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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
AIDS. Author manuscript; available in PMC 2014 May 27.
Published in final edited form as:
PMCID: PMC4035112

Alpha-defensins inhibit HIV infection of macrophages through upregulation of CC-chemokines

The possible involvement of α-defensins in CD8 T-cell-mediated anti-HIV activities has been the subject of recent investigations [13]. HIV host defence mechanisms are partly mediated by CD8 T-cell non-cytotoxic antiviral responses [4]. Walker et al. [5] first demonstrated that this anti-HIV activity involves a soluble factor(s) designated as CD8 cell antiviral factor (CAF) whose identity remains unknown [4]. Zhang et al. [1] proposed that α-defensins are produced by CD8 T cells and contribute to CAF-mediated anti-HIV activities. In contrast, the recent studies by Mackewicz et al. [2] and Chang et al. [3] demonstrated that the α-defensins are not produced by CD8 T cells but unexpectedly were found to be expressed by monocytes [2].

As CAF-mediated anti-HIV activity is also observed for macrophages [6,7] and monocytes express α-defensins [2], we investigated the capacity of α-defensins to suppress HIV infection of macrophages. The addition of α-defensins to peripheral blood monocyte-derived macrophage cultures markedly suppressed HIV Bal replication (Fig. 1a) [8,9]. In order to determine the mechanism(s) responsible for α-defensin-mediated HIV inhibition in macrophages, we investigated whether α-defensins regulate the expression of CC-chemokines. CC-chemokines [macrophage inflammatory protein (MIP)-1α, MIP-1β and Rantes] inhibit infection by competing with HIV M-tropic strains for the CCR5 receptor on macrophages [10,11]. Our experiments demonstrated that α-defensins dramatically enhance expression (as much as a 25-fold increase) of MIP-1α and MIP-1β messenger RNA in macrophages (Fig. 1b) [12]. This increased CC-chemokine gene expression by α-defensins was further confirmed by the demonstration of increased production (as much as a 57-fold increase) of MIP-1α and MIP-1β proteins in α-defensin-treated macrophage cultures (Fig. 1c). In addition, the antibodies to CC-chemokines completely abrogated α-defensin-mediated HIV inhibition in macrophages (Fig. 1d). Our data, therefore, indicate that the α-defensin-mediated inhibition of HIV infection of macrophages is mediated through the upregulation of CC-chemokines. This pathway is distinct from the anti-HIV activity of CAF in macrophages, because CC-chemokines are not responsible for the ability of CAF to suppress HIV infection of these cells [6,7].

Fig. 1
Effect of α-defensins on HIV infection and β-chemokine expression in macrophages

The biological interaction of defensins with chemokines and chemokine receptors has been documented. Defensins functionally overlap with chemokines in microbicidal activity [13]. The treatment of dendritic cells with β-defensin-2 upregulated the expression of CC-chemokines (MIP-1α and MIP-1β) and down-regulated CCR5 expression [14]. By utilizing chemokine receptors on immune cells, defensins may contribute to the regulation of host adaptive immunity against microbial invasion [15]. Taken together, our data provide evidence that α-defensins could play a role in host defence against HIV infection of macrophages. The biological interaction of α-defensins with CC-chemokines may constitute a unique mechanism of innate immunity against HIV disease.


Sponsorship: This work was supported by grants from the National Institutes of Health (DA12815 and DA16022 to W.Z.H., MH49981 and AA13547 to S.D.D.).


1. Zhang L, Yu W, He T, Yu J, Caffrey RE, Dalmasso EA, et al. Contribution of human alpha-defensin 1, 2, and 3 to the anti-HIV-1 activity of CD8 antiviral factor. Science. 2002;298:995–1000. [PubMed]
2. Mackewicz CEYJ, Tran P, Diaz L, Mack E, Selsted ME, Levy JA. α-Defensins can have anti-HIV activity but are not CD8 cell anti-HIV factors. AIDS. 2003;17:F23–F32. [PubMed]
3. Chang TL, Francois F, Mosoian A, Klotman ME. CAF-mediated human immunodeficiency virus (HIV) type 1 transcriptional inhibition is distinct from alpha-defensin-1 HIV inhibition. J Virol. 2003;77:6777–6784. [PMC free article] [PubMed]
4. Levy JA, Mackewicz CE, Barker E. Controlling HIV pathogenesis: the role of the noncytotoxic anti-HIV response of CD8+ T cells. Immunol Today. 1996;17:217–224. [PubMed]
5. Walker CM, Moody DJ, Stites DP, Levy JA. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science. 1986;234:1563–1566. [PubMed]
6. Moriuchi H, Moriuchi M, Combadiere C, Murphy PM, Fauci AS. CD8+ T-cell-derived soluble factor(s), but not beta-chemokines RANTES, MIP-1 alpha, and MIP-1 beta, suppress HIV-1 replication in monocyte/macrophages. Proc Natl Acad Sci U S A. 1996;93:15341–15345. [PubMed]
7. Barker E, Bossart KN, Levy JA. Primary CD8+ cells from HIV-infected individuals can suppress productive infection of macrophages independent of beta-chemokines. Proc Natl Acad Sci U S A. 1998;95:1725–1729. [PubMed]
8. Hassan NF, Campbell DE, Douglas SD. Purification of human monocytes on gelatin-coated surfaces. J Immunol Methods. 1986;95:273–276. [PubMed]
9. Ho WZ, Lioy J, Song L, Cutilli JR, Polin RA, Douglas SD. Infection of cord blood monocyte-derived macrophages with human immunodeficiency virus type 1. J Virol. 1992;66:573–579. [PMC free article] [PubMed]
10. Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science. 1995;270:1811–1815. [PubMed]
11. Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996;272:1955–1958. [PubMed]
12. Guo CJ, Douglas SD, Lai JP, Pleasure DE, Li Y, Williams M, et al. Interleukin-1beta stimulates macrophage inflammatory protein-1alpha and -1beta expression in human neuronal cells (NT2-N) J Neurochem. 2003;84:997–1005. [PMC free article] [PubMed]
13. Ganz T. Defensins and host defense. Science. 1999;286:420–421. [PubMed]
14. Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, et al. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science. 2002;298:1025–1029. [PubMed]
15. Yang D, Biragyn A, Kwak LW, Oppenheim JJ. Mammalian defensins in immunity: more than just microbicidal. Trends Immunol. 2002;23:291–296. [PubMed]