Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection.
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.
Department of Paediatrics, Peter Medawar Building for Pathogen Research, South Parks Road, University of Oxford, Oxford OX1 3SY, U.K. HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal (UKZN), Durban, South Africa. Max von Pettenkofer-Institute, Department of Virology, Ludwig-Maximilians-University Munich, Munich, Germany. German Center for Infection Research (DZIF), Partner Site Munich, Germany.
Maximilian
M
Muenchhoff
Department of Paediatrics, Peter Medawar Building for Pathogen Research, South Parks Road, University of Oxford, Oxford OX1 3SY, U.K.
Emily
E
Adland
Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa.
Owen
O
Karimanzira
Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa.
Carol
C
Crowther
Institute for Emerging Infections, Oxford Martin School, University of Oxford, Oxford, U.K. Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford OX1 3SY, U.K. Oxford National Institute of Health Research, Biomedical Research Centre, Oxford, U.K.
Matthew
M
Pace
Department of Paediatrics, Peter Medawar Building for Pathogen Research, South Parks Road, University of Oxford, Oxford OX1 3SY, U.K.
Anna
A
Csala
Department of Paediatrics, Peter Medawar Building for Pathogen Research, South Parks Road, University of Oxford, Oxford OX1 3SY, U.K.
Ellen
E
Leitman
Department of Paediatrics, Peter Medawar Building for Pathogen Research, South Parks Road, University of Oxford, Oxford OX1 3SY, U.K.
Angeline
A
Moonsamy
Department of Paediatrics, Peter Medawar Building for Pathogen Research, South Parks Road, University of Oxford, Oxford OX1 3SY, U.K. HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal (UKZN), Durban, South Africa.
Callum
C
McGregor
Institute of Cancer Research, Old Brompton Road, London SW7 3RP, U.K.
Jacob
J
Hurst
Department of Mathematics, Ludwig-Maximilians-University Munich, Theresienstrasse 39, 80333 Munich, Germany.
Andreas
A
Groll
Department of Paediatrics, Peter Medawar Building for Pathogen Research, South Parks Road, University of Oxford, Oxford OX1 3SY, U.K.
Masahiko
M
Mori
Department of Paediatrics, Peter Medawar Building for Pathogen Research, South Parks Road, University of Oxford, Oxford OX1 3SY, U.K.
Smruti
S
Sinmyee
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal (UKZN), Durban, South Africa.
Christina
C
Thobakgale
Department of Paediatrics, Imperial College London, London, U.K.
Gareth
G
Tudor-Williams
Blizard Institute, Queen Mary University of London, London, U.K.
Andrew J
AJ
Prendergast
KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), University of KwaZulu-Natal (UKZN), 4001 Durban, South Africa. Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Henrik
H
Kloverpris
Department of Paediatrics, Peter Medawar Building for Pathogen Research, South Parks Road, University of Oxford, Oxford OX1 3SY, U.K. HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal (UKZN), Durban, South Africa. KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), University of KwaZulu-Natal (UKZN), 4001 Durban, South Africa.
Julia
J
Roider
KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), University of KwaZulu-Natal (UKZN), 4001 Durban, South Africa.
Alasdair
A
Leslie
Department of Paediatric Infectious Diseases, Great Ormond Street Hospital for Children, London, U.K.
Delane
D
Shingadia
Paediatric Department, Kimberley Hospital, Northern Cape, South Africa.
Thea
T
Brits
Paediatric Department, Kimberley Hospital, Northern Cape, South Africa.
Samantha
S
Daniels
Institute for Emerging Infections, Oxford Martin School, University of Oxford, Oxford, U.K. Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford OX1 3SY, U.K. Oxford National Institute of Health Research, Biomedical Research Centre, Oxford, U.K.
John
J
Frater
Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford OX1 3SY, U.K. Oxford National Institute of Health Research, Biomedical Research Centre, Oxford, U.K.
Christian B
CB
Willberg
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal (UKZN), Durban, South Africa. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139-4307, USA.
Bruce D
BD
Walker
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal (UKZN), Durban, South Africa. KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), University of KwaZulu-Natal (UKZN), 4001 Durban, South Africa. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139-4307, USA. Max Planck Institute for Infection Biology, Berlin, Germany.
Thumbi
T
Ndung'u
Paediatric Department, Kimberley Hospital, Northern Cape, South Africa.
Pieter
P
Jooste
Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa. Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Center for the AIDS Programme of Research in South Africa (CAPRISA), 4001 Durban, South Africa.
Penny L
PL
Moore
Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa. Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Center for the AIDS Programme of Research in South Africa (CAPRISA), 4001 Durban, South Africa.
Lynn
L
Morris
Department of Paediatrics, Peter Medawar Building for Pathogen Research, South Parks Road, University of Oxford, Oxford OX1 3SY, U.K. HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal (UKZN), Durban, South Africa. Department of Paediatric Infectious Diseases, Great Ormond Street Hospital for Children, London, U.K. philip.goulder@paediatrics.ox.ac.uk.
Philip
P
Goulder
D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D002648:Child; D018450:Disease Progression; D015483:HIV Antibodies / Q000276:immunology; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D019713:Receptors, CCR5 / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000276:immunology*; D013045:Species Specificity; D019562:Viral Load / Q000276:immunology; D014766:Viremia / Q000097:blood / Q000276:immunology
D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D019713:Receptors, CCR5
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