Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4+ T cells, and disease progression

Daniel T. Claiborne, Jessica L. Prince, Eileen Scully, Gladys Macharia, Luca Micci, Benton Lawson, Jakub Kopycinski, Martin J. Deymier, Thomas H. Vanderford, Krystelle Nganou-Makamdop, Zachary Ende, Kelsie Brooks, Jianming Tang, Tianwei Yu, Shabir Lakhi, William Kilembe, Guido Silvestri, Daniel Douek, Paul A. Goepfert, Matthew A. PriceSusan A. Allen, Mirko Paiardini, Marcus Altfeld, Jill Gilmour, Eric Hunter

Research output: Contribution to journalArticlepeer-review

Abstract

HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1-induced immunopathology and subsequent CD4+ T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8+ T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4+ T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1-related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions.

Original languageEnglish (US)
Pages (from-to)E1480-E1489
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number12
DOIs
StatePublished - Mar 24 2015
Externally publishedYes

Keywords

  • Gag
  • HIV-1
  • Immune activation
  • Pathogenesis
  • Replicative capacity

ASJC Scopus subject areas

  • General

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