apart from Ch-Ph, all these animals share Patr-A*06, -B*03, and -C*03 molecules. Ch-Ph, however, only shares the Patr-B*03 and -C*03 molecules with the previously mentioned cells. Cells of Ch-Pea were not lysed confirming that the Patr-A*06 molecules were not able to present the peptide. To further differentiate between the Patr-B*03 and -C*03 molecules, cells of Ch-Yv were selected that are positive for the Patr-C*03 molecules. These target cells were not lysed. This indicates that CTL from Ch-Ze, that are described in this study, recognize the HIV-1 gag epitope KRWIILGLN in the context of Patr-B*03 molecules.


View this table:
[in this window]
[in a new window]
  		Table I. MHC class I restriction for the specific CTL of Ch-La and Ch-Ze1

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The cytolytic activities in the two chimpanzees, Ch-La and Ch-Ze, were found to be directed against two distinct 9-mer sequences in HIV-1 gag. CTL of Ch-La and Ch-Ze recognize the epitope HQAISPRTL and KRWIILGLN, respectively. At least two research groups reported independently, that in humans the CTL epitope HQAISPRTL is also recognized in the context of HLA-B*5701 molecules 26, 29 . Likewise the 9-mer KRWIILGLN is recognized by human CTL that are restricted by HLA-B*2705 gene products 56 . Both the HLA-B*57 and -B*27 specificities are observed more frequently in LTS than in rapid progressors to AIDS 3, 24, 26 . Based on these reports evidence suggests that these HLA specificities may be involved in protective immune responses against AIDS.

It is known that humans and chimpanzees share as much as 98% genetic similarity as determined at the DNA level. For that reason, it is possible that humans and chimpanzees share highly identical MHC molecules that have the capacity to bind the same peptide. That this possibility may reflect reality has been demonstrated for HLA-DR3-like molecules in humans and chimpanzees that were reported to bind the same peptide from the heat shock protein 65 of Mycobacterium tuberculosis 57 . With regard to the A locus in humans and chimpanzees a similar observation was made for the recognition of certain Hepatitis C virus epitopes 58 . The alternative possibility is that the same peptide binds to distinct types of MHC molecules in disparate species. To discriminate between these two possibilities, the chimpanzee restriction elements and their corresponding nucleotide sequences were determined to allow comparisons. CTL of Ch-La were found to be restricted by Patr-B*02 molecules that bind the HIV-1 gag epitope HQAISPRTL whereas CTL of Ch-Ze were found to recognize Patr-B*03 molecules presenting the HIV-1 gag epitope KRWIILGLN (Table IGo). As can be seen, comparison of the {alpha}1 and {alpha}2 sequences of the relevant human and chimpanzee MHC molecules show that the Patr-B*02 and HLA-B*5701 molecules that both bind the HQAISPRTL are rather distinct in the peptide binding pocket (Fig. 5Go). The same observation was made for the other set of molecules, Patr-B*03 and HLA-B*2705, which are involved in binding of KRWIILGLN peptide. As expected, this is consistent with phylogenetic analyses of the relevant nucleotide sequences 54 . Thus, the same HIV-1 gag peptides are bound by totally different types of HLA-B and Patr-B molecules, which group into distinct lineages. Due to promiscuity the same MHC molecule may bind a large set of peptides. As a consequence the same epitope may be bound by different MHC molecules. This has been described for a HCV CTL epitope 59 and for two HIV-1 nef CTL epitopes 60, 61, 62 . Human individuals, especially LTS, and chimpanzees that are relatively resistant to AIDS, recognize the same epitopes for mounting CTL responses. One may wonder whether there is a biological relevance to this phenomenon. Scanning of HIV-1 clades shows that particular regions are highly conserved. This appears to be the case for the two epitopes described here that map to such highly conserved HIV-1 gag regions (Fig. 6Go). In this light, the hypothesis would be that protective CTL responses are preferentially mounted against highly conserved epitopes. In other words, some individuals in the human population may have the right type of HLA molecules that can bind such peptides. In the case that a mutation in such an epitope occurs, progression to disease may follow. This is illustrated by a study of Goulder et al. 63 demonstrating that a mutation in the KRWIIMGLNK epitope, which took place 12 years after infection, correlated with subsequent progression to AIDS.



View larger version (25K):
[in this window]
[in a new window]
  		FIGURE 5. Amino acid sequences of the {alpha}1 and {alpha}2 region of the restricting MHC class I alleles in Ch-La (Patr-B*02) and Ch-Ze (Patr-B*03) and the restricting MHC class I alleles in humans (HLA-B*5701 and -B*2705) compared with the consensus sequence. The peptide binding pocket presenting the Ag is coded by the second half of the {alpha}1 region and the first half of the {alpha}2 region.

 


View larger version (14K):
[in this window]
[in a new window]
  		FIGURE 6. Amino acid sequences of the CTL epitope regions identified in this study, mapping across the HIV-1 clades. The amino acids present in all known HIV-1 strains are shown in uppercase letters and the amino acids present in the majority of known HIV-1 strains are shown in lowercase letters.

 
It is too early to conclude on the basis of only these two chimpanzees that CTL-mediated protection may solely explain why chimpanzees are relatively resistant to AIDS. It is likely that multiple immunological mechanisms are responsible for this resistance. Further studies are underway to investigate whether other conserved HIV-1 epitopes are recognized by chimpanzee CTL. Studies of the immune responses mounted by chimpanzees to HIV-1 infection may further elucidate the role of CTL in protection from progression to AIDS and provide insight for the development of effective HIV-1 vaccines or immunotherapeutic strategies.


   Acknowledgments
 
We thank Drs. Ivonne G. Nieuwenhuis for her technical assistance and Jeannette Schouw for her secretarial assistance. We also thank Dr. Michel R. Klein and Dr. Gerald Voss for their critical appraisal of the manuscript.


   Footnotes
 
1 This work was supported by the European Community Grant BMH4-CT97-2067. Reagents for this research were supplied by the European Union Program EVA (European Vaccine against AIDS). Back

2 Address correspondence and reprint requests to Dr. J. L. Heeney, Biomedical Primate Research Centre, Department of Virology, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands. E-mail address: Back

3 Abbreviations used in this paper: LTS, long-term survivor; GrA, granzyme A; GrB, granzyme B; TIA-1, T cell intracellular Ag 1. Back

Received for publication June 3, 1998. Accepted for publication November 10, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Mellors, J. W., Jr C. Rinaldo, P. Gupta, R. M. White, J. A. Todd, L. A. Kingsley. 1996. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272:1167.[Abstract]
  2. Pantaleo, G., S. Menzo, M. Vaccarezza, C. Graziosi, O. J. Cohen, J. F. Demarest, D. Montefiori, J. M. Orenstein, C. Fox, L. K. Schrager, et al 1995. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N. Engl. J. Med. 332:209.[Abstract/Free Full Text]
  3. Klein, M. R., F. Miedema. 1995. Long-term survivors of HIV-1 infection. Trends Microbiol. 3:386.[Medline]
  4. Rowland-Jones, S., R. Tan, A. McMichael. 1997. Role of cellular immunity in protection against HIV infection. Adv. Immunol. 65:277.[Medline]
  5. Harrer, T., E. Harrer, S. A. Kalams, P. Barbosa, A. Trocha, R. P. Johnson, T. Elbeik, M. B. Feinberg, S. P. Buchbinder, B. D. Walker. 1996. Cytotoxic T lymphocytes in asymptomatic long-term nonprogressing HIV-1 infection: breadth and specificity of the response and relation to in vivo viral quasispecies in a person with prolonged infection and low viral load. J. Immunol. 156:2616.[Abstract]
  6. Clerici, M., J. V. Giorgi, C. C. Chou, V. K. Gudeman, J. A. Zack, P. Gupta, H. N. Ho, P. G. Nishanian, J. A. Berzofsky, G. M. Shearer. 1992. Cell-mediated immune response to human immunodeficiency virus (HIV) type 1 in seronegative homosexual men with recent sexual exposure to HIV-1. J. Infect. Dis. 165:1012.[Medline]
  7. Rowland-Jones, S., J. Sutton, K. Ariyoshi, T. Dong, F. Gotch, S. McAdam, D. Whitby, S. Sabally, A. Gallimore, T. Corrah, et al 1995. HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women. Nat. Med. 1:59.[Medline]
  8. Furci, L., G. Scarlatti, S. Burastero, G. Tambussi, C. Colognesi, C. Quillent, R. Longhi, P. Loverro, B. Borgonovo, D. Gaffi, et al 1997. Antigen-driven C-C chemokine-mediated HIV-1 suppression by CD4+ T cells from exposed uninfected individuals expressing the wild-type CCR- 5 allele. J. Exp. Med. 186:455.[Abstract/Free Full Text]
  9. Mazzoli, S., D. Trabattoni, S. Lo Caputo, S. Piconi, C. Ble, F. Meacci, S. Ruzzante, A. Salvi, F. Semplici, R. Longhi, et al 1997. HIV-specific mucosal and cellular immunity in HIV-seronegative partners of HIV-seropositive individuals. Nat. Med. 3:1250.[Medline]
  10. Deacon, N. J., A. Tsykin, A. Solomon, K. Smith, M. Ludford-Menting, D. J. Hooker, D. A. McPhee, A. L. Greenway, A. Ellett, C. Chatfield, et al 1995. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 270:988.[Abstract/Free Full Text]
  11. Kirchhoff, F., T. C. Greenough, D. B. Brettler, J. L. Sullivan, R. C. Desrosiers. 1995. Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N. Engl. J. Med. 332:228.[Free Full Text]
  12. Paxton, W. A., S. R. Martin, D. Tse, T. R. O’Brien, J. Skurnick, N. L. VanDevanter, N. Padian, J. F. Braun, D. P. Kotler, S. M. Wolinsky, R. A. Koup. 1996. Relative resistance to HIV-1 infection of CD4 lymphocytes from persons who remain uninfected despite multiple high-risk sexual exposure. Nat. Med. 2:412.[Medline]
  13. Dean, M., M. Carrington, C. Winkler, G. A. Huttley, M. W. Smith, R. Allikmets, J. J. Goedert, S. P. Buchbinder, E. Vittinghoff, E. Gomperts, et al 1996. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 273:1856.[Abstract/Free Full Text]
  14. Huang, Y., W. A. Paxton, S. M. Wolinsky, A. U. Neumann, L. Zhang, T. He, S. Kang, D. Ceradini, Z. Jin, K. Yazdanbakhsh, et al 1996. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat. Med. 2:1240.[Medline]
  15. Samson, M., G. LaRosa, F. Libert, P. Paindavoine, M. Detheux, G. Vassart, M. Parmentier. 1997. The second extracellular loop of CCR5 is the major determinant of ligand specificity. J. Biol. Chem. 272:24934.[Abstract/Free Full Text]
  16. Smith, M. W., M. Dean, M. Carrington, C. Winkler, G. A. Huttley, D. A. Lomb, J. J. Goedert, T. R. O’Brien, L. P. Jacobson, R. Kaslow, et al 1997. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Science 277:959.[Abstract/Free Full Text]
  17. McMichael, A. J., F. M. Gotch, G. R. Noble, P. A. Beare. 1983. Cytotoxic T-cell immunity to influenza. N. Engl. J. Med. 309:13.[Abstract]
  18. Hou, S., M. Fishman, K. G. Murti, P. C. Doherty. 1993. Divergence between cytotoxic effector function and tumor necrosis factor {alpha} production for inflammatory CD4+ T cells from mice with Sendai virus pneumonia. J. Virol. 67:6299.[Abstract/Free Full Text]
  19. Nahill, S. R., R. M. Welsh. 1993. High frequency of cross-reactive cytotoxic T lymphocytes elicited during the virus-induced polyclonal cytotoxic T lymphocyte response. J. Exp. Med. 177:317.[Abstract/Free Full Text]
  20. Ogg, G. S., X. Jin, S. Bonhoeffer, P. R. Dunbar, M. A. Nowak, S. Monard, J. P. Segal, Y. Cao, S. L. Rowland-Jones, V. Cerundolo, et al 1998. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279:2103.[Abstract/Free Full Text]
  21. Pantaleo, G., J. F. Demarest, H. Soudeyns, C. Graziosi, F. Denis, J. W. Adelsberger, P. Borrow, M. S. Saag, G. M. Shaw, R. P. Sekaly, et al 1994. Major expansion of CD8+ T cells with a predominant V ß usage during the primary immune response to HIV. Nature 370:463.[Medline]
  22. Borrow, P., H. Lewicki, X. Wei, M. S. Horwitz, N. Peffer, H. Meyers, J. A. Nelson, J. E. Gairin, B. H. Hahn, M. B. Oldstone, G. M. Shaw. 1997. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat. Med. 3:205.[Medline]
  23. Musey, L., J. Hughes, T. Schacker, T. Shea, L. Corey, M. J. McElrath. 1997. Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection. N. Engl. J. Med. 337:1267.[Abstract/Free Full Text]
  24. 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, et al 1996. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat. Med. 2:405.[Medline]
  25. Klein, M. R., C. A. van Baalen, A. M. Holwerda, S. R. Kerkhof Garde, R. J. Bende, I. P. Keet, J. K. Eeftinck-Schattenkerk, A. D. Osterhaus, H. Schuitemaker, F. Miedema. 1995. Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics. J. Exp. Med. 181:1365.[Abstract/Free Full Text]
  26. Goulder, P. J., M. Bunce, P. Krausa, K. McIntyre, S. Crowley, B. Morgan, A. Edwards, P. Giangrande, R. E. Phillips, A. J. McMichael. 1996. Novel, cross-restricted, conserved, and immunodominant cytotoxic T lymphocyte epitopes in slow progressors in HIV type 1 infection. AIDS Res. Hum. Retroviruses 12:1691.[Medline]
  27. Carmichael, A., X. Jin, P. Sissons, L. Borysiewicz. 1993. Quantitative analysis of the human immunodeficiency virus type 1 (HIV- 1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein-Barr virus in late disease. J. Exp. Med. 177:249.[Abstract/Free Full Text]
  28. Rinaldo, C., X. L. Huang, Z. F. Fan, M. Ding, L. Beltz, A. Logar, D. Panicali, G. Mazzara, J. Liebmann, M. Cottrill, et al 1995. High levels of anti-human immunodeficiency virus type 1 (HIV-1) memory cytotoxic T-lymphocyte activity and low viral load are associated with lack of disease in HIV-1-infected long-term nonprogressors. J. Virol. 69:5838.[Abstract]
  29. Johnson, R. P., A. Trocha, L. Yang, G. P. Mazzara, D. L. Panicali, T. M. Buchanan, B. D. Walker. 1991. HIV-1 gag-specific cytotoxic T lymphocytes recognize multiple highly conserved epitopes: fine specificity of the gag-specific response defined by using unstimulated peripheral blood mononuclear cells and cloned effector cells. J. Immunol. 147:1512.[Abstract]
  30. Fultz, P. N., H. M. McClure, D. C. Anderson, R. B. Swenson, R. Anand, A. Srinivasan. 1986. Isolation of a T-lymphotropic retrovirus from naturally infected sooty mangabey monkeys (Cercocebus atys). Proc. Natl. Acad. Sci. USA 83:5286.[Abstract/Free Full Text]
  31. Murphey-Corb, M., L. N. Martin, S. R. Rangan, G. B. Baskin, B. J. Gormus, R. H. Wolf, W. A. Andes, M. West, R. C. Montelaro. 1986. Isolation of an HTLV-III-related retrovirus from macaques with simian AIDS and its possible origin in asymptomatic mangabeys. Nature 321:435.[Medline]
  32. Miller, M. D., C. I. Lord, V. Stallard, G. P. Mazzara, N. L. Letvin. 1990. The gag-specific cytotoxic T lymphocytes in rhesus monkeys infected with the simian immunodeficiency virus of macaques. J. Immunol. 144:122.[Abstract]
  33. Tsubota, H., C. I. Lord, D. I. Watkins, C. Morimoto, N. L. Letvin. 1989. A cytotoxic T lymphocyte inhibits acquired immunodeficiency syndrome virus replication in peripheral blood lymphocytes. J. Exp. Med. 169:1421.[Abstract/Free Full Text]
  34. Voss, G., N. L. Letvin. 1996. Definition of human immunodeficiency virus type 1 gp120 and gp41 cytotoxic T-lymphocyte epitopes and their restricting major histocompatibility complex class I alleles in simian-human immunodeficiency virus-infected rhesus monkeys. J. Virol. 70:7335.[Abstract/Free Full Text]
  35. Gallimore, A., M. Cranage, N. Cook, N. Almond, J. Bootman, E. Rud, P. Silvera, M. Dennis, T. Corcoran, J. Stott, et al 1995. Early suppression of SIV replication by CD8+ nef-specific cytotoxic T cells in vaccinated macaques. Nat. Med. 1:1167.[Medline]
  36. Heeney, J. L., C. van Els, P. de Vries, P. ten Haaft, N. Otting, W. Koornstra, J. Boes, R. Dubbes, H. Niphuis, M. Dings, et al 1994. Major histocompatibility complex class I-associated vaccine protection from simian immunodeficiency virus-infected peripheral blood cells. J. Exp. Med. 180:769.[Abstract/Free Full Text]
  37. Bontrop, R. E., N. Otting, H. Niphuis, R. Noort, V. Teeuwsen, J. L. Heeney. 1996. The role of major histocompatibility complex polymorphisms on SIV infection in rhesus macaques. Immunol. Lett. 51:35.[Medline]
  38. Baskin, G. B., R. E. Bontrop, H. Niphuis, R. Noort, J. Rice, J. L. Heeney. 1997. Correlation of major histocompatibility complex with opportunistic infections in simian immunodeficiency virus-infected rhesus monkeys. Lab. Invest. 77:305.[Medline]
  39. Heeney, J. L.. 1995. AIDS: a disease of impaired Th-cell renewal?. Immunol. Today 16:515.[Medline]
  40. Novembre, F. J., M. Saucier, D. C. Anderson, S. A. Klumpp, S. P. O’Neil, C. n. Brown, C. E. Hart, P. C. Guenthner, R. B. Swenson, H. M. McClure. 1997. Development of AIDS in a chimpanzee infected with human immunodeficiency virus type 1. J. Virol. 71:4086.[Abstract]
  41. ten Haaft, P. J., K. K. Murthy, B. E. Verstrepen, J. W. Eichberg, J. L. Heeney. 1997. Intact CCR-5 coreceptors in HIV-1-infected chimpanzees. AIDS 11:1291.[Medline]
  42. Heeney, J., W. Bogers, L. Buijs, R. Dubbes, P. ten Haaft, W. Koornstra, H. Niphuis, P. Nara, V. Teeuwsen. 1996. Immune strategies utilized by lentivirus infected chimpanzees to resist progression to AIDS. Immunol. Lett. 51:45.[Medline]
  43. Zarling, J. M., J. W. Eichberg, P. A. Moran, J. McClure, P. Sridhar, S. L. Hu. 1987. Proliferative and cytotoxic T cells to AIDS virus glycoproteins in chimpanzees immunized with a recombinant vaccinia virus expressing AIDS virus envelope glycoproteins. J. Immunol. 139:988.[Abstract]
  44. Boyer, J. D., K. E. Ugen, B. Wang, M. Agadjanyan, L. Gilbert, M. L. Bagarazzi, M. Chattergoon, P. Frost, A. Javadian, W. V. Williams, et al 1997. Protection of chimpanzees from high-dose heterologous HIV-1 challenge by DNA vaccination. Nat. Med. 3:526.[Medline]
  45. Lubeck, M. D., R. Natuk, M. Myagkikh, N. Kalyan, K. Aldrich, F. Sinangil, S. Alipanah, S. C. Murthy, P. K. Chanda, Jr S. Nigida, et al 1997. Long-term protection of chimpanzees against high-dose HIV-1 challenge induced by immunization. Nat. Med. 3:651.[Medline]
  46. Heeney, J., R. Jonker, W. Koornstra, R. Dubbes, H. Niphuis, A. M. Di Rienzo, M. L. Gougeon, L. Montagnier. 1993. The resistance of HIV-infected chimpanzees to progression to AIDS correlates with absence of HIV-related T-cell dysfunction. J. Med. Primatol. 22:194.[Medline]
  47. Gougeon, M. L., H. Lecoeur, F. Boudet, E. Ledru, S. Marzabal, S. Boullier, R. Roue, S. Nagata, J. Heeney. 1997. Lack of chronic immune activation in HIV-infected chimpanzees correlates with the resistance of T cells to Fas/Apo-1 (CD95)-induced apoptosis and preservation of a T helper 1 phenotype. J. Immunol. 158:2964.[Abstract]
  48. ten Haaft, P., M. Cornelissen, J. Goudsmit, W. Koornstra, R. Dubbes, H. Niphuis, M. Peeters, C. Thiriart, C. Bruck, J. L. Heeney. 1995. Virus load in chimpanzees infected with human immunodeficiency virus type 1: effect of pre-exposure vaccination. J. Gen. Virol. 76:1015.[Abstract/Free Full Text]
  49. Bruck, C., C. Thiriart, L. Fabry, M. Francotte, P. Pala, O. Van Opstal, J. Culp, M. Rosenberg, M. De Wilde, P. Heidt, et al 1994. HIV-1 envelope-elicited neutralizing antibody titres correlate with protection and virus load in chimpanzees. Vaccine 12:1141.[Medline]
  50. Bontrop, R. E., N. Otting, B. L. Slierendregt, J. S. Lanchbury. 1995. Evolution of major histocompatibility complex polymorphisms and T-cell receptor diversity in primates. Immunol. Rev. 143:33.[Medline]
  51. Ennis, P. D., J. Zemmour, R. D. Salter, P. Parham. 1990. Rapid cloning of HLA-A,B cDNA by using the polymerase chain reaction: frequency and nature of errors produced in amplification. Proc. Natl. Acad. Sci. USA 87:2833.[Abstract/Free Full Text]
  52. Slierendregt, B. L., M. Kenter, N. Otting, J. Anholts, M. Jonker, R. E. Bontrop. 1993. Major histocompatibility complex class II haplotypes in a breeding colony of chimpanzees (Pan troglodytes). Tissue Antigens 42:55.[Medline]
  53. Mayer, W. E., M. Jonker, D. Klein, P. Ivanyi, G. van Seventer, J. Klein. 1988. Nucleotide sequences of chimpanzee MHC class I alleles: evidence for trans-species mode of evolution. EMBO J. 7:2765.[Medline]
  54. McAdam, S. N., J. E. Boyson, X. Liu, T. L. Garber, A. L. Hughes, R. E. Bontrop, D. I. Watkins. 1994. A uniquely high level of recombination at the HLA-B locus. Proc. Natl. Acad. Sci. USA 91:5893.[Abstract/Free Full Text]
  55. Shi, L., S. Mai, S. Israels, K. Browne, J. A. Trapani, A. H. Greenberg. 1997. Granzyme B (GraB) autonomously crosses the cell membrane and perforin initiates apoptosis and GraB nuclear localization. J. Exp. Med. 185:855.[Abstract/Free Full Text]
  56. Buseyne, F., M. McChesney, F. Porrot, S. Kovarik, B. Guy, Y. Riviere. 1993. Gag-specific cytotoxic T lymphocytes from human immunodeficiency virus type 1-infected individuals: gag epitopes are clustered in three regions of the p24gag protein. J. Virol. 67:694.[Abstract/Free Full Text]
  57. Geluk, A., D. G. Elferink, B. L. Slierendregt, K. E. van Meijgaarden, R. R. de Vries, T. H. Ottenhoff, R. E. Bontrop. 1993. Evolutionary conservation of major histocompatibility complex- DR/peptide/T cell interactions in primates. J. Exp. Med. 177:979.[Abstract/Free Full Text]
  58. Kowalski, H., A. L. Erickson, S. Cooper, J. D. Domena, P. Parham, C. M. Walker. 1996. Patr-A and B, the orthologues of HLA-A and B, present hepatitis C virus epitopes to CD8+ cytotoxic T cells from two chronically infected chimpanzees. J. Exp. Med. 183:1761.[Abstract/Free Full Text]
  59. Cooper, S., H. Kowalski, A. L. Erickson, K. Arnett, A. M. Little, C. M. Walker, P. Parham. 1996. The presentation of a hepatitis C viral peptide by distinct major histocompatibility complex class I allotypes from two chimpanzee species. J. Exp. Med. 183:663.[Abstract/Free Full Text]
  60. Culmann, B., E. Gomard, M. P. Kieny, B. Guy, F. Dreyfus, A. G. Saimot, D. Sereni, J. P. Levy. 1989. An antigenic peptide of the HIV-1 NEF protein recognized by cytotoxic T lymphocytes of seropositive individuals in association with different HLA-B molecules. Eur. J. Immunol. 19:2383.[Medline]
  61. Koenig, S., T. R. Fuerst, L. V. Wood, R. M. Woods, J. A. Suzich, G. M. Jones, V. F. de la Cruz, Jr R. Davey, S. Venkatesan, B. Moss, et al 1990. Mapping the fine specificity of a cytolytic T cell response to HIV-1 nef protein. J. Immunol. 145:127.[Abstract]
  62. Hadida, F., G. Haas, N. Zimmermann, A. Hosmalin, R. Spohn, A. Samri, G. Jung, P. Debre, B. Autran. 1995. CTLs from lymphoid organs recognize an optimal HLA-A2-restricted and HLA-B52-restricted nonapeptide and several epitopes in the C-terminal region of HIV-1 Nef. J. Immunol. 154:4174.[Abstract]
  63. Goulder, P. J., R. E. Phillips, R. A. Colbert, S. McAdam, G. Ogg, M. A. Nowak, P. Giangrande, G. Luzzi, B. Morgan, A. Edwards, A. J. McMichael, S. Rowland-Jones. 1997. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat. Med. 3:212.[Medline]



This article has been cited by other articles:


Home page
 J. Gen. Virol.Home page
A. R. Rodriguez, B. P. Arulanandam, V. L. Hodara, H. M. McClure, E. K. Cobb, M. T. Salas, R. White, and K. K. Murthy
Influence of interleukin-15 on CD8+ natural killer cells in human immunodeficiency virus type 1-infected chimpanzees
J. Gen. Virol., February 1, 2007; 88(2): 641 - 651.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
E. Rutjens, S. Mazza, R. Biassoni, G. Koopman, L. Radic, M. Fogli, P. Costa, M. C. Mingari, L. Moretta, J. Heeney, et al.
Differential NKp30 Inducibility in Chimpanzee NK Cells and Conserved NK Cell Phenotype and Function in Long-Term HIV-1-Infected Animals
J. Immunol., February 1, 2007; 178(3): 1702 - 1712.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
J. L. Heeney, A. G. Dalgleish, and R. A. Weiss
Origins of HIV and the evolution of resistance to AIDS.
Science, July 28, 2006; 313(5786): 462 - 466.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
J. L. Heeney, E. Rutjens, E. J. Verschoor, H. Niphuis, P. ten Haaft, S. Rouse, H. McClure, S. Balla-Jhagjhoorsingh, W. Bogers, M. Salas, et al.
Transmission of Simian Immunodeficiency Virus SIVcpz and the Evolution of Infection in the Presence and Absence of Concurrent Human Immunodeficiency Virus Type 1 Infection in Chimpanzees
J. Virol., July 15, 2006; 80(14): 7208 - 7218.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
D. G. Kavanagh, D. E. Kaufmann, S. Sunderji, N. Frahm, S. Le Gall, D. Boczkowski, E. S. Rosenberg, D. R. Stone, M. N. Johnston, B. S. Wagner, et al.
Expansion of HIV-specific CD4+ and CD8+ T cells by dendritic cells transfected with mRNA encoding cytoplasm- or lysosome-targeted Nef
Blood, March 1, 2006; 107(5): 1963 - 1969.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
D. H. O'Connor, B. R. Mothe, J. T. Weinfurter, S. Fuenger, W. M. Rehrauer, P. Jing, R. R. Rudersdorf, M. E. Liebl, K. Krebs, J. Vasquez, et al.
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., August 15, 2003; 77(16): 9029 - 9040.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
N. G. de Groot, N. Otting, G. G. M. Doxiadis, S. S. Balla-Jhagjhoorsingh, J. L. Heeney, J. J. van Rood, P. Gagneux, and R. E. Bontrop
Evidence for an ancient selective sweep in the MHC class I gene repertoire of chimpanzees
PNAS, September 3, 2002; 99(18): 11748 - 11753.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
J. Tang, S. Tang, E. Lobashevsky, A. D. Myracle, U. Fideli, G. Aldrovandi, S. Allen, R. Musonda, and R. A. Kaslow
Favorable and Unfavorable HLA Class I Alleles and Haplotypes in Zambians Predominantly Infected with Clade C Human Immunodeficiency Virus Type 1
J. Virol., July 19, 2002; 76(16): 8276 - 8284.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
E. Mizukoshi, M. Nascimbeni, J. B. Blaustein, K. Mihalik, C. M. Rice, T. J. Liang, S. M. Feinstone, and B. Rehermann
Molecular and Immunological Significance of Chimpanzee Major Histocompatibility Complex Haplotypes for Hepatitis C Virus Immune Response and Vaccination Studies
J. Virol., May 13, 2002; 76(12): 6093 - 6103.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
T. Beaumont, S. Broersen, A. van Nuenen, H. G. Huisman, A.-M. de Roda Husman, J. L. Heeney, and H. Schuitemaker
Increased Neutralization Sensitivity and Reduced Replicative Capacity of Human Immunodeficiency Virus Type 1 after Short-Term In Vivo or In Vitro Passage through Chimpanzees
J. Virol., September 1, 2000; 74(17): 7699 - 7707.
[Abstract] [Full Text]

Home page
 J. Virol.Home page
S. Santra, P. N. Fultz, and N. L. Letvin
Virus-Specific Cytotoxic T Lymphocytes in Human Immunodeficiency Virus Type 1-Infected Chimpanzees
J. Virol., August 1, 1999; 73(8): 7065 - 7069.
[Abstract] [Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Balla-Jhagjhoorsingh, S. S.
Right arrow Articles by Heeney, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Balla-Jhagjhoorsingh, S. S.
Right arrow Articles by Heeney, J. L.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS