Rapid elimination of broadly neutralizing antibodies correlates with treatment failure in the acute phase of simian-human immunodeficiency virus infection

Yanling Wu, Jing Xue, Chunyu Wang, Wei Li, Lili Wang, Weizao Chen, Ponraj Prabakaran, Desheng Kong, Yujia Jin, Dan Hu, Yulu Wang, Cheng Lei, Diao Yu, Chao Tu, Ariola Bardhi, Igor Sidorov, Liying Ma, Harris Goldstein, Chuan Qin, Lu LuShibo Jiang, Dimiter S. Dimitrov, Tianlei Ying

Research output: Contribution to journalArticle

Abstract

Early human immunodeficiency virus type 1 (HIV-1) treatment during the acute period of infection can significantly limit the seeding of viral reservoirs and modify the course of disease. However, while a number of HIV-1 broadly neutralizing antibodies (bnAbs) have demonstrated remarkable efficacy as prophylaxis in macaques chronically infected with simian-human immunodeficiency virus (SHIV), intriguingly, their inhibitory effects were largely attenuated in the acute period of SHIV infection. To investigate the mechanism for the disparate performance of bnAbs in different periods of SHIV infection, we used LSEVh-LS-F, a bispecific bnAb targeting the CD4 binding site and CD4-induced epitopes, as a representative bnAb and assessed its potential therapeutic benefit in controlling virus replication in acutely or chronically SHIV-infected macaques. We found that a single infusion of LSEVh-LS-F resulted in rapid decline of plasma viral loads to undetectable levels without emergence of viral resistance in the chronically infected macaques. In contrast, the inhibitory effect was robust but transient in the acutely infected macaques, despite the fact that all macaques had comparable plasma viral loads initially. Infusing multiple doses of LSEVh-LS-F did not extend its inhibitory duration. Furthermore, the pharmacokinetics of the infused LSEVh-LS-F in the acutely SHIV-infected macaques significantly differed from that in the uninfected or chronically infected macaques. Host SHIV-specific immune responses may play a role in the viremia-dependent pharmacokinetics. Our results highlight the correlation between the fast clearance of infused bnAbs and the treatment failure in the acute period of SHIV infection and may have important implications for the therapeutic use of bnAbs to treat acute HIV infections. IMPORTANCE Currently, there is no bnAb-based monotherapy that has been reported to clear the virus in the acute SHIV infection period. Since early HIV treatment is considered critical to restricting the establishment of viral reservoirs, investigation into the mechanism for treatment failure in acutely infected macaques would be important for the therapeutic use of bnAbs and eventually towards the functional cure of HIV/AIDS. Here we report the comparative study of the therapeutic efficacy of a bnAb in acutely and chronically SHIV-infected macaques. This study revealed the correlation between the fast clearance of infused bnAbs and treatment failure during the acute period of infection.

Original languageEnglish (US)
Article numbere01077-19
JournalJournal of virology
Volume93
Issue number20
DOIs
StatePublished - Oct 1 2019

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Simian Immunodeficiency Virus
HIV infections
Virus Diseases
Neutralizing Antibodies
Treatment Failure
neutralizing antibodies
Macaca
HIV
Human immunodeficiency virus
therapeutics
viral load
Human immunodeficiency virus 1
pharmacokinetics
Therapeutic Uses
Viral Load
HIV-1
Pharmacokinetics
viremia
virus replication
disease course

Keywords

  • Acute SHIV infection
  • Broadly neutralizing antibodies
  • HIV-1

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Rapid elimination of broadly neutralizing antibodies correlates with treatment failure in the acute phase of simian-human immunodeficiency virus infection. / Wu, Yanling; Xue, Jing; Wang, Chunyu; Li, Wei; Wang, Lili; Chen, Weizao; Prabakaran, Ponraj; Kong, Desheng; Jin, Yujia; Hu, Dan; Wang, Yulu; Lei, Cheng; Yu, Diao; Tu, Chao; Bardhi, Ariola; Sidorov, Igor; Ma, Liying; Goldstein, Harris; Qin, Chuan; Lu, Lu; Jiang, Shibo; Dimitrov, Dimiter S.; Ying, Tianlei.

In: Journal of virology, Vol. 93, No. 20, e01077-19, 01.10.2019.

Research output: Contribution to journalArticle

Wu, Y, Xue, J, Wang, C, Li, W, Wang, L, Chen, W, Prabakaran, P, Kong, D, Jin, Y, Hu, D, Wang, Y, Lei, C, Yu, D, Tu, C, Bardhi, A, Sidorov, I, Ma, L, Goldstein, H, Qin, C, Lu, L, Jiang, S, Dimitrov, DS & Ying, T 2019, 'Rapid elimination of broadly neutralizing antibodies correlates with treatment failure in the acute phase of simian-human immunodeficiency virus infection', Journal of virology, vol. 93, no. 20, e01077-19. https://doi.org/10.1128/JVI.01077-19
Wu, Yanling ; Xue, Jing ; Wang, Chunyu ; Li, Wei ; Wang, Lili ; Chen, Weizao ; Prabakaran, Ponraj ; Kong, Desheng ; Jin, Yujia ; Hu, Dan ; Wang, Yulu ; Lei, Cheng ; Yu, Diao ; Tu, Chao ; Bardhi, Ariola ; Sidorov, Igor ; Ma, Liying ; Goldstein, Harris ; Qin, Chuan ; Lu, Lu ; Jiang, Shibo ; Dimitrov, Dimiter S. ; Ying, Tianlei. / Rapid elimination of broadly neutralizing antibodies correlates with treatment failure in the acute phase of simian-human immunodeficiency virus infection. In: Journal of virology. 2019 ; Vol. 93, No. 20.
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T1 - Rapid elimination of broadly neutralizing antibodies correlates with treatment failure in the acute phase of simian-human immunodeficiency virus infection

AU - Wu, Yanling

AU - Xue, Jing

AU - Wang, Chunyu

AU - Li, Wei

AU - Wang, Lili

AU - Chen, Weizao

AU - Prabakaran, Ponraj

AU - Kong, Desheng

AU - Jin, Yujia

AU - Hu, Dan

AU - Wang, Yulu

AU - Lei, Cheng

AU - Yu, Diao

AU - Tu, Chao

AU - Bardhi, Ariola

AU - Sidorov, Igor

AU - Ma, Liying

AU - Goldstein, Harris

AU - Qin, Chuan

AU - Lu, Lu

AU - Jiang, Shibo

AU - Dimitrov, Dimiter S.

AU - Ying, Tianlei

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Early human immunodeficiency virus type 1 (HIV-1) treatment during the acute period of infection can significantly limit the seeding of viral reservoirs and modify the course of disease. However, while a number of HIV-1 broadly neutralizing antibodies (bnAbs) have demonstrated remarkable efficacy as prophylaxis in macaques chronically infected with simian-human immunodeficiency virus (SHIV), intriguingly, their inhibitory effects were largely attenuated in the acute period of SHIV infection. To investigate the mechanism for the disparate performance of bnAbs in different periods of SHIV infection, we used LSEVh-LS-F, a bispecific bnAb targeting the CD4 binding site and CD4-induced epitopes, as a representative bnAb and assessed its potential therapeutic benefit in controlling virus replication in acutely or chronically SHIV-infected macaques. We found that a single infusion of LSEVh-LS-F resulted in rapid decline of plasma viral loads to undetectable levels without emergence of viral resistance in the chronically infected macaques. In contrast, the inhibitory effect was robust but transient in the acutely infected macaques, despite the fact that all macaques had comparable plasma viral loads initially. Infusing multiple doses of LSEVh-LS-F did not extend its inhibitory duration. Furthermore, the pharmacokinetics of the infused LSEVh-LS-F in the acutely SHIV-infected macaques significantly differed from that in the uninfected or chronically infected macaques. Host SHIV-specific immune responses may play a role in the viremia-dependent pharmacokinetics. Our results highlight the correlation between the fast clearance of infused bnAbs and the treatment failure in the acute period of SHIV infection and may have important implications for the therapeutic use of bnAbs to treat acute HIV infections. IMPORTANCE Currently, there is no bnAb-based monotherapy that has been reported to clear the virus in the acute SHIV infection period. Since early HIV treatment is considered critical to restricting the establishment of viral reservoirs, investigation into the mechanism for treatment failure in acutely infected macaques would be important for the therapeutic use of bnAbs and eventually towards the functional cure of HIV/AIDS. Here we report the comparative study of the therapeutic efficacy of a bnAb in acutely and chronically SHIV-infected macaques. This study revealed the correlation between the fast clearance of infused bnAbs and treatment failure during the acute period of infection.

AB - Early human immunodeficiency virus type 1 (HIV-1) treatment during the acute period of infection can significantly limit the seeding of viral reservoirs and modify the course of disease. However, while a number of HIV-1 broadly neutralizing antibodies (bnAbs) have demonstrated remarkable efficacy as prophylaxis in macaques chronically infected with simian-human immunodeficiency virus (SHIV), intriguingly, their inhibitory effects were largely attenuated in the acute period of SHIV infection. To investigate the mechanism for the disparate performance of bnAbs in different periods of SHIV infection, we used LSEVh-LS-F, a bispecific bnAb targeting the CD4 binding site and CD4-induced epitopes, as a representative bnAb and assessed its potential therapeutic benefit in controlling virus replication in acutely or chronically SHIV-infected macaques. We found that a single infusion of LSEVh-LS-F resulted in rapid decline of plasma viral loads to undetectable levels without emergence of viral resistance in the chronically infected macaques. In contrast, the inhibitory effect was robust but transient in the acutely infected macaques, despite the fact that all macaques had comparable plasma viral loads initially. Infusing multiple doses of LSEVh-LS-F did not extend its inhibitory duration. Furthermore, the pharmacokinetics of the infused LSEVh-LS-F in the acutely SHIV-infected macaques significantly differed from that in the uninfected or chronically infected macaques. Host SHIV-specific immune responses may play a role in the viremia-dependent pharmacokinetics. Our results highlight the correlation between the fast clearance of infused bnAbs and the treatment failure in the acute period of SHIV infection and may have important implications for the therapeutic use of bnAbs to treat acute HIV infections. IMPORTANCE Currently, there is no bnAb-based monotherapy that has been reported to clear the virus in the acute SHIV infection period. Since early HIV treatment is considered critical to restricting the establishment of viral reservoirs, investigation into the mechanism for treatment failure in acutely infected macaques would be important for the therapeutic use of bnAbs and eventually towards the functional cure of HIV/AIDS. Here we report the comparative study of the therapeutic efficacy of a bnAb in acutely and chronically SHIV-infected macaques. This study revealed the correlation between the fast clearance of infused bnAbs and treatment failure during the acute period of infection.

KW - Acute SHIV infection

KW - Broadly neutralizing antibodies

KW - HIV-1

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