Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia

Science

Volumn 278, Issue 5342, 1997, Pages 1447-1450

  Rosenberg, Eric S ^a   Billingsley, James M ^a   Caliendo, Angela M ^a   Boswell, Steven L ^b   Sax, Paul E ^c   Kalams, Spyros A ^a   Walker, Bruce D ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b FENWAY INSTITUTE   (United States)

^c BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; CD4 ANTIGEN; CHEMOKINE; GAMMA INTERFERON;

ARTICLE; CHRONIC DISEASE; CONTROLLED STUDY; HELPER CELL; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; PRIORITY JOURNAL; T LYMPHOCYTE SUBPOPULATION; VACCINE PRODUCTION; VIREMIA;

AMINO ACID SEQUENCE; ANTI-HIV AGENTS; CHEMOKINES; COHORT STUDIES; CYTOTOXICITY, IMMUNOLOGIC; DISEASE PROGRESSION; DRUG THERAPY, COMBINATION; HIV CORE PROTEIN P24; HIV ENVELOPE PROTEIN GP160; HIV INFECTIONS; HIV-1; HUMANS; IMMUNOLOGIC MEMORY; INTERFERON TYPE II; LYMPHOCYTE ACTIVATION; MOLECULAR SEQUENCE DATA; PEPTIDE FRAGMENTS; T-LYMPHOCYTES, CYTOTOXIC; T-LYMPHOCYTES, HELPER-INDUCER; VIRAL LOAD; VIREMIA; VIRUS REPLICATION;

EID: 0030665257     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.278.5342.1447     Document Type: Article

References (54)

1. H. W. Murray, B. Y. Rubin, H. Masur, R. B. Roberts, N. Engl. J. Med. 310, 883 (1984); J. S. Epstein et al., J. Infect. Dis. 152, 727 (1985); H. C. Lane et al., N. Engl. J. Med. 313, 79 (1985).
2. H. W. Murray, B. Y. Rubin, H. Masur, R. B. Roberts, N. Engl. J. Med. 310, 883 (1984); J. S. Epstein et al., J. Infect. Dis. 152, 727 (1985); H. C. Lane et al., N. Engl. J. Med. 313, 79 (1985).
3. H. W. Murray, B. Y. Rubin, H. Masur, R. B. Roberts, N. Engl. J. Med. 310, 883 (1984); J. S. Epstein et al., J. Infect. Dis. 152, 727 (1985); H. C. Lane et al., N. Engl. J. Med. 313, 79 (1985).
4. F. Miedema, J. Clin. Invest. 82, 1908 (1988); J. Laurence, S. M. Friedman, E. K. Chartash, M. K. Crow, D. N. Posnett, ibid. 83, 1843 (1989); M. Clerioi et al., Nature 339, 383 (1989).
5. F. Miedema, J. Clin. Invest. 82, 1908 (1988); J. Laurence, S. M. Friedman, E. K. Chartash, M. K. Crow, D. N. Posnett, ibid. 83, 1843 (1989); M. Clerioi et al., Nature 339, 383 (1989).
6. F. Miedema, J. Clin. Invest. 82, 1908 (1988); J. Laurence, S. M. Friedman, E. K. Chartash, M. K. Crow, D. N. Posnett, ibid. 83, 1843 (1989); M. Clerioi et al., Nature 339, 383 (1989).
7. M.T. Roos et al., J. Infect. Dis. 171, 531 (1995); M. J. Dotan et al., ibid. 172, 79 (1995).
8. M.T. Roos et al., J. Infect. Dis. 171, 531 (1995); M. J. Dotan et al., ibid. 172, 79 (1995).
9. F. Miedema et al., Immunol. Rev. 140, 35 (1994).
10. M. Battegay et al., J. Virol. 68, 4700 (1994); M. Matloubian, R. J. Conception, R. Ahmed, ibid., p. 8056; M. G. von Herrath, M. Yokoyama, J. Dockter, M. B. Oldstone, J. L. Whitton, ibid. 70, 1072 (1996); A. R. Thomsen, J. Johansen, O. Marker, J. P. Christensen, J. Immunol. 157, 3074 (1996); O. Planz et al., Proc. Natl. Acad. Sci. U.S.A. 94, 6874 (1997).
11. M. Battegay et al., J. Virol. 68, 4700 (1994); M. Matloubian, R. J. Conception, R. Ahmed, ibid., p. 8056; M. G. von Herrath, M. Yokoyama, J. Dockter, M. B. Oldstone, J. L. Whitton, ibid. 70, 1072 (1996); A. R. Thomsen, J. Johansen, O. Marker, J. P. Christensen, J. Immunol. 157, 3074 (1996); O. Planz et al., Proc. Natl. Acad. Sci. U.S.A. 94, 6874 (1997).
12. M. Battegay et al., J. Virol. 68, 4700 (1994); M. Matloubian, R. J. Conception, R. Ahmed, ibid., p. 8056; M. G. von Herrath, M. Yokoyama, J. Dockter, M. B. Oldstone, J. L. Whitton, ibid. 70, 1072 (1996); A. R. Thomsen, J. Johansen, O. Marker, J. P. Christensen, J. Immunol. 157, 3074 (1996); O. Planz et al., Proc. Natl. Acad. Sci. U.S.A. 94, 6874 (1997).
13. M. Battegay et al., J. Virol. 68, 4700 (1994); M. Matloubian, R. J. Conception, R. Ahmed, ibid., p. 8056; M. G. von Herrath, M. Yokoyama, J. Dockter, M. B. Oldstone, J. L. Whitton, ibid. 70, 1072 (1996); A. R. Thomsen, J. Johansen, O. Marker, J. P. Christensen, J. Immunol. 157, 3074 (1996); O. Planz et al., Proc. Natl. Acad. Sci. U.S.A. 94, 6874 (1997).
14. M. Battegay et al., J. Virol. 68, 4700 (1994); M. Matloubian, R. J. Conception, R. Ahmed, ibid., p. 8056; M. G. von Herrath, M. Yokoyama, J. Dockter, M. B. Oldstone, J. L. Whitton, ibid. 70, 1072 (1996); A. R. Thomsen, J. Johansen, O. Marker, J. P. Christensen, J. Immunol. 157, 3074 (1996); O. Planz et al., Proc. Natl. Acad. Sci. U.S.A. 94, 6874 (1997).
15. B. Wahren et al., J. Virol. 61, 2017 (1987); J. A. Berzofsky et al., Nature 334, 706 (1988); J. F. Krowka et al., J. Clin. Invest. 83, 1198 (1989); R. D. Schrier et al., J. Immunol. 142, 1166 (1989); D. Schwanz et al., AIDS Res. Hum. Retroviruses 10, 1703 (1994); O. Pontesilli et al., ibid., p. 113.
16. B. Wahren et al., J. Virol. 61, 2017 (1987); J. A. Berzofsky et al., Nature 334, 706 (1988); J. F. Krowka et al., J. Clin. Invest. 83, 1198 (1989); R. D. Schrier et al., J. Immunol. 142, 1166 (1989); D. Schwanz et al., AIDS Res. Hum. Retroviruses 10, 1703 (1994); O. Pontesilli et al., ibid., p. 113.
17. B. Wahren et al., J. Virol. 61, 2017 (1987); J. A. Berzofsky et al., Nature 334, 706 (1988); J. F. Krowka et al., J. Clin. Invest. 83, 1198 (1989); R. D. Schrier et al., J. Immunol. 142, 1166 (1989); D. Schwanz et al., AIDS Res. Hum. Retroviruses 10, 1703 (1994); O. Pontesilli et al., ibid., p. 113.
18. B. Wahren et al., J. Virol. 61, 2017 (1987); J. A. Berzofsky et al., Nature 334, 706 (1988); J. F. Krowka et al., J. Clin. Invest. 83, 1198 (1989); R. D. Schrier et al., J. Immunol. 142, 1166 (1989); D. Schwanz et al., AIDS Res. Hum. Retroviruses 10, 1703 (1994); O. Pontesilli et al., ibid., p. 113.
19. B. Wahren et al., J. Virol. 61, 2017 (1987); J. A. Berzofsky et al., Nature 334, 706 (1988); J. F. Krowka et al., J. Clin. Invest. 83, 1198 (1989); R. D. Schrier et al., J. Immunol. 142, 1166 (1989); D. Schwanz et al., AIDS Res. Hum. Retroviruses 10, 1703 (1994); O. Pontesilli et al., ibid., p. 113.
20. B. Wahren et al., J. Virol. 61, 2017 (1987); J. A. Berzofsky et al., Nature 334, 706 (1988); J. F. Krowka et al., J. Clin. Invest. 83, 1198 (1989); R. D. Schrier et al., J. Immunol. 142, 1166 (1989); D. Schwanz et al., AIDS Res. Hum. Retroviruses 10, 1703 (1994); O. Pontesilli et al., ibid., p. 113.
21. B. F. Haynes, G. Pantateo, A. S. Fauci, Science 271, 324 (1996).
22. M. R. Klein et al., J. Exp. Med. 181, 1365 (1995); Y. Cao, L. Qin, L. Zhang, J. Safrit, D. D. Ho, N. Engl. J. Med. 332, 201 (1995); G. Pantaleo et al., ibid., p. 209; C. Rinaldo et al., J. Virol. 69, 5838 (1995).
23. M. R. Klein et al., J. Exp. Med. 181, 1365 (1995); Y. Cao, L. Qin, L. Zhang, J. Safrit, D. D. Ho, N. Engl. J. Med. 332, 201 (1995); G. Pantaleo et al., ibid., p. 209; C. Rinaldo et al., J. Virol. 69, 5838 (1995).
24. M. R. Klein et al., J. Exp. Med. 181, 1365 (1995); Y. Cao, L. Qin, L. Zhang, J. Safrit, D. D. Ho, N. Engl. J. Med. 332, 201 (1995); G. Pantaleo et al., ibid., p. 209; C. Rinaldo et al., J. Virol. 69, 5838 (1995).
25. M. R. Klein et al., J. Exp. Med. 181, 1365 (1995); Y. Cao, L. Qin, L. Zhang, J. Safrit, D. D. Ho, N. Engl. J. Med. 332, 201 (1995); G. Pantaleo et al., ibid., p. 209; C. Rinaldo et al., J. Virol. 69, 5838 (1995).
26. T. Harrer et al., J. Immunol. 156, 2616 (1996).
27. 51Cr release did not exceed the mean plus three standard deviations of the spontaneous release of the 24 control wells over the number of the assayed wells. Activated cell frequency was calculated by the maximum likelihood method [F. de St. Groth, J. Immunol. Methods 49, 11 (1982)].
28. The HIV-1-specific proliferative responses to p24 were tested 12 times over 24 months, with Sls ranging from 38 to 465 (mean, 134).
29. 3 (<400 copies/ml).
30. S. Kalams, E. Rosenberg, J. Billingsley, B. Walker, in preparation.
31. E. Rosenberg, J. Billingsley, B. Walker, unpublished observations.
32. Lymphocyte proliferation assays were performed as described in Fig. 1. Concentration of p24 was titrated to determine the lowest amount of antigen required to stimulate a p24-specific lymphocyte proliferative response. For subject 161-J, a p24 concentration of 0.05 μg/ml still elicited a response, whereas for subject CTS-01, the response was lost at concentrations <0.5 μg/ml.
33. 6 cells/ml in 24 replicate wells of 96-well U-bottom microtiter plates in the presence of HIV-1 p24, and in 12 replicate wells in the presence of control proteins. Plates were incubated and harvested as described in Fig. 1. For each cell concentration, the fraction of nonresponding wells was determined to be the fraction of wells with fewer counts per minute than the mean plus three standard deviations for the 12 control wells. Activated cell frequency was determined by the maximum likelihood method (10).
34. T. R. Mosmann, H. Cherwinski, M. W. Bond, M. A. Giedlin, R. L. Coffman, J. Immunol. 136, 2348 (1986); T. R. Mosmann and S. Sad, Immunol. Today 17, 138 (1996).
35. T. R. Mosmann, H. Cherwinski, M. W. Bond, M. A. Giedlin, R. L. Coffman, J. Immunol. 136, 2348 (1986); T. R. Mosmann and S. Sad, Immunol. Today 17, 138 (1996).
36. F. Cocchi et al., Science 270, 1811 (1995).
37. E. Rosenberg and B. Walker, unpublished observations.
38. M. Clerici et al., J. Clin. Invest. 93, 768 (1994).
39. Single-letter abbreviations for the amino acid residues are as follows: A, Ala; C, Cys; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; W, Trp; and Y, Tyr.
40. Three p24 peptides were recognized by both individuals with SI > 10: residues 163 to 184 (AFSPEVIPMFSALSEGATPQDL), 243 to 264 (LQECHGWMTNNPPIFVGEIYKR), and 263 to 284 (KRWIILGLNKIVRMYSPTSILD).
41. PBMC from seronegative persons resulted in SI < 3 for all p24 peptides.
42. The diagnosis was made on the basis of a negative HIV-1/2 enzyme immunoassay (Abbott Laboratories, Abbott Park, IL), the presence of HIV-1 viral RNA (AMPLICOR HIV MONITOR TEST, Roche Diagnostic Systems, Branchberg, NJ), and subsequent seroconversion documented by both HIV-1/2 enzyme immunoassay and protein immunoblot (Abbott Laboratories). Proliferation assays were performed at baseline (before initiation of antiviral therapy) and at designated intervals during therapy, with the use of baculovirus-derived p24 antigen at 5 μg/ml.
43. A. D. Kelleher, A. Carr, J. Zaunders, D. A. Cooper, J. Infect. Dis. 173, 321 (1996); S. M. Schnittman and L. Fox, AIDS Res. Hum. Retroviruses 13, 815 (1997); M. Connors et al., Nature Med. 3, 533 (1997); B. Autran et al., Science 277, 112 (1997).
44. A. D. Kelleher, A. Carr, J. Zaunders, D. A. Cooper, J. Infect. Dis. 173, 321 (1996); S. M. Schnittman and L. Fox, AIDS Res. Hum. Retroviruses 13, 815 (1997); M. Connors et al., Nature Med. 3, 533 (1997); B. Autran et al., Science 277, 112 (1997).
45. A. D. Kelleher, A. Carr, J. Zaunders, D. A. Cooper, J. Infect. Dis. 173, 321 (1996); S. M. Schnittman and L. Fox, AIDS Res. Hum. Retroviruses 13, 815 (1997); M. Connors et al., Nature Med. 3, 533 (1997); B. Autran et al., Science 277, 112 (1997).
46. A. D. Kelleher, A. Carr, J. Zaunders, D. A. Cooper, J. Infect. Dis. 173, 321 (1996); S. M. Schnittman and L. Fox, AIDS Res. Hum. Retroviruses 13, 815 (1997); M. Connors et al., Nature Med. 3, 533 (1997); B. Autran et al., Science 277, 112 (1997).
47. E. A. Walter et al., N. Engl. J. Med. 333, 1038 (1995).
48. D. Weissman, T. D. Barker, A. S. Fauci, J. Exp. Med. 183, 687 (1996); S. Stanley et al., N. Engl. J. Med. 334, 1222 (1996).
49. D. Weissman, T. D. Barker, A. S. Fauci, J. Exp. Med. 183, 687 (1996); S. Stanley et al., N. Engl. J. Med. 334, 1222 (1996).
50. A. K. Abbas, Cell 84, 655 (1996).
51. C. Lekutis and N. L. Letvin, J. Immunol. 159, 2049 (1997); C. Lekutis, J. W. Shiver, M. A. Liu, N. L. Letvin, ibid. 158, 4471 (1997).
52. C. Lekutis and N. L. Letvin, J. Immunol. 159, 2049 (1997); C. Lekutis, J. W. Shiver, M. A. Liu, N. L. Letvin, ibid. 158, 4471 (1997).
53. 3H]-thymidine at 1.0 μCi per well, and uptake was measured 6 hours later with a scintillation counter (Packard Topcount, Packard Instruments, Meriden, CT). The HIV-1 p24 and gp160 proteins (Protein Science, Meriden, CT) are recombinant proteins derived from the gag or env gene of HIV-1 (NY-5 and LAV strains, respectively) produced in a baculovirus expression system and demonstrated 90 to 95% purity. These proteins were tested over a range of concentrations, with 0.5 μg/ml as the standard concentration. A mixture of baculovirus proteins was used as a control antigen at 0.015 μg/ml (equal to the baculovirus antigen concentration in the recombinant proteins), with comparable results obtained at 1.5 μg/ml. Yeast-and CHO-derived HIV-1 proteins were provided by Chiron (Emeryville, CA). The yeast-derived p24 Gag protein (residues 139 to 369) is recombinantly derived in a yeast expression system using the HIV-1 strain SF2. The gp120 was derived from HIV-SF2 expressed in CHO cells. These proteins demonstrated >90 and 94.8% purity, respectively. Each protein was used at a concentration of 0.5 μg/ml, and preparations of CHO and yeast proteins were used as controls for these antigens at 0.5 μg/ml. Tetanus toxoid (Connaught Laboratories, Willowdale, Ontario, Canada) was used at 2 μg/ml. For the recombinant HIV-1 proteins, a stimulation index (SI) was defined as the ratio of the mean counts per minute (CPM) of the HIV-1 protein wells to the mean CPM of the control protein wells. For tetanus toxoid, SI was defined as the ratio of the mean CPM of the stimulated wells to the mean CPM of six control wells containing PBMC and medium alone. For assays using CD4-or CDS-depleted PBMC, cells were cultured as described above in the presence of γ-irradiated (40 Gy) autologous PBMC and antigen.
54. We thank D. K. H. Wong for help and advice with statistical analysis, M. Hirsch , D. Cotton, V. Young, and C. Hay for review of manuscript, T. Flynn and L. Larosa for help with patients, and D. J. Ruhl for technical help. This project was supported by NIH grants R01-A128568, F32-A109738, R01-A136550, U19-A136611, and UO1-AI41531.