Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

Zaza M. Ndhlovu; Philomena Kamya; Nikoshia Mewalal; Henrik N. Kløverpris; Thandeka Nkosi; Karyn Pretorius; Faatima Laher; Funsho Ogunshola; Denis Chopera; Karthik Shekhar; Musie Ghebremichael; Nasreen Ismail; Amber Moodley; Amna Malik; Alasdair Leslie; Philip J.R. Goulder; Søren Buus; Arup Chakraborty; Krista Dong; Thumbi Ndung'u; Bruce D. Walker

doi:10.1016/j.immuni.2015.08.012

Magnitude and Kinetics of CD8⁺ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

Zaza M. Ndhlovu, Philomena Kamya, Nikoshia Mewalal, Henrik N. Kløverpris, Thandeka Nkosi, Karyn Pretorius, Faatima Laher, Funsho Ogunshola, Denis Chopera, Karthik Shekhar, Musie Ghebremichael, Nasreen Ismail, Amber Moodley, Amna Malik, Alasdair Leslie, Philip J.R. Goulder, Søren Buus, Arup Chakraborty, Krista Dong, Thumbi Ndung'uBruce D. Walker

Research output: Contribution to journal › Article › peer-review

206 Scopus citations

Abstract

CD8⁺ T cells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8⁺ T cell response, with limited bystander activation of non-HIV memory CD8⁺ T cells. HIV-specific CD8⁺ T cells secreted little interferon-γ, underwent rapid apoptosis, and failed to upregulate the interleukin-7 receptor, known to be important for T cell survival. The rapidity to peak CD8⁺ T cell activation and the absolute magnitude of activation induced by the exponential rise in viremia were inversely correlated with set point viremia. These data indicate that rapid, high magnitude HIV-induced CD8⁺ T cell responses are crucial for subsequent immune control of acute infection, which has important implications for HIV vaccine design.

Original language	English
Article number	3155
Pages (from-to)	591-604
Number of pages	14
Journal	Immunity
Volume	43
Issue number	3
DOIs	https://doi.org/10.1016/j.immuni.2015.08.012
State	Published - 15 Sep 2015
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Inc.

Funding

We would like to thank the FRESH participants, as well as the FRESH and HIV Pathogenesis Programme (HPP) laboratory staff. This work was supported by the Bill and Melinda Gates Foundation and the Collaboration for AIDS Vaccine Discovery , the Witten Family Foundation , Dan and Marjorie Sullivan, the Mark and Lisa Schwartz Foundation , Ursula Brunner, Gary and Loren Cohen, the International AIDS Vaccine Initiative (IAVI) ( UKZNRSA1001 ), the NIAID ( R37AI067073 ), and an NIH funded Center for AIDS Research ( P30 AI060354 ), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID , NCI , NICHD , NHLBI , NIDA , NIMH , NIA , FIC , and OAR , and the Howard Hughes Medical Institute . Additional funding was received from the South African Research Chairs Initiative . We would like to thank Drs. Alan S. Perelson and Ruy M. Rubeiro for their expert advice on viral growth kinetics calculations, and Dr. Daniel E. Kaufmann, MD for critical reading of the manuscript.

Funders	Funder number
Collaboration for AIDS Vaccine Discovery
Mark and Lisa Schwartz Foundation
NIH funded Center for AIDS Research	P30 AI060354
Witten Family Foundation
National Institutes of Health
Howard Hughes Medical Institute
National Institute of Mental Health
National Institute on Aging
National Heart, Lung, and Blood Institute
National Cancer Institute
National Institute of Allergy and Infectious Diseases	P30AI060354, R37AI067073, R01AI046995
Fogarty International Center
Bill and Melinda Gates Foundation
International AIDS Vaccine Initiative	UKZNRSA1001
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Office for the Advancement of Research, John Jay College of Criminal Justice
National Institute of Development Administration

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.immuni.2015.08.012

Cite this

Ndhlovu, Z. M., Kamya, P., Mewalal, N., Kløverpris, H. N., Nkosi, T., Pretorius, K., Laher, F., Ogunshola, F., Chopera, D., Shekhar, K., Ghebremichael, M., Ismail, N., Moodley, A., Malik, A., Leslie, A., Goulder, P. J. R., Buus, S., Chakraborty, A., Dong, K., ... Walker, B. D. (2015). Magnitude and Kinetics of CD8⁺ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point. Immunity, 43(3), 591-604. Article 3155. https://doi.org/10.1016/j.immuni.2015.08.012

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abstract = "CD8+ T cells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8+ T cell response, with limited bystander activation of non-HIV memory CD8+ T cells. HIV-specific CD8+ T cells secreted little interferon-γ, underwent rapid apoptosis, and failed to upregulate the interleukin-7 receptor, known to be important for T cell survival. The rapidity to peak CD8+ T cell activation and the absolute magnitude of activation induced by the exponential rise in viremia were inversely correlated with set point viremia. These data indicate that rapid, high magnitude HIV-induced CD8+ T cell responses are crucial for subsequent immune control of acute infection, which has important implications for HIV vaccine design.",

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Ndhlovu, ZM, Kamya, P, Mewalal, N, Kløverpris, HN, Nkosi, T, Pretorius, K, Laher, F, Ogunshola, F, Chopera, D, Shekhar, K, Ghebremichael, M, Ismail, N, Moodley, A, Malik, A, Leslie, A, Goulder, PJR, Buus, S, Chakraborty, A, Dong, K, Ndung'u, T & Walker, BD 2015, 'Magnitude and Kinetics of CD8⁺ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point', Immunity, vol. 43, no. 3, 3155, pp. 591-604. https://doi.org/10.1016/j.immuni.2015.08.012

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AU - Leslie, Alasdair

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