title: Targeting of conserved gag-epitopes in early HIV infection is associated with lower plasma viral load and slower CD4(+) T cell depletion.
abstract: We aimed to investigate whether the character of the immunodominant HIV-Gag peptide (variable or conserved) targeted by CD8(+) T cells in early HIV infection would influence the quality and quantity of T cell responses, and whether this would affect the rate of disease progression. Treatment-naive HIV-infected study subjects within the OPTIONS cohort at the University of California, San Francisco, were monitored from an estimated 44 days postinfection for up to 6 years. CD8(+) T cells responses targeting HLA-matched HIV-Gag-epitopes were identified and characterized by multicolor flow cytometry. The autologous HIV gag sequences were obtained. We demonstrate that patients targeting a conserved HIV-Gag-epitope in early infection maintained their epitope-specific CD8(+) T cell response throughout the study period. Patients targeting a variable epitope showed decreased immune responses over time, although there was no limitation of the functional profile, and they were likely to target additional variable epitopes. Maintained immune responses to conserved epitopes were associated with no or limited sequence evolution within the targeted epitope. Patients with immune responses targeting conserved epitopes had a significantly lower median viral load over time compared to patients with responses targeting a variable epitope (0.63 log(10) difference). Furthermore, the rate of CD4(+) T cell decline was slower for subjects targeting a conserved epitope (0.85% per month) compared to subjects targeting a variable epitope (1.85% per month). Previous studies have shown that targeting of antigens based on specific HLA types is associated with a better disease course. In this study we show that categorizing epitopes based on their variability is associated with clinical outcome.
authors.affiliation: Department of Virology, Swedish Institute for Communicable Disease Control, Solna, Sweden.
authors.forename: Carina L
authors.initials: CL
authors.lastname: Perez
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Milush
authors.forename: Marcus
authors.initials: M
authors.lastname: Buggert
authors.forename: Emily M
authors.initials: EM
authors.lastname: Eriksson
authors.forename: Mette V
authors.initials: MV
authors.lastname: Larsen
authors.forename: Teri
authors.initials: T
authors.lastname: Liegler
authors.forename: Wendy
authors.initials: W
authors.lastname: Hartogensis
authors.forename: Peter
authors.initials: P
authors.lastname: Bacchetti
authors.forename: Ole
authors.initials: O
authors.lastname: Lund
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.forename: Annika C
authors.initials: AC
authors.lastname: Karlsson
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D018450:Disease Progression; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D006678:HIV / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D006801:Humans; D008969:Molecular Sequence Data; D010949:Plasma / Q000821:virology; D012367:RNA, Viral / Q000235:genetics; D012495:San Francisco; D017422:Sequence Analysis, DNA; D019562:Viral Load; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D000939:Epitopes; D012367:RNA, Viral; D054301:gag Gene Products, Human Immunodeficiency Virus