title: Emergence of individual HIV-specific CD8 T cell responses during primary HIV-1 infection can determine long-term disease outcome.
abstract: Events during primary HIV-1 infection have been shown to be critical for the subsequent rate of disease progression. Early control of viral replication, resolution of clinical symptoms and development of a viral set point have been associated with the emergence of HIV-specific CD8 T cell responses. Here we assessed which particular HIV-specific CD8 T cell responses contribute to long-term control of HIV-1. A total of 620 individuals with primary HIV-1 infection were screened by gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay for HLA class I-restricted, epitope-specific CD8 T cell responses using optimally defined epitopes approximately 2 months after initial presentation. The cohort was predominantly male (97%) and Caucasian (83%) (Fiebig stages II/III [n = 157], IV [n = 64], V [n = 286], and VI [n = 88] and Fiebig stage not determined [n = 25]). Longitudinal viral loads, CD4 count, and time to ART were collected for all patients. We observed strong associations between viral load at baseline (initial viremia) and the established early viral set points (P < 0.0001). Both were significantly associated with HLA class I genotypes (P = 0.0009). While neither the breadth nor the magnitude of HIV-specific CD8 T cell responses showed an influence on the early viral set point, a broader HIV-specific CD8 T cell response targeting epitopes within HIV-1 Gag during primary HIV-1 infection was associated with slower disease progression. Moreover, the induction of certain HIV-specific CD8 T cell responses--but not others--significantly influenced the time to ART initiation. Individual epitope-specific CD8 T cell responses contribute significantly to HIV-1 disease control, demonstrating that the specificity of the initial HIV-specific CD8 T cell response rather than the restricting HLA class I molecule alone is a critical determinant of antiviral function.
  
  
  OBJECTIVE
  Understanding which factors are involved in the control of HIV-1 infection is critical for the design of therapeutic strategies for patients living with HIV/AIDS. Here, using a cohort of over 600 individuals with acute and early HIV-1 infection, we assessed in unprecedented detail the individual contribution of epitope-specific CD8 T cell responses directed against HIV-1 to control of viremia and their impact on the overall course of disease progression.
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA hstreeck@hivresearch.org.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Streeck
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Lu
authors.affiliation: Harvard School of Medicine, Boston, Massachusetts, USA.
authors.forename: Noor
authors.initials: N
authors.lastname: Beckwith
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Milazzo
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Liu
authors.affiliation: McGill University, Division of Hematology and Immunodeficiency Service, Royal Victoria Hospital, Montreal, Quebec, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, California, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Little
authors.affiliation: HIV Clinic Praxis Jessen, Berlin, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Jessen
authors.affiliation: Kirby Institute, UNSW, Sydney, New South Wales, Australia.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Hecht
authors.affiliation: Division of Infectious Diseases, Vaccine and Gene Therapy Institute-Florida, Port Saint Lucie, Florida, USA.
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sekaly
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
authors.affiliation: eScience Group, Microsoft Research, Los Angeles, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: Massachussetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA Heinrich-Pette-Institute, Hamburg-Eppendorf, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
mesh_terms: D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D007371:Interferon-gamma