Surfactant Protein D Inhibits HIV-1 Infection of Target Cells via Interference with gp120-CD4 Interaction and Modulates Pro-Inflammatory Cytokine Production

Abstract

Surfactant Protein SP-D, a member of the collectin family, is a pattern recognition protein, secreted by mucosal epithelial cells and has an important role in innate immunity against various pathogens. In this study, we confirm that native human SP-D and a recombinant fragment of human SP-D (rhSP-D) bind to gp120 of HIV-1 and significantly inhibit viral replication in vitro in a calcium and dose-dependent manner. We show, for the first time, that SP-D and rhSP-D act as potent inhibitors of HIV-1 entry in to target cells and block the interaction between CD4 and gp120 in a dose-dependent manner. The rhSP-D-mediated inhibition of viral replication was examined using three clinical isolates of HIV-1 and three target cells: Jurkat T cells, U937 monocytic cells and PBMCs. HIV-1 induced cytokine storm in the three target cells was significantly suppressed by rhSP-D. Phosphorylation of key kinases p38, Erk1/2 and AKT, which contribute to HIV-1 induced immune activation, was significantly reduced in vitro in the presence of rhSP-D. Notably, anti-HIV-1 activity of rhSP-D was retained in the presence of biological fluids such as cervico-vaginal lavage and seminal plasma. Our study illustrates the multi-faceted role of human SP-D against HIV-1 and potential of rhSP-D for immunotherapy to inhibit viral entry and immune activation in acute HIV infection.

Pulmonary Innate Immune Dysfunction in Human Immunodeficiency Virus

“…Similar effects have been seen with SP-D, which has direct antiviral effects via binding of HIV envelope glycoprotein 120 and inhibition of viral replication (5). It prevents viral entry into target cells (6), but also facilitates transfer of virus from DCs to T cells (7). A recent pilot study showed evidence of reduced serum SP-D levels with ART (8), pointing to a need for further investigation on the effects of ART on pulmonary homeostasis.…”

Antiviral activity of recombinant porcine surfactant protein A against porcine reproductive and respiratory syndrome virus in vitro

“…Researchers have confirmed that lectins inhibit virus entry [27,29,34,35], and each step of the viral entry pathway is a potential target for antiviral agents. We conducted virus attachment and penetration assays to assess whether RpSP-A also interfered with PRRSV entry.…”

“…However, studies on the antiviral activity of SP-D, which has a primary structure that resembles that of SP-A, have been reported more frequently. SP-D had an inhibitory effect on HIV infection through inhibition of viral entry by affecting gp120-CD4 interactions [29]. Marine and colleagues demonstrated that recombinant porcine SP-D prevented the attachment of human seasonal H 1 N 1 and H 3 N 2 virus to receptors on epithelial cells of the upper respiratory tract [?…”

Collectins: Innate Immune Pattern Recognition Molecules

“…Yet, in dendritic cells (DC), SP-A increases HIV uptake, through enhanced binding to gp120 and facilitates transfer of HIV from DC to CD4 + T cells (Gaiha et al 2008). SP-D is also able to bind to HIV gp120 and inhibit viral infectivity (Meschi et al 2005), whilst rfhSP-D was also able to bind to gp120 and prevent infection of Jurkat T cells, U937 monocytic cells and PBMC, and significantly suppress the HIV-1 induced cytokine storm in these cells (Pandit et al 2014). Interestingly, a direct protein-protein interaction between rfhSP-D and DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin) modulates the capture of HIV-1 and its transfer to CD4 + T cells, revealing a novel and distinct anti-viral mechanism against HIV-1 by SP-D (Dodagatta-Marri et al 2017).…”