Potent and broad neutralizing activity of a single chain antibody fragment against cell-free and cell-associated HIV-1.
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Several human monoclonal antibodies (hmAbs) exhibit relatively potent and broad neutralizing activity against HIV-1, but there has not been much success in using them as potential therapeutics. We have previously hypothesized and demonstrated that small engineered antibodies can target highly conserved epitopes that are not accessible by full-size antibodies. However, their potency has not been comparatively evaluated with known HIV-1-neutralizing hmAbs against large panels of primary isolates. We report here the inhibitory activity of an engineered single chain antibody fragment (scFv), m9, against several panels of primary HIV-1 isolates from group M (clades A-G) using cell-free and cell-associated virus in cell line-based assays. M9 was much more potent than scFv 17b, and more potent than or comparable to the best-characterized broadly neutralizing hmAbs IgG(1) b12, 2G12, 2F5 and 4E10. It also inhibited cell-to-cell transmission of HIV-1 with higher potency than enfuvirtide (T-20, Fuzeon). M9 competed with a sulfated CCR5 N-terminal peptide for binding to gp120-CD4 complex, suggesting an overlapping epitope with the coreceptor binding site. M9 did not react with phosphatidylserine (PS) and cardiolipin (CL), nor did it react with a panel of autoantigens in an antinuclear autoantibody (ANA) assay. We further found that escape mutants resistant to m9 did not emerge in an immune selection assay. These results suggest that m9 is a novel anti-HIV-1 candidate with potential therapeutic or prophylactic properties, and its epitope is a new target for drug or vaccine development.
Dose-Response Relationship, Immunologic
HIV Envelope Protein gp120
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McLellan, JS; Pancera, M; Carrico, C; Gorman, J; Julien, J-P; Khayat, R; Louder, R; Pejchal, R; Sastry, M; Dai, K; O'Dell, S; Patel, N; Shahzad-ul-Hussan, S; Yang, Y; Zhang, B; Zhou, T; Zhu, J; Boyington, JC; Chuang, G-Y; Diwanji, D; Georgiev, I; Kwon, YD; Lee, D; Louder, MK; Moquin, S; Schmidt, SD; Yang, Z-Y; Bonsignori, Mattia; Crump, John Andrew; Kapiga, SH; Sam, NE; Haynes, BF; Burton, DR; Koff, WC; Walker, LM; Phogat, S; Wyatt, R; Orwenyo, J; Wang, L-X; Arthos, J; Bewley, CA; Mascola, JR; Nabel, GJ; Schief, WR; Ward, AB; Wilson, IA; Kwong, PD (Nature, 2011-11-23)Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence ...
Association of HIV-1 Envelope-Specific Breast Milk IgA Responses with Reduced Risk of Postnatal Mother-to-Child Transmission of HIV-1. Pollara, J; McGuire, E; Fouda, GG; Rountree, W; Eudailey, J; Overman, RG; Seaton, KE; Deal, A; Edwards, RW; Tegha, G; Kamwendo, D; Kumwenda, J; Nelson, JA; Liao, HX; Brinkley, C; Denny, TN; Ochsenbauer, C; Ellington, S; King, CC; Jamieson, DJ; van der Horst, C; Kourtis, AP; Tomaras, GD; Ferrari, G; Permar, SR (J Virol, 2015-10)UNLABELLED: Infants born to HIV-1-infected mothers in resource-limited areas where replacement feeding is unsafe and impractical are repeatedly exposed to HIV-1 throughout breastfeeding. Despite this, the majority of infants ...
HIV-specific functional antibody responses in breast milk mirror those in plasma and are primarily mediated by IgG antibodies. Fouda, GG; Yates, NL; Pollara, Justin Joseph; Shen, X; Overman, GR; Mahlokozera, T; Wilks, AB; Kang, HH; Salazar-Gonzalez, JF; Salazar, MG; Kalilani, L; Meshnick, SR; Hahn, BH; Shaw, GM; Lovingood, RV; Denny, Thomas Norton; Haynes, B; Letvin, NL; Ferrari, Guido; Montefiori, DC; Tomaras, GD; Permar, SR; Center for HIV/AIDS Vaccine Immunology (J Virol, 2011-09)Despite months of mucosal virus exposure, the majority of breastfed infants born to HIV-infected mothers do not become infected, raising the possibility that immune factors in milk inhibit mucosal transmission of HIV. HIV ...