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Science 298 (5595): 995-1000

Copyright © 2002 by the American Association for the Advancement of Science

Contribution of Human alpha -Defensin 1, 2, and 3 to the Anti-HIV-1 Activity of CD8 Antiviral Factor

Linqi Zhang,1* Wenjie Yu,1 Tian He,1 Jian Yu,1 Rebecca E. Caffrey,2 Enrique A. Dalmasso,2 Siyu Fu,2 Thang Pham,2 Jianfeng Mei,2 Jaclyn J. Ho,1 Wenyong Zhang,1 Peter Lopez,1 David D. Ho1*

It has been known since 1986 that CD8 T lymphocytes from certain HIV-1-infected individuals who are immunologically stable secrete a soluble factor, termed CAF, that suppresses HIV-1 replication. However, the identity of CAF remained elusive despite an extensive search. By means of a protein-chip technology, we identified a cluster of proteins that were secreted when CD8 T cells from long-term nonprogressors with HIV-1 infection were stimulated. These proteins were identified as alpha -defensin 1, 2, and 3 on the basis of specific antibody recognition and amino acid sequencing. CAF activity was eliminated or neutralized by an antibody specific for human alpha -defensins. Synthetic and purified preparations of alpha -defensins also inhibited the replication of HIV-1 isolates in vitro. Taken together, our results indicate that alpha -defensin 1, 2, and 3 collectively account for much of the anti-HIV-1 activity of CAF that is not attributable to beta -chemokines.

1 Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Avenue, New York, NY 10016, USA.
2 Ciphergen Biosystems, Inc., 6611 Dumbarton Circle, Fremont, CA 94555, USA.
*   To whom correspondence should be addressed. E-mail: lzhang{at} (L.Z.); dho{at} (D.D.H.)

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J. Stebbing, B. Gazzard, S. Portsmouth, F. Gotch, L. Kim, M. Bower, S. Mandalia, R. Binder, P. Srivastava, and S. Patterson (2003)
Blood 102, 1806-1814
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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.
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. (2003)
J. Virol. 77, 9029-9040
   Abstract »    Full Text »    PDF »
Haptoglobin-{alpha} Subunit As Potential Serum Biomarker in Ovarian Cancer: Identification and Characterization Using Proteomic Profiling and Mass Spectrometry.
B. Ye, D. W. Cramer, S. J. Skates, S. P. Gygi, V. Pratomo, L. Fu, N. K. Horick, L. J. Licklider, J. O. Schorge, R. S. Berkowitz, et al. (2003)
Clin. Cancer Res. 9, 2904-2911
   Abstract »    Full Text »    PDF »
Biomarker Discovery and Identification in Laser Microdissected Head and Neck Squamous Cell Carcinoma with ProteinChip(R) Technology, Two-dimensional Gel Electrophoresis, Tandem Mass Spectrometry, and Immunohistochemistry.
C. Melle, G. Ernst, B. Schimmel, A. Bleul, S. Koscielny, A. Wiesner, R. Bogumil, U. Moller, D. Osterloh, K.-J. Halbhuber, et al. (2003)
Mol. Cell. Proteomics 2, 443-452
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CAF-Mediated Human Immunodeficiency Virus (HIV) Type 1 Transcriptional Inhibition Is Distinct from {alpha}-Defensin-1 HIV Inhibition.
T. L.-Y. Chang, F. Francois, A. Mosoian, and M. E. Klotman (2003)
J. Virol. 77, 6777-6784
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Human Immunodeficiency Virus Type 1 Infection of Human Uterine Epithelial Cells: Viral Shedding and Cell Contact-Mediated Infectivity.
S. N. Asin, D. Wildt-Perinic, S. I. Mason, A. L. Howell, C. R. Wira, and M. W. Fanger (2003)
The Journal of Infectious Disease 187, 1522-1533
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The heat-shock protein receptor CD91 is up-regulated in monocytes of HIV-1-infected "true" long-term nonprogressors.
J. Stebbing, B. Gazzard, L. Kim, S. Portsmouth, A. Wildfire, I. Teo, M. Nelson, M. Bower, F. Gotch, S. Shaunak, et al. (2003)
Blood 101, 4000-4004
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Retrocyclin, an Antiretroviral {theta}-Defensin, Is a Lectin.
W. Wang, A. M. Cole, T. Hong, A. J. Waring, and R. I. Lehrer (2003)
J. Immunol. 170, 4708-4716
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Innate Immunity in Human Immunodeficiency Virus Infection: Effect of Viremia on Natural Killer Cell Function.
S. Kottilil, T.-W. Chun, S. Moir, S. Liu, M. McLaughlin, C. W. Hallahan, F. Maldarelli, L. Corey, and A. S. Fauci (2003)
The Journal of Infectious Disease 187, 1038-1045
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The CD8+ cell noncytotoxic anti-HIV response can be blocked by protease inhibitors.
C. E. Mackewicz, C. S. Craik, and J. A. Levy (2003)
PNAS 100, 3433-3438
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Mechanisms of Antimicrobial Peptide Action and Resistance.
M. R. Yeaman and N. Y. Yount (2003)
Pharmacol. Rev. 55, 27-55
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Nicotinamide: An Oral Antimicrobial Agent with Activity against Both Mycobacterium tuberculosis and Human Immunodeficiency Virus.
M. F. Murray (2003)
Clinical Infectious Diseases 36, 453-460
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NP-1, a Rabbit {alpha}-Defensin, Prevents the Entry and Intercellular Spread of Herpes Simplex Virus Type 2.
S. Sinha, N. Cheshenko, R. I. Lehrer, and B. C. Herold (2003)
Antimicrob. Agents Chemother. 47, 494-500
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HIV-1 Antiviral Activity of Recombinant Natural Killer Cell Enhancing Factors, NKEF-A and NKEF-B, Members of the Peroxiredoxin Family.
R. Geiben-Lynn, M. Kursar, N. V. Brown, M. M. Addo, H. Shau, J. Lieberman, A. D. Luster, and B. D. Walker (2003)
J. Biol. Chem. 278, 1569-1574
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Cutting Edge: L-Selectin (CD62L) Expression Distinguishes Small Resting Memory CD4+ T Cells That Preferentially Respond to Recall Antigen.
R. L. Hengel, V. Thaker, M. V. Pavlick, J. A. Metcalf, G. Dennis Jr., J. Yang, R. A. Lempicki, I. Sereti, and H. C. Lane (2003)
J. Immunol. 170, 28-32
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Mono-ADP-Ribosylation: A Tool for Modulating Immune Response and Cell Signaling.
D. Corda and M. Di Girolamo (2002)
Sci. STKE 2002, pe53
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Mysterious CD8 Antiviral Factor Unmasked.
Journal Watch Infectious Diseases 2002, 5
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IMMUNOLOGY: Versatile Defensins.
T. Ganz (2002)
Science 298, 977-979
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CD8 Antiviral Factor identified.
AIDS Clinical Care 2002, 12
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