Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes

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

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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 and CHK-166) against the E2 and E1 structural proteins, which had therapeutic efficacy in immunocompetent and immunocompromised mice. Combination MAb therapy was required as administration of a single MAb resulted in the rapid selection of neutralization escape variants and 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 and CHK-166 reduced viral spread and infection in distant tissue sites and also neutralized reservoirs of infectious virus. Escape viruses were not detected in the residual viral RNA present in tissues and organs of rhesus macaques. To evaluate the possible significance of MAb resistance, we engineered neutralization escape variant viruses (E1-K61T, E2- D59N, and the double mutant E1-K61T E2-D59N) that conferred resistance to CHK-152 and CHK-166 and tested them for fitness in mosquito cells, mammalian cells, mice, and Aedes albopictus mosquitoes. In both cell culture and mosquitoes, the mutant viruses grew equivalently and 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 and a prolonged survival time in immunocompromised Ifnar1 -/- mice. Unexpectedly, this was not associated with decreased infectivity, and 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, and likely would not be purified during the enzootic cycle.

Original languageEnglish (US)
Pages (from-to)8213-8226
Number of pages14
JournalJournal of Virology
Volume88
Issue number15
DOIs
StatePublished - 2014

Fingerprint

Chikungunya virus
Culicidae
monoclonal antibodies
Monoclonal Antibodies
neutralization
therapeutics
Viruses
mice
viruses
Macaca mulatta
mutants
Therapeutics
infection
Musculoskeletal Diseases
musculoskeletal diseases
Alphavirus
Aedes albopictus
Aedes
structural proteins
Viral RNA

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Pal, P., Fox, J. M., Hawman, D. W., Huang, Y. J. S., Messaoudi, I., Kreklywich, C., ... Diamond, M. S. (2014). Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes. Journal of Virology, 88(15), 8213-8226. https://doi.org/10.1128/JVI.01032-14

Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes. / 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; Vanlandingham, Dana L.; Streblow, Daniel; Higgs, Stephen; Morrison, Thomas E.; Diamond, Michael S.

In: Journal of Virology, Vol. 88, No. 15, 2014, p. 8213-8226.

Research output: Contribution to journalArticle

Pal, P, Fox, JM, Hawman, DW, Huang, YJS, Messaoudi, I, Kreklywich, C, Denton, M, Legasse, AW, Smith, PP, Johnson, S, Axthelm, M, Vanlandingham, DL, Streblow, D, Higgs, S, Morrison, TE & Diamond, MS 2014, 'Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes', Journal of Virology, vol. 88, no. 15, pp. 8213-8226. https://doi.org/10.1128/JVI.01032-14
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 ; Vanlandingham, Dana L. ; Streblow, Daniel ; Higgs, Stephen ; Morrison, Thomas E. ; Diamond, Michael S. / Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes. In: Journal of Virology. 2014 ; Vol. 88, No. 15. pp. 8213-8226.
@article{0316664092d4417db849e65a3f8af0e0,
title = "Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes",
abstract = "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 and CHK-166) against the E2 and E1 structural proteins, which had therapeutic efficacy in immunocompetent and immunocompromised mice. Combination MAb therapy was required as administration of a single MAb resulted in the rapid selection of neutralization escape variants and 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 and CHK-166 reduced viral spread and infection in distant tissue sites and also neutralized reservoirs of infectious virus. Escape viruses were not detected in the residual viral RNA present in tissues and organs of rhesus macaques. To evaluate the possible significance of MAb resistance, we engineered neutralization escape variant viruses (E1-K61T, E2- D59N, and the double mutant E1-K61T E2-D59N) that conferred resistance to CHK-152 and CHK-166 and tested them for fitness in mosquito cells, mammalian cells, mice, and Aedes albopictus mosquitoes. In both cell culture and mosquitoes, the mutant viruses grew equivalently and 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 and a prolonged survival time in immunocompromised Ifnar1 -/- mice. Unexpectedly, this was not associated with decreased infectivity, and 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, and likely would not be purified during the enzootic cycle.",
author = "Pankaj Pal and Fox, {Julie M.} and Hawman, {David W.} and Huang, {Yan Jang S} and Ilhem Messaoudi and Craig Kreklywich and Michael Denton and Legasse, {Alfred W.} and Smith, {Patricia P.} and Syd Johnson and Michael Axthelm and Vanlandingham, {Dana L.} and Daniel Streblow and Stephen Higgs and Morrison, {Thomas E.} and Diamond, {Michael S.}",
year = "2014",
doi = "10.1128/JVI.01032-14",
language = "English (US)",
volume = "88",
pages = "8213--8226",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "15",

}

TY - JOUR

T1 - Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes

AU - Pal, Pankaj

AU - Fox, Julie M.

AU - Hawman, David W.

AU - Huang, Yan Jang S

AU - Messaoudi, Ilhem

AU - Kreklywich, Craig

AU - Denton, Michael

AU - Legasse, Alfred W.

AU - Smith, Patricia P.

AU - Johnson, Syd

AU - Axthelm, Michael

AU - Vanlandingham, Dana L.

AU - Streblow, Daniel

AU - Higgs, Stephen

AU - Morrison, Thomas E.

AU - Diamond, Michael S.

PY - 2014

Y1 - 2014

N2 - 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 and CHK-166) against the E2 and E1 structural proteins, which had therapeutic efficacy in immunocompetent and immunocompromised mice. Combination MAb therapy was required as administration of a single MAb resulted in the rapid selection of neutralization escape variants and 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 and CHK-166 reduced viral spread and infection in distant tissue sites and also neutralized reservoirs of infectious virus. Escape viruses were not detected in the residual viral RNA present in tissues and organs of rhesus macaques. To evaluate the possible significance of MAb resistance, we engineered neutralization escape variant viruses (E1-K61T, E2- D59N, and the double mutant E1-K61T E2-D59N) that conferred resistance to CHK-152 and CHK-166 and tested them for fitness in mosquito cells, mammalian cells, mice, and Aedes albopictus mosquitoes. In both cell culture and mosquitoes, the mutant viruses grew equivalently and 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 and a prolonged survival time in immunocompromised Ifnar1 -/- mice. Unexpectedly, this was not associated with decreased infectivity, and 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, and likely would not be purified during the enzootic cycle.

AB - 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 and CHK-166) against the E2 and E1 structural proteins, which had therapeutic efficacy in immunocompetent and immunocompromised mice. Combination MAb therapy was required as administration of a single MAb resulted in the rapid selection of neutralization escape variants and 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 and CHK-166 reduced viral spread and infection in distant tissue sites and also neutralized reservoirs of infectious virus. Escape viruses were not detected in the residual viral RNA present in tissues and organs of rhesus macaques. To evaluate the possible significance of MAb resistance, we engineered neutralization escape variant viruses (E1-K61T, E2- D59N, and the double mutant E1-K61T E2-D59N) that conferred resistance to CHK-152 and CHK-166 and tested them for fitness in mosquito cells, mammalian cells, mice, and Aedes albopictus mosquitoes. In both cell culture and mosquitoes, the mutant viruses grew equivalently and 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 and a prolonged survival time in immunocompromised Ifnar1 -/- mice. Unexpectedly, this was not associated with decreased infectivity, and 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, and likely would not be purified during the enzootic cycle.

UR - http://www.scopus.com/inward/record.url?scp=84903890722&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903890722&partnerID=8YFLogxK

U2 - 10.1128/JVI.01032-14

DO - 10.1128/JVI.01032-14

M3 - Article

C2 - 24829346

AN - SCOPUS:84903890722

VL - 88

SP - 8213

EP - 8226

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 15

ER -