Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4+ T cells, and disease progression.
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.
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Daniel T
DT
Claiborne
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Jessica L
JL
Prince
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;
Eileen
E
Scully
Human Immunology Laboratory, International AIDS Vaccine Initiative, London SW10 9NH, United Kingdom;
Gladys
G
Macharia
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Luca
L
Micci
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Benton
B
Lawson
Human Immunology Laboratory, International AIDS Vaccine Initiative, London SW10 9NH, United Kingdom; Faculty of Medicine, Imperial College, London SW7 2AZ, United Kingdom;
Jakub
J
Kopycinski
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Martin J
MJ
Deymier
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Thomas H
TH
Vanderford
Vaccine Research Center, National Institutes of Health, Bethesda, MD 20817;
Krystelle
K
Nganou-Makamdop
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Zachary
Z
Ende
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Kelsie
K
Brooks
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
Jianming
J
Tang
Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322;
Tianwei
T
Yu
Zambia-Emory HIV Research Project, Lusaka, Zambia;
Shabir
S
Lakhi
Zambia-Emory HIV Research Project, Lusaka, Zambia;
William
W
Kilembe
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Guido
G
Silvestri
Vaccine Research Center, National Institutes of Health, Bethesda, MD 20817;
Daniel
D
Douek
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
Paul A
PA
Goepfert
Epidemiology Unit, International AIDS Vaccine Initiative, San Francisco, CA 94143; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143;
Matthew A
MA
Price
Zambia-Emory HIV Research Project, Lusaka, Zambia; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322; Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322; and.
Susan A
SA
Allen
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329;
Mirko
M
Paiardini
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; Virus Immunology Unit, Heinrich-Pette-Institut, 20251 Hamburg, Germany.
Marcus
M
Altfeld
Human Immunology Laboratory, International AIDS Vaccine Initiative, London SW10 9NH, United Kingdom; Faculty of Medicine, Imperial College, London SW7 2AZ, United Kingdom;
Jill
J
Gilmour
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322; ehunte4@emory.edu.
Eric
E
Hunter
D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007156:Immunologic Memory; D007249:Inflammation; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation; D008297:Male; D008969:Molecular Sequence Data; D013997:Time Factors; D019562:Viral Load; D014779:Virus Replication
D016207:Cytokines
Gag; HIV-1; immune activation; pathogenesis; replicative capacity