Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound

Afam Okoye, Scott Hansen, Mukta Vaidya, Yoshinori Fukazawa, Haesun Park, Derick M. Duell, Richard Lum, Colette M. Hughes, Abigail B. Ventura, Emily Ainslie, Julia C. Ford, David Morrow, Roxanne M. Gilbride, Alfred W. Legasse, Joseph Hesselgesser, Romas Geleziunas, Yuan Li, Kelli Oswald, Rebecca Shoemaker, Randy Fast & 6 others William J. Bosche, Bhavesh R. Borate, Paul T. Edlefsen, Michael Axthelm, Louis Picker, Jeffrey D. Lifson

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Prophylactic vaccination of rhesus macaques with rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) elicits immune responses that stringently control highly pathogenic SIV infection, with subsequent apparent clearance of the infection, in ~50% of vaccinees. In contrast, here, we show that therapeutic RhCMV/SIV vaccination of rhesus macaques previously infected with SIV and given continuous combination antiretroviral therapy (cART) beginning 4–9 d post-SIV infection does not mediate measurable SIV reservoir clearance during over 600 d of follow-up on cART relative to RhCMV/control vaccination. However, none of the six animals started on cART on day four or five, across both RhCMV/SIV- and RhCMV/control-vaccinated groups, those rhesus macaques with SIV reservoirs most closely resembling those of prophylactically RhCMV/SIV-vaccinated and protected animals early in their course, showed post-cART viral rebound with up to nine months of follow-up. Moreover, at necropsy, these rhesus macaques showed little to no evidence of replication-competent SIV. These results suggest that the early SIV reservoir is limited in durability and that effective blockade of viral replication and spread in this critical time window by either pharmacologic or immunologic suppression may result in reduction, and potentially loss, of rebound-competent virus over a period of ~two years.

Original languageEnglish (US)
Pages (from-to)1430-1440
Number of pages11
JournalNature Medicine
Volume24
Issue number9
DOIs
StatePublished - Sep 1 2018

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Simian Immunodeficiency Virus
Secondary Prevention
Viruses
Cytomegalovirus
Macaca mulatta
Therapeutics
Vaccination
Virus Diseases
Animals

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound. / Okoye, Afam; Hansen, Scott; Vaidya, Mukta; Fukazawa, Yoshinori; Park, Haesun; Duell, Derick M.; Lum, Richard; Hughes, Colette M.; Ventura, Abigail B.; Ainslie, Emily; Ford, Julia C.; Morrow, David; Gilbride, Roxanne M.; Legasse, Alfred W.; Hesselgesser, Joseph; Geleziunas, Romas; Li, Yuan; Oswald, Kelli; Shoemaker, Rebecca; Fast, Randy; Bosche, William J.; Borate, Bhavesh R.; Edlefsen, Paul T.; Axthelm, Michael; Picker, Louis; Lifson, Jeffrey D.

In: Nature Medicine, Vol. 24, No. 9, 01.09.2018, p. 1430-1440.

Research output: Contribution to journalArticle

Okoye, A, Hansen, S, Vaidya, M, Fukazawa, Y, Park, H, Duell, DM, Lum, R, Hughes, CM, Ventura, AB, Ainslie, E, Ford, JC, Morrow, D, Gilbride, RM, Legasse, AW, Hesselgesser, J, Geleziunas, R, Li, Y, Oswald, K, Shoemaker, R, Fast, R, Bosche, WJ, Borate, BR, Edlefsen, PT, Axthelm, M, Picker, L & Lifson, JD 2018, 'Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound', Nature Medicine, vol. 24, no. 9, pp. 1430-1440. https://doi.org/10.1038/s41591-018-0130-7
Okoye, Afam ; Hansen, Scott ; Vaidya, Mukta ; Fukazawa, Yoshinori ; Park, Haesun ; Duell, Derick M. ; Lum, Richard ; Hughes, Colette M. ; Ventura, Abigail B. ; Ainslie, Emily ; Ford, Julia C. ; Morrow, David ; Gilbride, Roxanne M. ; Legasse, Alfred W. ; Hesselgesser, Joseph ; Geleziunas, Romas ; Li, Yuan ; Oswald, Kelli ; Shoemaker, Rebecca ; Fast, Randy ; Bosche, William J. ; Borate, Bhavesh R. ; Edlefsen, Paul T. ; Axthelm, Michael ; Picker, Louis ; Lifson, Jeffrey D. / Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound. In: Nature Medicine. 2018 ; Vol. 24, No. 9. pp. 1430-1440.
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abstract = "Prophylactic vaccination of rhesus macaques with rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) elicits immune responses that stringently control highly pathogenic SIV infection, with subsequent apparent clearance of the infection, in ~50{\%} of vaccinees. In contrast, here, we show that therapeutic RhCMV/SIV vaccination of rhesus macaques previously infected with SIV and given continuous combination antiretroviral therapy (cART) beginning 4–9 d post-SIV infection does not mediate measurable SIV reservoir clearance during over 600 d of follow-up on cART relative to RhCMV/control vaccination. However, none of the six animals started on cART on day four or five, across both RhCMV/SIV- and RhCMV/control-vaccinated groups, those rhesus macaques with SIV reservoirs most closely resembling those of prophylactically RhCMV/SIV-vaccinated and protected animals early in their course, showed post-cART viral rebound with up to nine months of follow-up. Moreover, at necropsy, these rhesus macaques showed little to no evidence of replication-competent SIV. These results suggest that the early SIV reservoir is limited in durability and that effective blockade of viral replication and spread in this critical time window by either pharmacologic or immunologic suppression may result in reduction, and potentially loss, of rebound-competent virus over a period of ~two years.",
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AU - Okoye, Afam

AU - Hansen, Scott

AU - Vaidya, Mukta

AU - Fukazawa, Yoshinori

AU - Park, Haesun

AU - Duell, Derick M.

AU - Lum, Richard

AU - Hughes, Colette M.

AU - Ventura, Abigail B.

AU - Ainslie, Emily

AU - Ford, Julia C.

AU - Morrow, David

AU - Gilbride, Roxanne M.

AU - Legasse, Alfred W.

AU - Hesselgesser, Joseph

AU - Geleziunas, Romas

AU - Li, Yuan

AU - Oswald, Kelli

AU - Shoemaker, Rebecca

AU - Fast, Randy

AU - Bosche, William J.

AU - Borate, Bhavesh R.

AU - Edlefsen, Paul T.

AU - Axthelm, Michael

AU - Picker, Louis

AU - Lifson, Jeffrey D.

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N2 - Prophylactic vaccination of rhesus macaques with rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) elicits immune responses that stringently control highly pathogenic SIV infection, with subsequent apparent clearance of the infection, in ~50% of vaccinees. In contrast, here, we show that therapeutic RhCMV/SIV vaccination of rhesus macaques previously infected with SIV and given continuous combination antiretroviral therapy (cART) beginning 4–9 d post-SIV infection does not mediate measurable SIV reservoir clearance during over 600 d of follow-up on cART relative to RhCMV/control vaccination. However, none of the six animals started on cART on day four or five, across both RhCMV/SIV- and RhCMV/control-vaccinated groups, those rhesus macaques with SIV reservoirs most closely resembling those of prophylactically RhCMV/SIV-vaccinated and protected animals early in their course, showed post-cART viral rebound with up to nine months of follow-up. Moreover, at necropsy, these rhesus macaques showed little to no evidence of replication-competent SIV. These results suggest that the early SIV reservoir is limited in durability and that effective blockade of viral replication and spread in this critical time window by either pharmacologic or immunologic suppression may result in reduction, and potentially loss, of rebound-competent virus over a period of ~two years.

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