Adaptation of an R5 simian-human immunodeficiency virus encoding an HIV clade a envelope with or without ablation of adaptive host immunity

Differential selection of viral mutants

Mingkui Zhou, Michael Humbert, Muhammad M. Mukhtar, Hanna B. Scinto, Hemant K. Vyas, Samir K. Lakhashe, Siddappa N. Byrareddy, Gregor Maurer, Swati Thorat, Joshua Owuor, Zhao Lai, Yidong Chen, Anthony Griffiths, Agnès Laurence Chenine, Sanjeev Gumber, François Villinger, David Montefiori, Ruth M. Ruprecht

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere02267-18
JournalJournal of Virology
Volume93
Issue number9
DOIs
StatePublished - May 1 2019

Fingerprint

Simian Immunodeficiency Virus
Human immunodeficiency virus
Adaptive Immunity
immunity
HIV
mutants
Macaca mulatta
Human immunodeficiency virus 1
mutation
Mutation
HIV-1
B-lymphocytes
Virus Diseases
T-lymphocytes
Immunity
B-Lymphocytes
viruses
Viruses
viremia
Serial Passage

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Adaptation of an R5 simian-human immunodeficiency virus encoding an HIV clade a envelope with or without ablation of adaptive host immunity : Differential selection of viral mutants. / Zhou, Mingkui; Humbert, Michael; Mukhtar, Muhammad M.; Scinto, Hanna B.; Vyas, Hemant K.; Lakhashe, Samir K.; Byrareddy, Siddappa N.; Maurer, Gregor; Thorat, Swati; Owuor, Joshua; Lai, Zhao; Chen, Yidong; Griffiths, Anthony; Chenine, Agnès Laurence; Gumber, Sanjeev; Villinger, François; Montefiori, David; Ruprecht, Ruth M.

In: Journal of Virology, Vol. 93, No. 9, e02267-18, 01.05.2019.

Research output: Contribution to journalArticle

Zhou, M, Humbert, M, Mukhtar, MM, Scinto, HB, Vyas, HK, Lakhashe, SK, Byrareddy, SN, Maurer, G, Thorat, S, Owuor, J, Lai, Z, Chen, Y, Griffiths, A, Chenine, AL, Gumber, S, Villinger, F, Montefiori, D & Ruprecht, RM 2019, 'Adaptation of an R5 simian-human immunodeficiency virus encoding an HIV clade a envelope with or without ablation of adaptive host immunity: Differential selection of viral mutants', Journal of Virology, vol. 93, no. 9, e02267-18. https://doi.org/10.1128/JVI.02267-18
Zhou, Mingkui ; Humbert, Michael ; Mukhtar, Muhammad M. ; Scinto, Hanna B. ; Vyas, Hemant K. ; Lakhashe, Samir K. ; Byrareddy, Siddappa N. ; Maurer, Gregor ; Thorat, Swati ; Owuor, Joshua ; Lai, Zhao ; Chen, Yidong ; Griffiths, Anthony ; Chenine, Agnès Laurence ; Gumber, Sanjeev ; Villinger, François ; Montefiori, David ; Ruprecht, Ruth M. / Adaptation of an R5 simian-human immunodeficiency virus encoding an HIV clade a envelope with or without ablation of adaptive host immunity : Differential selection of viral mutants. In: Journal of Virology. 2019 ; Vol. 93, No. 9.
@article{f709f196faa94c2db39754f14d2ea10b,
title = "Adaptation of an R5 simian-human immunodeficiency virus encoding an HIV clade a envelope with or without ablation of adaptive host immunity: Differential selection of viral mutants",
abstract = "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.",
author = "Mingkui Zhou and Michael Humbert and Mukhtar, {Muhammad M.} and Scinto, {Hanna B.} and Vyas, {Hemant K.} and Lakhashe, {Samir K.} and Byrareddy, {Siddappa N.} and Gregor Maurer and Swati Thorat and Joshua Owuor and Zhao Lai and Yidong Chen and Anthony Griffiths and Chenine, {Agn{\`e}s Laurence} and Sanjeev Gumber and Fran{\cc}ois Villinger and David Montefiori and Ruprecht, {Ruth M.}",
year = "2019",
month = "5",
day = "1",
doi = "10.1128/JVI.02267-18",
language = "English (US)",
volume = "93",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "9",

}

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85065022244&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065022244&partnerID=8YFLogxK

U2 - 10.1128/JVI.02267-18

DO - 10.1128/JVI.02267-18

M3 - Article

VL - 93

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 9

M1 - e02267-18

ER -