TY - JOUR
T1 - Adaptation of an R5 simian-human immunodeficiency virus encoding an HIV clade a envelope with or without ablation of adaptive host immunity
T2 - Differential selection of viral mutants
AU - Zhou, Mingkui
AU - Humbert, Michael
AU - Mukhtar, Muhammad M.
AU - Scinto, Hanna B.
AU - Vyas, Hemant K.
AU - Lakhashe, Samir K.
AU - Byrareddy, Siddappa N.
AU - Maurer, Gregor
AU - Thorat, Swati
AU - Owuor, Joshua
AU - Lai, Zhao
AU - Chen, Yidong
AU - Griffiths, Anthony
AU - Chenine, Agnès Laurence
AU - Gumber, Sanjeev
AU - Villinger, François
AU - Montefiori, David
AU - Ruprecht, Ruth M.
N1 - Funding Information:
This work was supported in part by NIH grants R37 AI034266, R01 AI100703, and P01 AI048240 to Ruth M. Ruprecht, NIH/NCI P30CA54174 to Yidong Chen and Zhao Lai, and NIH/NCATS 8UL1TR000149 (CTSA) to Yidong Chen. This research was also supported in part by the Genome Sequencing Facility of the Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, which provided deep sequencing of SHIVs and bioinformatics services and is supported by NIH Shared Instrument S10 grant 1S10OD021805-01 and CPRIT Core Facility Award RP160732. Base grants P51 OD011132 and P51 OD011133 provided support to the YNPRC and to the Southwest National Primate Research Center, respectively.
Funding Information:
We thank Francine McCutchan (U.S. Military HIV Research Program, Silver Spring, MD, and Henry M. Jackson Foundation, Rockville, MD) for the gift of HIV KNH1144 and Christina Ochsenbauer (University of Alabama, Birmingham) for the gift of pNL-LucR.T2A. We thank Ruijiang Song, Barbara Bachler, and Hung-I. Chen for their support with assays. We also thank Girish Hemashettar and Helena Ong for technical support and Juan Esquivel for assistance in manuscript preparation. We have no competing interest. This work was supported in part by NIH grants R37 AI034266, R01 AI100703, and P01 AI048240 to Ruth M. Ruprecht, NIH/NCI P30CA54174 to Yidong Chen and Zhao Lai, and NIH/NCATS 8UL1TR000149 (CTSA) to Yidong Chen. This research was also supported in part by the Genome Sequencing Facility of the Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, which provided deep sequencing of SHIVs and bioinformatics services and is supported by NIH Shared Instrument S10 grant 1S10OD021805-01 and CPRIT Core Facility Award RP160732. Base grants P51 OD011132 and P51 OD011133 provided support to the YNPRC and to the Southwest National Primate Research Center, respectively.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Simian-human immunodeficiency virus (SHIV) infection in rhesus macaques (RMs) resembles human immunodeficiency virus type 1 (HIV-1) infection in humans and serves as a tool to evaluate candidate AIDS vaccines. HIV-1 clade A (HIV-A) predominates in parts of Africa. We constructed an R5 clade A SHIV (SHIV-A; strain SHIV-KNH1144) carrying env from a Kenyan HIV-A. SHIV-A underwent rapid serial passage through six RMs. To allow unbridled replication without adaptive immunity, we simultaneously ablated CD8+ and B cells with cytotoxic monoclonal antibodies in the next RM, resulting in extremely high viremia and CD4+ T-cell loss. Infected blood was then transferred into two non-immune-depleted RMs, where progeny SHIV-A showed increased replicative capacity and caused AIDS. We reisolated SHIV-KNH1144p4, which was replication competent in peripheral blood mononuclear cells (PBMC) of all RMs tested. Next-generation sequencing of early- and late-passage SHIV-A strains identified mutations that arose due to “fitness” virus optimization in the former and mutations exhibiting signatures typical for adaptive host immunity in the latter. “Fitness” mutations are best described as mutations that allow for better fit of the HIV-A Env with SIV-derived virion building blocks or host proteins and mutations in noncoding regions that accelerate virus replication, all of which result in the outgrowth of virus variants in the absence of adaptive T-cell and antibody-mediated host immunity. IMPORTANCE In this study, we constructed a simian-human immunodeficiency virus carrying an R5 Kenyan HIV-1 clade A env (SHIV-A). To bypass host immunity, SHIV-A was rapidly passaged in naive macaques or animals depleted of both CD8+ and B cells. Next-generation sequencing identified different mutations that resulted from optimization of viral replicative fitness either in the absence of adaptive immunity or due to pressure from adaptive immune responses.
AB - Simian-human immunodeficiency virus (SHIV) infection in rhesus macaques (RMs) resembles human immunodeficiency virus type 1 (HIV-1) infection in humans and serves as a tool to evaluate candidate AIDS vaccines. HIV-1 clade A (HIV-A) predominates in parts of Africa. We constructed an R5 clade A SHIV (SHIV-A; strain SHIV-KNH1144) carrying env from a Kenyan HIV-A. SHIV-A underwent rapid serial passage through six RMs. To allow unbridled replication without adaptive immunity, we simultaneously ablated CD8+ and B cells with cytotoxic monoclonal antibodies in the next RM, resulting in extremely high viremia and CD4+ T-cell loss. Infected blood was then transferred into two non-immune-depleted RMs, where progeny SHIV-A showed increased replicative capacity and caused AIDS. We reisolated SHIV-KNH1144p4, which was replication competent in peripheral blood mononuclear cells (PBMC) of all RMs tested. Next-generation sequencing of early- and late-passage SHIV-A strains identified mutations that arose due to “fitness” virus optimization in the former and mutations exhibiting signatures typical for adaptive host immunity in the latter. “Fitness” mutations are best described as mutations that allow for better fit of the HIV-A Env with SIV-derived virion building blocks or host proteins and mutations in noncoding regions that accelerate virus replication, all of which result in the outgrowth of virus variants in the absence of adaptive T-cell and antibody-mediated host immunity. IMPORTANCE In this study, we constructed a simian-human immunodeficiency virus carrying an R5 Kenyan HIV-1 clade A env (SHIV-A). To bypass host immunity, SHIV-A was rapidly passaged in naive macaques or animals depleted of both CD8+ and B cells. Next-generation sequencing identified different mutations that resulted from optimization of viral replicative fitness either in the absence of adaptive immunity or due to pressure from adaptive immune responses.
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U2 - 10.1128/JVI.02267-18
DO - 10.1128/JVI.02267-18
M3 - Article
C2 - 30760566
AN - SCOPUS:85065022244
VL - 93
JO - Journal of Virology
JF - Journal of Virology
SN - 0022-538X
IS - 9
M1 - e02267-18
ER -