title: Early induction and maintenance of Env-specific T-helper cells following human immunodeficiency virus type 1 infection.
abstract: Mounting evidence points to a role for CD4+ T-helper (Th) cell activities in controlling human immunodeficiency virus type 1 (HIV-1) infection. To determine the induction and evolution of Th responses following acute infection, we prospectively analyzed Env- and Gag-specific Th responses longitudinally for 92 patients with acute (n = 28) or early (n = 64) HIV-1 infection (median, 55 days postinfection [DPI]). The probability of detecting HIV-1-specific lymphoproliferative responses was remarkably low, and when present, the responses were more likely to be Gag specific than Env specific (16 versus 5%). Env-specific responses were significantly more common in patients presenting at <30 DPI than in those presenting at 30 to 365 DPI (21 versus 0.5%, P = 0.001). By contrast, Gag-specific responses occurred with similar frequencies among subjects presenting at <30 DPI and 30 to 365 DPI (13 versus 17%, P = 0.6). After treatment, and regardless of the duration of infection before therapy, Gag-specific Th responses predominated. Furthermore, some acutely infected subjects lost detectable Env-specific Th proliferative responses, which failed to reemerge upon treatment. Detailed analysis for one such subject revealed Env-specific lymphoproliferation at 11 DPI but no detectable Env-specific lymphoproliferation or ex vivo gamma interferon (IFN-gamma) secretion at multiple subsequent time points. Env-specific CD4+ T-cell clones from 11 DPI recognized six epitopes in both conserved and variable regions within gp120 and gp41, exhibited major histocompatibility complex-restricted cytotoxicity, and secreted high levels of antiviral cytokines. T-cell receptor clonal transcript analyses and autologous virus sequencing revealed that Th cells induced during acute infection were maintained and there were no Th escape mutations. Subsequent analysis for this subject and six of seven others revealed detectable IFN-gamma-secreting cells, but only following in vitro gp160 stimulation. In summary, we conclude that Env-specific Th responses are elicited very early in acute infection and may precede Gag-specific responses. The inability to detect Env-specific Th responses over time and despite antiretroviral therapy may reflect low frequencies and impaired proliferative capacity, and viral escape is not necessary for this to occur.
authors.affiliation: Program in Infectious Diseases, Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, WA 98109, USA.
authors.forename: Uma
authors.initials: U
authors.lastname: Malhotra
authors.forename: Sarah
authors.initials: S
authors.lastname: Holte
authors.forename: Tuofu
authors.initials: T
authors.lastname: Zhu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Delpit
authors.forename: Claire
authors.initials: C
authors.lastname: Huntsberry
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Raj
authors.initials: R
authors.lastname: Shankarappa
authors.forename: Janine
authors.initials: J
authors.lastname: Maenza
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000627:therapeutic use; D001483:Base Sequence; D000939:Epitopes; D005260:Female; D015686:Gene Products, env / Q000276:immunology*; D015683:Gene Products, gag / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D019380:Anti-HIV Agents; D000939:Epitopes; D015686:Gene Products, env; D015683:Gene Products, gag; D007371:Interferon-gamma