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-␥) 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-␥-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.

Early proliferation of CCR5+ CD38+++ antigen-specific CD4+ Th1 effector cells during primary HIV-1 infection

“…Most studies do suggest that CD4 ϩ T-cell responses to HIV-1 Gag are highly immunodominant, 1 particularly in patients during acute infection 16 as well as patients treated during acute infection who underwent treatment interruption. 41,42 However, glycoprotein (gp) 160-specific CD4 ϩ T-cell responses were also commonly found in very early PHI in 1 report. 41 Additional responses might also be detected to variant autologous sequences, 43 to frame-shifted peptides, 44 or to peptides from recombinant variants, 45 but these were not tested in the present study.…”

Scanning the HIV Genome for CD4+ T Cell Epitopes Restricted to HLA-DP4, the Most Prevalent HLA Class II Molecule

“…Peptide screening has been performed in HIV-1 seropositive donors by evaluating the proliferative responses of peptides spanning selected HIV Ags (17,21,22,24,26). This approach has identified many CD4 ϩ T cell epitopes.…”

“…The response is raised against a reduced number of components (24, (16,26,43). Most of the CD4 ϩ T cell epitopes characterized using seropositive donors are HLA-DR-restricted (17,21,24).…”

“…They are almost all restricted to HLA-DR, very few epitopes being HLA-DQ-restricted (25,29) and HLA-DP5-restricted (25). Some of these peptides were able to bind to multiple HLA-DR molecules and were recognized by T cell lines deriving from multiple individuals (21,24,26). However, none of them are restricted to the prevalent HLA-DP4 molecules.…”

“…They derived from GAG (21)(22)(23)(24), env (25,26), POL (21,27,28), and Nef (24,29). They are almost all restricted to HLA-DR, very few epitopes being HLA-DQ-restricted (25,29) and HLA-DP5-restricted (25).…”