Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection

Maximilian Muenchhoff; Emily Adland; Owen Karimanzira; Carol Crowther; Matthew Pace; Anna Csala; Ellen Leitman; Angeline Moonsamy; Callum McGregor; Jacob Hurst; Andreas Groll; Masahiko Mori; Smruti Sinmyee; Christina Thobakgale; Gareth Tudor-Williams; Andrew J. Prendergast; Henrik Kloverpris; Julia Roider; Alasdair Leslie; Delane Shingadia; Thea Brits; Samantha Daniels; John Frater; Christian B. Willberg; Bruce D. Walker; Thumbi Ndung'u; Pieter Jooste; Penny L. Moore; Lynn Morris; Philip Goulder

doi:10.1126/scitranslmed.aag1048

Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection

Maximilian Muenchhoff, Emily Adland, Owen Karimanzira, Carol Crowther, Matthew Pace, Anna Csala, Ellen Leitman, Angeline Moonsamy, Callum McGregor, Jacob Hurst, Andreas Groll, Masahiko Mori, Smruti Sinmyee, Christina Thobakgale, Gareth Tudor-Williams, Andrew J. Prendergast, Henrik Kloverpris, Julia Roider, Alasdair Leslie, Delane ShingadiaThea Brits, Samantha Daniels, John Frater, Christian B. Willberg, Bruce D. Walker, Thumbi Ndung'u, Pieter Jooste, Penny L. Moore, Lynn Morris, Philip Goulder^*

^*Corresponding author for this work

66 Citations (Scopus)

Abstract

Disease-free infection in HIV-infected adults is associated with human leukocyte antigen-mediated suppression of viremia, whereas in the sooty mangabey and other healthy natural hosts of simian immunodeficiency virus (SIV), viral replication continues unabated. To better understand factors preventing HIV disease, we investigated pediatric infection, where AIDS typically develops more rapidly than in adults. Among 170 nonprogressing antiretroviral therapy-naïve children aged >5 years maintaining normal-for-Age CD4 T cell counts, immune activation levels were low despite high viremia (median, 26,000 copies/ml). Potent, broadly neutralizing antibody responses in most of the subjects and strong virus-specific T cell activity were present but did not drive pediatric nonprogression. However, reduced CCR5 expression and low HIV infection in long-lived central memory CD4 T cells were observed in pediatric nonprogressors. These children therefore express two cardinal immunological features of nonpathogenic SIV infection in sooty mangabeys-low immune activation despite high viremia and low CCR5 expression on long-lived central memory CD4 T cells-suggesting closer similarities with nonpathogenetic mechanisms evolved over thousands of years in natural SIV hosts than those operating in HIV-infected adults.

Original language	English
Article number	358ra125
Journal	Science Translational Medicine
Volume	8
Issue number	358
Number of pages	15
ISSN	1946-6234
DOIs	https://doi.org/10.1126/scitranslmed.aag1048
Publication status	Published - 28 Sept 2016

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Muenchhoff, M., Adland, E., Karimanzira, O., Crowther, C., Pace, M., Csala, A., Leitman, E., Moonsamy, A., McGregor, C., Hurst, J., Groll, A., Mori, M., Sinmyee, S., Thobakgale, C., Tudor-Williams, G., Prendergast, A. J., Kloverpris, H., Roider, J., Leslie, A., ... Goulder, P. (2016). Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection. Science Translational Medicine, 8(358), [358ra125]. https://doi.org/10.1126/scitranslmed.aag1048

Muenchhoff, M, Adland, E, Karimanzira, O, Crowther, C, Pace, M, Csala, A, Leitman, E, Moonsamy, A, McGregor, C, Hurst, J, Groll, A, Mori, M, Sinmyee, S, Thobakgale, C, Tudor-Williams, G, Prendergast, AJ, Kloverpris, H, Roider, J, Leslie, A, Shingadia, D, Brits, T, Daniels, S, Frater, J, Willberg, CB, Walker, BD, Ndung'u, T, Jooste, P, Moore, PL, Morris, L & Goulder, P 2016, 'Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection', Science Translational Medicine, vol. 8, no. 358, 358ra125. https://doi.org/10.1126/scitranslmed.aag1048

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title = "Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection",

abstract = "Disease-free infection in HIV-infected adults is associated with human leukocyte antigen-mediated suppression of viremia, whereas in the sooty mangabey and other healthy natural hosts of simian immunodeficiency virus (SIV), viral replication continues unabated. To better understand factors preventing HIV disease, we investigated pediatric infection, where AIDS typically develops more rapidly than in adults. Among 170 nonprogressing antiretroviral therapy-na{\"i}ve children aged >5 years maintaining normal-for-Age CD4 T cell counts, immune activation levels were low despite high viremia (median, 26,000 copies/ml). Potent, broadly neutralizing antibody responses in most of the subjects and strong virus-specific T cell activity were present but did not drive pediatric nonprogression. However, reduced CCR5 expression and low HIV infection in long-lived central memory CD4 T cells were observed in pediatric nonprogressors. These children therefore express two cardinal immunological features of nonpathogenic SIV infection in sooty mangabeys-low immune activation despite high viremia and low CCR5 expression on long-lived central memory CD4 T cells-suggesting closer similarities with nonpathogenetic mechanisms evolved over thousands of years in natural SIV hosts than those operating in HIV-infected adults.",

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AU - Crowther, Carol

AU - Pace, Matthew

AU - Csala, Anna

AU - Leitman, Ellen

AU - Moonsamy, Angeline

AU - McGregor, Callum

AU - Hurst, Jacob

AU - Groll, Andreas

AU - Mori, Masahiko

AU - Sinmyee, Smruti

AU - Thobakgale, Christina

AU - Tudor-Williams, Gareth

AU - Prendergast, Andrew J.

AU - Kloverpris, Henrik

AU - Roider, Julia

AU - Leslie, Alasdair

AU - Shingadia, Delane

AU - Brits, Thea

AU - Daniels, Samantha

AU - Frater, John

AU - Willberg, Christian B.

AU - Walker, Bruce D.

AU - Ndung'u, Thumbi

AU - Jooste, Pieter

AU - Moore, Penny L.

AU - Morris, Lynn

AU - Goulder, Philip

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N2 - Disease-free infection in HIV-infected adults is associated with human leukocyte antigen-mediated suppression of viremia, whereas in the sooty mangabey and other healthy natural hosts of simian immunodeficiency virus (SIV), viral replication continues unabated. To better understand factors preventing HIV disease, we investigated pediatric infection, where AIDS typically develops more rapidly than in adults. Among 170 nonprogressing antiretroviral therapy-naïve children aged >5 years maintaining normal-for-Age CD4 T cell counts, immune activation levels were low despite high viremia (median, 26,000 copies/ml). Potent, broadly neutralizing antibody responses in most of the subjects and strong virus-specific T cell activity were present but did not drive pediatric nonprogression. However, reduced CCR5 expression and low HIV infection in long-lived central memory CD4 T cells were observed in pediatric nonprogressors. These children therefore express two cardinal immunological features of nonpathogenic SIV infection in sooty mangabeys-low immune activation despite high viremia and low CCR5 expression on long-lived central memory CD4 T cells-suggesting closer similarities with nonpathogenetic mechanisms evolved over thousands of years in natural SIV hosts than those operating in HIV-infected adults.

AB - Disease-free infection in HIV-infected adults is associated with human leukocyte antigen-mediated suppression of viremia, whereas in the sooty mangabey and other healthy natural hosts of simian immunodeficiency virus (SIV), viral replication continues unabated. To better understand factors preventing HIV disease, we investigated pediatric infection, where AIDS typically develops more rapidly than in adults. Among 170 nonprogressing antiretroviral therapy-naïve children aged >5 years maintaining normal-for-Age CD4 T cell counts, immune activation levels were low despite high viremia (median, 26,000 copies/ml). Potent, broadly neutralizing antibody responses in most of the subjects and strong virus-specific T cell activity were present but did not drive pediatric nonprogression. However, reduced CCR5 expression and low HIV infection in long-lived central memory CD4 T cells were observed in pediatric nonprogressors. These children therefore express two cardinal immunological features of nonpathogenic SIV infection in sooty mangabeys-low immune activation despite high viremia and low CCR5 expression on long-lived central memory CD4 T cells-suggesting closer similarities with nonpathogenetic mechanisms evolved over thousands of years in natural SIV hosts than those operating in HIV-infected adults.

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JO - Science Translational Medicine

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Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection

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