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. Price; Susan A. Allen; Mirko Paiardini; Marcus Altfeld; Jill Gilmour; Eric Hunter

doi:10.1073/pnas.1421607112

Edited by Malcolm A. Martin, National Institute of Allergy and Infectious Diseases, Bethesda, MD, and approved January 21, 2015 (received for review November 11, 2014)

Significance

HIV infection is associated with elevated inflammation and aberrant cellular immune activation. Indeed, the activation status of an HIV-infected individual is often more predictive of disease trajectory than viral load. Here, we highlight the importance of the replicative fitness of the transmitted viral variant in driving an early inflammatory state, characterized by T-cell activation and immune dysfunction. This impact on T-cell homeostasis is independent of protective host immune response genes and viral load. Highly replicating transmitted variants were also significantly more efficient at infecting memory CD4⁺ T cells, a population important for maintaining the latent viral reservoir. Together, these data provide a mechanism whereby viral replicative fitness acts as a major determinant of disease progression and persistence.

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.

Footnotes

↵¹D.T.C. and J.L.P. contributed equally to this work.
↵²To whom correspondence should be addressed. Email: ehunte4{at}emory.edu.

Author contributions: D.T.C., J.L.P., E.S., L.M., B.L., J.K., M.J.D., T.H.V., Z.E., J.T., S.L., W.K., G.S., D.D., P.A.G., M.A.P., S.A.A., M.P., M.A., J.G., and E.H. designed research; D.T.C., J.L.P., E.S., G.M., L.M., B.L., J.K., M.J.D., K.N.-M., Z.E., K.B., and J.T. performed research; E.S., T.Y., S.L., W.K., D.D., S.A.A., and M.A. contributed new reagents/analytic tools; D.T.C., J.L.P., E.S., G.M., L.M., J.K., J.T., T.Y., G.S., M.A.P., M.A., J.G., and E.H. analyzed data; and D.T.C., J.L.P., and E.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. KP715723–KP715849).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1421607112/-/DCSupplemental.

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