Autor(es): Pal Pankaj, Fox Julie M, Hawman David W, Huang Yan-Jang S, Messaoudi Ilhem, Kreklywich Craig, Denton Michael, Legasse Alfred W, Smith Patricia P, Johnson Syd, Axthelm Michael K, Vanlandingham Dana L, Streblow Daniel N, Higgs Stephen, Morrison Thomas E, Diamond Michael S

Resumo: Chikungunya virus (CHIKV) is a reemerging mosquito-transmitted alphavirus that causes epidemics of debilitating polyarthritis in humans. A prior study identified two anti-CHIKV monoclonal antibodies ([MAbs] CHK-152 - CHK-166) against the E2 - E1 structural proteins, which had therapeutic efficacy in immunocompetent - immunocompromised mice. Combination MAb therapy was required as administration of a single MAb resulted in the rapid selection of neutralization escape variants - treatment failure in mice. Here, we initially evaluated the efficacy of combination MAb therapy in a nonhuman primate model of CHIKV infection. Treatment of rhesus macaques with CHK-152 - CHK-166 reduced viral spread - infection in distant tissue sites - also neutralized reservoirs of infectious virus. Escape viruses were not detected in the residual viral RNA present in tissues - organs of rhesus macaques. To evaluate the possible significance of MAb resistance, we engineered neutralization escape variant viruses (E1-K61T, E2-D59N, - the double mutant E1-K61T E2-D59N) that conferred resistance to CHK-152 - CHK-166 - tested them for fitness in mosquito cells, mammalian cells, mice, - Aedes albopictus mosquitoes. In both cell culture - mosquitoes, the mutant viruses grew equivalently - did not revert to wild-type (WT) sequence. All escape variants showed evidence of mild clinical attenuation, with decreased musculoskeletal disease at early times after infection in WT mice - a prolonged survival time in immunocompromised Ifnar1(-/-) mice. Unexpectedly, this was not associated with decreased infectivity, - consensus sequencing from tissues revealed no evidence of reversion or compensatory mutations. Competition studies with CHIKV WT also revealed no fitness compromise of the double mutant (E1-K61T E2-D59N) neutralization escape variant in WT mice. Collectively, our study suggests that neutralization escape viruses selected during combination MAb therapy with CHK-152 plus CHK-166 retain fitness, cause less severe clinical disease, - likely would not be purified during the enzootic cycle. Chikungunya virus (CHIKV) causes explosive epidemics of acute - chronic arthritis in humans in Africa, the Indian subcontinent, - Southeast Asia - recently has spread to the New World. As there are no approved vaccines or therapies for human use, the possibility of CHIKV-induced debilitating disease is high in many parts of the world. To this end, our laboratory recently generated a combination monoclonal antibody therapy that aborted lethal - arthritogenic disease in wild-type - immunocompromised mice when administered as a single dose several days after infection. In this study, we show the efficacy of the antibody combination in nonhuman primates - also evaluate the significance of possible neutralization escape mutations in mosquito - mammalian cells, mice, - Aedes albopictus vector mosquitoes. Our experiments show that escape viruses from combination antibody therapy cause less severe CHIKV clinical disease, retain fitness, - likely would not be purified by mosquito vectors.

Imprenta: Journal of Virology, v. 88, n. 15, p. 8213-8226, 2014

Identificador do objeto digital: 10.1128/JVI.01032-14

Descritores: Chikungunya virus - Cell ; Chikungunya virus - Cytopathology ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Proteins ; Chikungunya virus - RNA ; Chikungunya virus - Antibodies ; Chikungunya virus - Viral infections ; Chikungunya virus - Molecular methods ; Chikungunya Virus - Virus ; Chikungunya virus - Vaccine ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Epidemic ; Chikungunya virus - Immunology ; Chikungunya virus - Public health

Data de publicação: 2014

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