HIV-1 neutralization profile and plant-based recombinant expression of actinohivin, an Env Glycan-specific lectin devoid of T-cell mitogenic activity
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The development of a topical microbicide blocking the sexual transmission of HIV-1 is urgently needed to control the global HIV/AIDS pandemic. The actinomycete-derived lectin actinohivin (AH) is highly specific to a cluster of high-mannose-type glycans uniquely found on the viral envelope (Env). Here, we evaluated AH's candidacy toward a microbicide in terms of in vitro anti-HIV-1 activity, potential side effects, and recombinant producibility. Two validated assay systems based on human peripheral blood mononuclear cell (hPBMC) infection with primary isolates and TZM-bl cell infection with Env-pseudotyped viruses were employed to characterize AH's anti-HIV-1 activity. In hPMBCs, AH exhibited nanomolar neutralizing activity against primary viruses with diverse cellular tropisms, but did not cause mitogenicity or cytotoxicity that are often associated with other anti-HIV lectins. In the TZM-bl-based assay, AH showed broad anti-HIV-1 activity against clinically-relevant, mucosally transmitting strains of clades B and C. By contrast, clade A viruses showed strong resistance to AH. Correlation analysis suggested that HIV-1′s AH susceptibility is significantly linked to the N-glycans at the Env C2 and V4 regions. For recombinant (r)AH expression, we evaluated a tobacco mosaic virus-based system in Nicotiana benthamiana plants as a means to facilitate molecular engineering and cost-effective mass production. Biochemical analysis and an Env-mediated syncytium formation assay demonstrated high-level expression of functional rAH within six days. Taken together, our study revealed AH's cross-clade anti-HIV-1 activity, apparent lack of side effects common to lectins, and robust producibility using plant biotechnology. These findings justify further efforts to develop rAH toward a candidate HIV-1 microbicide. © 2010 Matoba et al.
Published Version (Please cite this version)10.1371/journal.pone.0011143
Publication InfoMatoba, Nobuyuki; Husk, Adam S; Barnett, Brian W; Pickel, Michelle M; Arntzen, Charles J; Montefiori, David C; ... Tanaka, Haruo (2010). HIV-1 neutralization profile and plant-based recombinant expression of actinohivin, an Env Glycan-specific lectin devoid of T-cell mitogenic activity. PLoS ONE, 5(6). pp. e11143. 10.1371/journal.pone.0011143. Retrieved from https://hdl.handle.net/10161/4548.
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Professor of Surgery
Dr. Montefiori is Professor and Director of the Laboratory for AIDS Vaccine Research and Development in the Department of Surgery, Division of Surgical Sciences, Duke University Medical Center. His major research interests are viral immunology and AIDS vaccine development, with a special emphasis on neutralizing antibodies. One of his highest priorities is to identify immunogens that generate broadly cross-reactive neutralizing antibodies for inclusion in HIV vaccines. Many aspects of the