Soluble factors that are produced by cells of the immune system can limit and even protect against HIV infection. Our interest in this field started when we (Drs. Gallo, DeVico, Cocchi, and Garzino-Demo) set out to characterize a soluble HIV suppressive activity produced by CD8+ T cells. The identity of the activity directed against R5 isolates of HIV was identified as the three chemokines RANTES, MIP-1α, and MIP-1β. CCR5, the receptor for the chemokines we identified, was subsequently identified as a co-receptor (together with CD4) for HIV. CCR5 is the key receptor for primary HIV infection, while a second co-receptor, CXCR4 is used sometimes in late phases of the infection. The importance of CCR5 has been clearly established by genetic studies that have linked the inactivating mutation Δ32CCR5 to protection (in homozygous Δ32CCR5 subjects) or slower AIDS progression (in heterozygous Δ32CCR5/CCR5). Our own studies have shown that higher levels of the CCR5 ligands, especially MIP-1α and MIP-1β, are associated with protection from infection and disease progression, thus mimicking the effect of receptor defects. Genetic studies have shown that high copy number of the genes for these two chemokines are associated with slower course of HIV infection. The quest for novel factors that limit HIV infection, produced by T cells is still vigorously pursued at our Institute, to determine the composition of the factors that inhibit X4 HIV.
In addition, Drs. Garzino-Demo, Lu, De Leeuw, and Pazgier pursue studies on the activity of defensins, a family of peptides that inhibit a wide range of microbes such as bacteria, fungi and viruses, neutralize many secreted bacterial toxins such as anthrax, and interact with chemokine receptors. At IHV, we have thoroughly evaluated their activities from a broad biological perspective (Drs. Lu, De Leeuw, and Pazgier) and as HIV inhibitors (Dr. Garzino-Demo).
Sun L., Abdelwahab S.F., Lewis G.K., Gallo, and Garzino-Demo A. Antigen activation induces release of CCR5 ligands from peripheral blood mononuclear cells: potential role in immunization. Int Immunol 6:1623-1631, 2004.
Sun L., Finnegan C., Blumenthal R., Kleinman C., Wu Z., Abdelwahab S., Lu W., and Garzino-Demo, A. Human beta-defensins suppress HIV infection: potential role in mucosal protection. J. Virol. 79: 14318-14329, 2005.
Human neutrophil alpha-defensin 4 inhibits HIV-1 infection in vitro. Wu Z, Cocchi F, Gentles D, Ericksen B, Lubkowski J, Devico A, Lehrer RI, Lu W. FEBS Lett. 579:162-166, 2005
Garzino-Demo A. Chemokines and defensins as HIV suppressive factors. Current Pharma Design, 13:163-172, 2007.
Lafferty, M., Sun, L. DeMasi, L., Lu, W., Garzino-Demo, A. CCR6 Ligands Inhibit HIV by Inducing APOBEC3G. Blood, 115:1564-1571, 2010
de Leeuw E, Li C, Zeng P, Li C, Buin MD, Lu WY, Breukink E, Lu, W. (2010). Functional interaction of human neutrophil peptide-1 with the cell wall precursor lipid II. FEBS Lett 584(8):1543-8.
Wei, G., Pazgier, M., de Leeuw, E., Rajabi, M., Li, J., Zou, G., Jung, G., Yuan, W., Lu, W-Y., Lehrer, R.I. & Lu, W. (2010). Trp-26 Imparts Functional Versatility to Human α-Defensin HNP1. J Biol Chem 285(21):16275 85.
Wei, G., E. de Leeuw, M. Pazgier, W. Yuan, G. Zou, J. Wang, B. Ericksen, W. Y. Lu, R. I. Lehrer, and W. Lu (2009). Through the looking glass, mechanistic insights from enantiomeric human defensins. J Biol Chem 284:29180-29192.
Rajabi, M., de Leeuw, E., Pazgier, M., Li, J., Lubkowski, J., and Lu, W. (2008). The conserved salt bridge in human α-defensin 5 is required for its precursor processing and proteolytic stability. J. Biol. Chem. 283(31):21509-18
Zou, G., de Leeuw, E., Li, C., Li, C., Zeng, P., Lubkowski, J., Lu, W.-Y., and Lu, W. (2007). Toward understanding the cationicity of defensins: Arg and Lys versus their noncoded analogs. J. Biol. Chem. 282(27):19653-19665.
Pazgier M, Hoover D., Prahl A., Lubkowski J. Studies of biological properties of human β-defensin 1. J Biol Chem. 282(3):1819-1829, 2007.
|Figure Legend: HIV suppressive factors include chemokines that bind to CCR5 (RANTES, MIP-1α, MIP-1β), and that therefore inhibit virus that binds to that receptor (i.e., R5 HIV) and yet-to-be fully identified factors that inhibit virus that binds to CXCR4 (i.e., X-4 HIV). These factors are produced by T cell, macrophages, and by other cells. We hypothesize that when these factors are produced and/or accumulated at sufficient levels, they can confer protection from infection or from disease progression. Production of factors might protect cells susceptible to HIV, or might self-protect cells CD4 T cells. In the mucosa, existing levels of these factors might prevent HIV infection. The strains of HIV that are involved in primary transmission use CCR5 to enter cells, high levels of CCR5 chemokines could afford effective protection by inhibiting entry of the virus. Anti-X4 factors could play a similar role both in mucosae and in the periphery, inhibiting virus at steps to be elucidated. Other factors that are expressed by mucosal epithelial cells, such as defensins, could also protect from infection, due to their ability to block both free virus and intracellular viral replication. Of interest, some beta-defensins have been shown to decrease expression of CXCR4, which could help explain preferential transmission of R5 HIV in primary infection.|