Journal Article

N-terminal Slit2 inhibits HIV-1 replication by regulating the actin cytoskeleton

Anand, Appakkudal R, Robinson, Lisa A, Ganju, Ramesh K, Nagaraja, Tirumuru, Zhao, Helong

2013

Overview

Background Slit2 is a ~ 200 kDa secreted glycoprotein that has been recently shown to regulate immune functions. However, not much is known about its role in HIV (human immunodeficiency virus)-1 pathogenesis. Results In the present study, we have shown that the N-terminal fragment of Slit2 (Slit2N) (~120 kDa) inhibits replication of both CXCR4 and CCR5-tropic HIV-1 viruses in T-cell lines and peripheral blood T-cells. Furthermore, we demonstrated inhibition of HIV-1 infection in resting CD4+ T-cells. In addition, we showed that Slit2N blocks cell-to-cell transmission of HIV-1. We have shown that Slit2N inhibits HIV-1 infection by blocking viral entry into T-cells. We also ruled out Slit2N-mediated inhibition of various other steps in the life cycle including binding, integration and viral transcription. Elucidation of the molecular mechanism revealed that Slit2N mediates its functional effects by binding to Robo1 receptor. Furthermore, we found that Slit2N inhibited Gp120-induced Robo1-actin association suggesting that Slit2N may inhibit cytoskeletal rearrangements facilitating HIV-1 entry. Studies into the mechanism of inhibition of HIV-1 revealed that Slit2N abrogated HIV-1 envelope-induced actin cytoskeletal dynamics in both T-cell lines and primary T-cells. We further showed that Slit2N specifically attenuated the HIV-1 envelope-induced signaling pathway consisting of Rac1, LIMK and cofilin that regulates actin polymerization. Conclusions Taken together, our results show that Slit2N inhibits HIV-1 replication through novel mechanisms involving modulation of cytoskeletal dynamics. Our study, thus, provides insights into the role of Slit2N in HIV-1 infection and underscores its potential in limiting viral replication in T-cells.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acquired immune deficiency syndrome / Actin / Actin Cytoskeleton - metabolism / AIDS / Antibodies / Biomedical and Life Sciences / Biomedicine / Cancer Research / CD4 antigen / CD4-Positive T-Lymphocytes - metabolism / CD4-Positive T-Lymphocytes - virology / Cell Line / Cells, Cultured / Cofilin / CXCR4 protein / Cytoskeleton / Disease transmission / Down-Regulation / Epidermal growth factor / Experiments / Flow cytometry / Glycoproteins / Health aspects / HIV (Viruses) / HIV Infections - metabolism / HIV Infections - virology / HIV-1 - genetics / HIV-1 - physiology / Human immunodeficiency virus 1 / Humans / Immune response / Immunodeficiency / Infection / Infectious Diseases / Integration / Intercellular Signaling Peptides and Proteins - chemistry / Intercellular Signaling Peptides and Proteins - genetics / Intercellular Signaling Peptides and Proteins - metabolism / Kinases / Life cycle / Lymphocytes T / Molecular modelling / Nerve Tissue Proteins - chemistry / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Peripheral blood / Polymerization / Protein Structure / Protein Structure, Tertiary / Proteins / rac1 GTP-Binding Protein - genetics / rac1 GTP-Binding Protein - metabolism / Rac1 protein / Replication / Signal Transduction / Studies / T cells / Transcription / Vaccine / Virology / Virus Internalization / Virus Replication