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Journal of Virology, June 2008, p. 5631-5635, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.02749-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Contribution of CD8+ T Cells to Containment of Viral Replication and Emergence of Mutations in Mamu-A*01-Restricted Epitopes in Simian Immunodeficiency Virus-Infected Rhesus Monkeys{triangledown} ,{dagger}

Eun-Young Kim,1* Ronald S. Veazey,2 Roland Zahn,3 Kimberly J. McEvers,3 Susanne H. C. Baumeister,3 Gabriel J. Foster,3 Melisa D. Rett,3 Michael H. Newberg,3 Marcelo J. Kuroda,2 E. Peter Rieber,4 Michael Piatak Jr.,5 Jeffrey D. Lifson,5 Norman L. Letvin,3 Steven M. Wolinsky,1 and Jörn E. Schmitz3*

Division of Infectious Diseases, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611,1 Tulane National Primate Research Center, Covington, Louisiana 70433,2 Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115,3 Institute of Immunology, Technical University of Dresden, 01101 Dresden, Germany,4 AIDS Vaccine Program, SAIC Fredrick, Inc., National Cancer Institute at Frederick, Frederick, Maryland 217025

Received 27 December 2007/ Accepted 11 March 2008


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ABSTRACT
 
Here, we investigated the containment of virus replication in simian immunodeficiency virus (SIV) infection by CD8+ lymphocytes. Escape mutations in Mamu-A*01 epitopes appeared first in SIV Tat TL8 and then in SIV Gag p11C. The appearance of escape mutations in SIV Gag p11C was coincident with compensatory changes outside of the epitope. Eliminating CD8+ lymphocytes from rhesus monkeys during primary infection resulted in more rapid disease progression that was associated with preservation of canonical epitopes. These results confirm the importance of cytotoxic T cells in controlling viremia and the constraint on epitope sequences that require compensatory changes to go to fixation.


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TEXT
 
Virus-specific CD8+ T-cell responses are critical to control viral replication in humans infected with human immunodeficiency virus type 1 and rhesus monkeys infected with simian immunodeficiency virus (SIV) (6, 10, 12, 13, 16). While the appearance of measurable cytotoxic T-lymphocyte (CTL) responses is temporally correlated with the initial decline in plasma viremia seen in primary infection (6, 10, 12), the virus-specific CTL response may be a consequence rather than the cause of diminished viral replication (5). Eliminating CD8+ lymphocytes from rhesus monkeys during primary and chronic infection with SIVmac251 has given the most compelling evidence for control of viral replication by CTLs (9, 14, 16). Depletion of CD8+ lymphocytes from peripheral blood and lymphoid tissue of rhesus monkeys by treatment with the CD8-specific mouse-human chimeric monoclonal antibody cM-T807 was associated with a substantial acceleration in the SIVmac251-induced course of disease (16).

Additional evidence for CTLs' playing a role in curtailing viral replication comes from studies demonstrating the emergence of escape mutations, indicative of significant selection pressure exerted by CTLs. The temporal appearance of mutations in selected Mamu-A*01-restricted epitopes that confer viral escape from CTLs in SIV-infected rhesus monkeys has been well studied; mutations first appear in the SIV Tat TL8 epitope within about 3 weeks after infection and then in the SIV Gag p11C epitope over the subsequent several months (1, 3-5). Here, we investigated the kinetics of viral sequence variation in major histocompatibility complex class I (MHC-I)-restricted Mamu-A*01 SIV Tat TL8 and Gag p11C epitopes (2, 15) and asked the question whether CD8+ lymphocyte depletion would influence the temporal appearance of escape mutations within these epitopes.

Two cohorts of antibody-treated Mamu-A*01-positive rhesus monkeys were analyzed in this study (see Table S1 in the supplemental material). The first group was comprised of eight rhesus monkeys that received the CD8-specific mouse-human chimeric monoclonal antibody cM-T807 (Centocor, Malvern, PA) to deplete CD8+ lymphocytes (both CD8+ CD3+ T cells and CD8+ CD3– NK cells) from their peripheral blood and lymphatic tissues (16, 17). The second group was comprised of four rhesus monkeys that received the isotype-matched control chimeric monoclonal antibody specific for respiratory syncytial virus (chimeric 1129; Medimmune, Gaithersburg, MD). Antibodies were administered at 10 mg/kg of body weight subcutaneously on day 0 (the day of SIV infection) followed by 5 mg/kg intravenously on days 3 and 7. The monkeys were inoculated intravenously on day 0 with the SIVmac251 stock diluted in 1 ml of RPMI 1640 medium supplemented with 10% fetal calf serum to yield 0.15 ng/ml SIV p27 Gag antigen.

We determined the effect of CD8+ lymphocyte depletion on the control of infection with SIVmac251 by measuring the levels of viral RNA in plasma by a quantitative real-time reverse transcription-PCR assay (limit of detection, 60 copies of SIVmac251 RNA/ml) (8). In cM-T807-treated monkeys and control antibody-treated monkeys, the peak levels of viral RNA in plasma were attained between days 7 and 12 after inoculation with SIVmac251 (Fig. 1A to C); control antibody-treated animals experienced an earlier peak of viremia than the anti-CD8-treated animals by about 5 days. In monkeys depleted of CD8+ lymphocytes, the decreases in the levels of SIVmac251 in plasma after the peak were smaller than in the control antibody-treated group. The elevated levels of viral RNA in plasma were associated with the duration of CD8+ lymphocyte depletion, and the differences between the three groups of animals were statistically significant by the Kruskal-Wallis test (P < 0.05) (Fig. 1D).


Figure 1
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  		FIG. 1. The effect of CD8+ lymphocyte depletion on the control of virus replication in monkeys during acute infection. Monkeys infected with SIVmac251 received either a control monoclonal antibody (A) or the mouse-human chimeric anti-CD8 antibody cM-T807 to deplete CD8+ lymphocytes. Antibodies were administered subcutaneously on day 0 (10 mg/kg of body weight) and intravenously on days 3 and 7 (5 mg/kg). Monkeys treated with cM-T807 were stratified into short-term (≤21 days; B) and long-term (≥28 days; C) CD8+ lymphocyte-depleted animals. Plasma SIV RNA levels were measured by a real-time reverse transcription-PCR assay (limit of detection, 60 copies of viral RNA/ml of plasma). Data in panels A to C represent four animals per group. (D) Median levels of plasma viral RNA. The data shown depict only those time points where at least three of four animals in each of the three groups of monkeys were still alive. The star indicates a statistically significant difference (P < 0.05) at each time point as determined by a Kruskal-Wallis test.

We evaluated the SIVmac251-specific immune response mediated by CD8+ T cells in cM-T807-treated and control antibody-treated animals by quantifying SIV-specific CD8+ T cells in peripheral blood with fluorochrome-labeled Mamu-A*01 SIVmac251 Tat TL8 (TTPESANL; amino acids 28 to 35) and Gag p11C (CTPYDINQM; amino acids 181 to 189) peptide tetramers by flow cytometry using a FACSCalibur flow cytometer as described previously (11). In the Mamu-A*01-positive monkeys that received control antibody, SIV Tat TL8 and Gag p11C tetramer-binding CD8+ T cells were detected 12 days after acute infection (Fig. 2). The appearance of virus-specific CD8+ T cells corresponded with the decline in peak viremia. In the Mamu-A*01-positive monkeys treated with cM-T807, the animals with short-term CD8+ lymphocyte depletion had an attenuated virus-specific immune response. The appearance of SIV Tat TL8 and Gag p11C tetramer-binding CD8+ T cells was detected 3 weeks after acute infection, and their emergence paralleled the decline in the plasma SIVmac251 levels. In cM-T807-treated Mamu-A*01-positive monkeys that achieved long-term CD8+ lymphocyte depletion, virus replication was not controlled, and virus-specific CD8+ T cells were observed rarely. The differences were significant (Kruskal-Wallis test, P < 0.05).


Figure 2
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  		FIG. 2. The appearance of SIV Tat TL8- and Gag p11C-specific CD8+ T cells during acute infection. SIV Tat TL8 (A) and Gag p11C (B) tetramer-binding CD8+ T cells were enumerated in blood with fluorochrome-labeled Mamu-A*01 TL8 or Gag p11C tetrameric complexes. The data shown depict only those time points where at least three of four animals in each of the three groups of monkeys were still alive. A star indicates a statistically significant difference (P < 0.05) at each time point as determined by a Kruskal-Wallis test.

To determine the effect of the timing and magnitude of the cellular immune response on the emergence of mutations in MHC-I-restricted Mamu-A*01 epitopes that conferred escape from immune recognition, we examined viral evolution after primary infection with SIVmac251. We studied an additional nine monkeys, including three monkeys in each of three different MHC groups (Mamu-A*01 positive and Mamu-A*02 negative; Mamu-A*01 negative and Mamu-A*02 positive; and Mamu-A*01 negative and Mamu-A*02 negative), challenged with the same SIVmac251 stock without CD8+ lymphocyte depletion (see Table S1 in the supplemental material). The challenge stock had limited genetic diversity, and no substitutions were detected in the Mamu-A*01-restricted Tat TL8 and Gag p11C epitopes (60 individual clones analyzed at limiting dilution) (data not shown). The viral sequences were amplified from plasma obtained at interval time points by limiting-dilution PCR using primers that span SIV Tat TL8 and SIV Gag p11C (see Table S2 in the supplemental material).

The appearance of virus-specific CD8+ lymphocytes was followed by the emergence of mutations that confer escape from CTL (Fig. 3; see also Tables S3 to S6 in the supplemental material). Nucleotide sequence changes appeared more rapidly in short-term lymphocyte-depleted animals than in long-term lymphocyte-depleted animals. In the Mamu-A*01-positive monkeys that received control antibody, amino acid changes resulted in CTL escape in all viral sequences in SIV Tat TL8 by week 3 and in SIV Gag p11C by week 17 after virus inoculation (see Tables S3 and S5 in the supplemental material). In the Mamu-A*01-positive monkeys treated with cM-T807, amino acid changes in SIV Tat TL8 were found more frequently in viral sequences from the animals with short-term CD8+ lymphocyte depletion than viral sequences from the animals with long-term CD8+ lymphocyte depletion (Fig. 3) (see Table S3 in the supplemental material). In contrast, few nonsynonymous substitutions accumulated in SIV Gag p11C; only one of four monkeys with short-term CD8+ T lymphocyte depletion had a single viral clone each with an amino acid change in SIV Gag p11C (see Table S5 in the supplemental material). Very little change in SIV Tat TL8 and SIV Gag p11C was observed in the 6 Mamu-A*01-negative animals (see Tables S4 and S6 in the supplemental material).


Figure 3
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  		FIG. 3. Nonsynonymous substitutions within the Mamu-A*01-restricted Tat TL8 epitope (TTPESANL) that appeared in the virus population in plasma over time. The deduced amino acid sequence of the SIV Tat TL8 epitope was determined following amplification of the SIVmac251 RNA from plasma at a limiting dilution. The DNA sequences of 10 clones were obtained from monkeys infected with SIVmac251 that received the control monoclonal antibody or were depleted of CD8+ lymphocytes (short-term, depletion for ≤21 days; long-term, depletion for ≥28 days). Data are expressed as the median percentage of mutated Tat sequences when one or more epitopes within each single clone differed from the canonical SIV Tat TL8 epitope. The data shown depict only those time points where at least three of four animals in each of the three groups of monkeys were still alive. The star indicates a statistical significant difference (P < 0.05) at each time point as determined by a Kruskal-Wallis test.

To investigate the relationship between disease course and genetic diversity, we tracked the diversification of viral sequences in CD8+ lymphocyte-depleted and control antibody-treated monkeys by examining viral sequences encoding Tat and Gag over time (Fig. 4). In both CD8+ lymphocyte-depleted and control antibody-treated monkeys, the percent divergence was greater in Tat than Gag, consistent with the more significant structural constraints of the latter protein (Fig. 4A and B). Also, the percent divergence in these epitopes was greater in Mamu-A*01-positive than in Mamu-A*01-negative animals that did not receive an antibody treatment (Fig. 4C and D). Monkeys with long-term CD8+ lymphocyte depletion had an accelerated disease course and maintained a relatively homogeneous population of protein variants throughout the course of infection. In contrast, control antibody-treated monkeys showed the highest diversity among all the monkeys. Monkeys with a short-term CD8+ lymphocyte depletion had a percent diversity between the long-term CD8+ lymphocyte-depleted and control antibody-treated monkeys (Fig. 4A).


Figure 4
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  		FIG. 4. Sequence diversity of SIV Tat and Gag in the virus population. The viral sequences encoding Tat and Gag were examined from plasma over time within monkeys that were either control antibody-treated or CD8+ lymphocyte-depleted with cM-T807 (A and B) and monkeys that did not receive an antibody treatment (C and D). The SIV Tat and Gag protein sequence diversity is shown in panels A and C. The SIV Tat TL8 and Gag p11C epitope sequences diversity is shown in panels B and D. A black bar in each graph shows the degree of sequence variability of the challenge stock of SIVmac251. The divergence was calculated by comparing sequence pairs in relation to the reconstructed phylogeny by MegAlign. The bars indicate mean values ± standard error of the mean.

The amino acid changes in SIV Gag p11C that conferred escape from immune recognition were associated with compensatory changes outside the epitope (both upstream and downstream), suggesting that the targeted region was under structural constraints (see Fig. S1 and Table S7 in the supplemental material). SIV Gag p11C is embedded in a highly conserved region of SIV p27 Gag important for virus particle maturation (2). Nonsynonymous substitutions in this epitope decrease SIV p27 Gag expression and virus replication and affect SIV p27 Gag assembly and virion core condensation (7, 18). The compensatory amino acid changes rescued the defects that accumulated following immune pressure by virus-specific CTLs. Accordingly, compensatory changes outside SIV Gag p11C facilitate escape from immune recognition by restoring the structural and functional integrity of the virus.

This study confirms that virus-specific CD8+ T cells play an important role in the control of viral replication during acute infection. Consistent with the importance of cellular immunity in the control of SIVmac251 infection, the evolutionary dynamics exhibited by the virus population is compatible with selection by the immune system. These data suggest that the kinetics, breadth, extent, and anatomical location of the cellular immune responses may be important for the eventual success of an AIDS vaccine.

Nucleotide sequence accession numbers. The sequences of SIV Tat and SIV Gag have been deposited in the GenBank under accession numbers EU260492 to EU262258.


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ACKNOWLEDGMENTS
 
This work was support by NIH grants AI48394 and AI065335 (J.E.S.), AI060354 (R.S.V.), and AI20729 (N.L.L.); Harvard Medical School Center for AIDS Research grant AI060354; and in part with federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400 (J.D.L. and M.P.). The NIH Nonhuman Primate Reagent Resource Program provided reagents used in this work (contracts AI040101 and RR016001).

Centocor, Inc., generously provided the antibody cM-T807.


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FOOTNOTES
 
* Corresponding author. Mailing address for Eun-Young Kim: Division of Infectious Diseases, The Feinberg School of Medicine, Northwestern University, 676 N. St. Clair St., Suite 200, Chicago, IL 60611. Phone: (312) 695-5085. Fax: (312) 695-5088. E-mail: e-kim{at}northwestern.edu. Mailing address for Jörn E. Schmitz: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, RE-213D, 41 Avenue Louis Pasteur, Boston, MA 02115. Phone: (617) 667-5206. Fax: (617) 667-8210. E-mail: jschmitz{at}bidmc.harvard.edu Back

{triangledown} Published ahead of print on 26 March 2008. Back

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/. Back


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Journal of Virology, June 2008, p. 5631-5635, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.02749-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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