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Author Notes:

Corresponding Author: Eric Hunter Email: ehunte4@emory.edu

The investigators thank all the volunteers in Zambia who participated in this study and all the staff at the Zambia-Emory HIV Research Project in Lusaka who made this study possible.

The investigators would like to thank Jonathan Carlson for in depth statistical discussions and manuscript review, and Victor Du, Jon Allen, and Mackenzie Hurlston for technical assistance and sample management.

The contents are the responsibility of the study authors and do not necessarily reflect the views of USAID or the United States Government.

D.C. Mónaco was supported in part by an Action Cycling Fellowship.

The authors declare no competing financial interests.

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Research Funding:

This study was funded by grants R01 AI64060, R01 AI112566, and R37 AI51231 (E. Hunter and P. Goepfert) from the National Institutes of Allergy and Infectious Diseases, National Institutes of Health, and by the International AIDS Vaccine Initiative (S. Allen), and made possible in part by the generous support of the American people through the United States Agency for International Development (USAID).

This work was also supported, in part, by the Biostatistics and Biomedical Informatics and Virology Cores at the Emory Center for AIDS Research (grant P30 AI050409), the Yerkes National Primate Research Center (base grant 2P51RR000165-51), the National Center for Research Resources (grant P51RR165), and the Office of Research Infrastructure Programs (grant P51OD11132).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • IMMUNODEFICIENCY-VIRUS TYPE-1
  • RANDOM SURVIVAL FORESTS
  • T-LYMPHOCYTE RESPONSES
  • ESCAPE MUTATIONS
  • VIRAL-LOAD
  • REPLICATION CAPACITY
  • DISCORDANT COUPLES
  • IMMUNE-RESPONSES
  • CELL RESPONSE
  • CLASS-I

Balance between transmitted HLA preadapted and nonassociated polymorphisms is a major determinant of HIV-1 disease progression

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Journal Title:

Journal of Experimental Medicine

Volume:

Volume 213, Number 10

Publisher:

, Pages 2049-2063

Type of Work:

Article | Final Publisher PDF

Abstract:

HIV-1 adapts to a new host through mutations that facilitate immune escape. Here, we evaluate the impact on viral control and disease progression of transmitted polymorphisms that were either preadapted to or nonassociated with the new host's HLA. In a cohort of 169 Zambian heterosexual transmission pairs, we found that almost one-third of possible HLA-linked target sites in the transmitted virus Gag protein are already adapted, and that this transmitted preadaptation significantly reduced early immune recognition of epitopes. Transmitted preadapted and nonassociated polymorphisms showed opposing effects on set-point VL and the balance between the two was significantly associated with higher set-point VLs in a multivariable model including other risk factors. Transmitted preadaptation was also significantly associated with faster CD4 decline (< 350 cells/μl) and this association was stronger after accounting for nonassociated polymorphisms, which were linked with slower CD4 decline. Overall, the relative ratio of the two classes of polymorphisms was found to be the major determinant of CD4 decline in a multivariable model including other risk factors. This study reveals that, even before an immune response is mounted in the new host, the balance of these opposing factors can significantly influence the outcome of HIV-1 infection.

Copyright information:

© 2016 Mónaco et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License (http://creativecommons.org/licenses/by-nc-sa/3.0/).

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