Jennifer Govero, Prabagaran Esakky, Suzanne M. Scheaffer, Estefania Fernandez, Andrea Drury, Derek J. Platt, Matthew J. Gorman, Justin M. Richner, Elizabeth A. Caine, Vanessa Salazar, Kelle H. Moley, Michael S. Diamond, Govero, Jennifer, Esakky, Prabagaran, Scheaffer, Suzanne M, Fernandez, Estefania, Drury, Andrea, Platt, Derek J, Gorman, Matthew J, Richner, Justin M, Caine, Elizabeth A, Salazar, Vanessa, Moley, Kelle H, Diamond, Michael S

Zika virus (ZIKV) infection of pregnant women can cause congenital malformations including microcephaly, which has focused global attention on this emerging pathogen(1). In addition to transmission by mosquitoes, ZIKV can be detected in the seminal fluid of affected males for extended periods of time and transmitted sexually(2). Here, using a mouse-adapted African ZIKV strain (Dakar 41519), we evaluated the consequences of infection in the male reproductive tract of mice. We observed persistence of ZIKV, but not the closely related Dengue virus (DENV), in the testis and epididymis of male mice, and this was associated with tissue injury that caused diminished testosterone and inhibin B levels, and oligospermia. ZIKV preferentially infected spermatogonia, primary spermatocytes, and Sertoli cells in the testis, resulting in cell death and destruction of the seminiferous tubules. Less damage was observed with a contemporary Asian ZIKV strain (H/PF/2013), in part because this virus replicates less efficiently in mice. The extent to which these observations in mice translate to humans remains unclear, but longitudinal studies of sperm function and viability in ZIKV-infected humans seem warranted.

Gopal Sapparapu, Estefania Fernandez, Nurgun Kose, Bin Cao, Julie M. Fox, Robin G. Bombardi, Haiyan Zhao, Christopher A. Nelson, Aubrey L. Bryan, Trevor Barnes, Edgar Davidson, Indira U. Mysorekar, Daved H. Fremont, Benjamin J. Doranz, Michael S. Diamond, James E. Crowe, Sapparapu, Gopal, Fernandez, Estefania, Kose, Nurgun, Cao, Bin, Fox, Julie M, Bombardi, Robin G, Zhao, Haiyan, Nelson, Christopher A, Bryan, Aubrey L, Barnes, Trevor, Davidson, Edgar, Mysorekar, Indira U, Fremont, Daved H, Doranz, Benjamin J, Diamond, Michael S, Crowe, James E

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that can cause severe disease, including congenital birth defects during pregnancy(1). To develop candidate therapeutic agents against ZIKV, we isolated a panel of human monoclonal antibodies (mAbs) from subjects with prior ZIKV infection. A subset of mAbs recognized diverse epitopes on the envelope (E) protein and exhibited potently neutralizing activity. One of the most inhibitory mAbs, ZIKV-117, broadly neutralized infection of ZIKV strains corresponding to African, Asian, and American lineages. Epitope mapping studies revealed that ZIKV-117 recognized a unique quaternary epitope on the E protein dimer-dimer interface. We evaluated the therapeutic efficacy of ZIKV-117 in pregnant and non-pregnant mice. mAb treatment markedly reduced tissue pathology, placental and fetal infection, and mortality in mice. Thus, neutralizing human mAbs can protect against maternal-fetal transmission, infection and disease, and reveal important determinants for structure-based rational vaccine design efforts.