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

• Authors: Daniela Monaco, Emory University; Dario Dilernia, Emory University; Andrew Fiore-Gartland, Fred Hutchinson Cancer Research Center; Tianwei Yu, Emory University; Jessica L. Prince, Emory University; Kristine K. Dennis, Emory University; Kai Qin, University of Alabama Birmingham; Malinda Schaefer, Emory University; Daniel T. Claiborne, Emory University; William Kilembe, Zambia-Emory HIV Research Project; Jianming Tang, University of Alabama Birmingham; Matt A. Price, International AIDS Vaccine Initiative; Paul Farmer, Emory University; Jill Gilmour, International AIDS Vaccine Initiative; Anju Bansal, University of Alabama Birmingham; Susan Allen, Emory University; Paul Goepfert, University of Alabama Birmingham; Eric Hunter, Emory University
• Journal Title: Journal of Experimental Medicine
• Volume: Volume 213, Number 10
• Publisher: Rockefeller University Press | 2016-09-01, Pages 2049-2063
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1084/jem.20151984
• Subjects: Health Sciences, Immunology; Health Sciences, Pathology
• 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

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.