Background: Understanding the interrelationships between the HIV-specific CD8⁺ T-cell response, CD4⁺ T-cell response and HIV viral load has been somewhat elusive. Several studies have addressed this issue but with inconsistent and sometimes contradictory conclusions. In part these discrepancies can be explained by methodological differences. To examine these interrelationships in a large cohort of HAART-naïve South African subjects, CD4⁺ and CD8⁺ T-cell IFN-g responses to a comprehensive panel of overlapping peptides were studied.

Methods: PBMC from 86 HAART-naïve, C clade-infected subjects from Durban, South Africa, were analyzed according to intracellular IFN-g staining. A panel of overlapping peptides was used whose synthesis was based upon the consensus C-clade sequence. The peptides were arranged in 4 pools to measure CD8 and CD4⁺ T-cell responses to Gag, Pol, Env, and the regulatory/accessory proteins (Nef/Tat/Rev/Vif/Vpr/Vpu: "NTRVVV"), respectively.

Results: The Gag, Pol, and NTRVVV pools were all well targeted by CD8⁺ T cells compared with the Env pool. However, the Gag response dominated the CD4⁺ T-cell response (median 0.18% CD4s) compared with Pol, NTRVVV, and Env (0.02 to 0.06%). There was a strong association between the magnitude of the CD4⁺ T-cell response and the CD8⁺ T-cell response (r=0.40, p=0.0004). This association was confirmed in a second cohort of 75 subjects (r</i=0.45, p=0.006). There was a significant inverse relationship between the Gag-specific CD8⁺ T-cell response and viral load (p=0.0005). There was a trend toward an inverse relationship between the Gag-specific CD4⁺ T-cell response and viral load (p=0.12). However, for each of the other proteins, and for both CD4⁺ and CD8⁺ T-cell responses, the direction of the association with viral load or absolute CD4 count was opposite to that of the Gag protein.

Conclusions: These data demonstrate a strong and consistent association between the magnitude of the CD4⁺ IFN-g response and the CD8⁺ response. The T helper response is dominated by the Gag specificity. The Gag-specific CD8⁺ T-cell response showed a strong negative association with viral load. The opposite trends were observed for CD4⁺ and CD8⁺ T-cell responses to HIV proteins other than Gag. These results suggest that overall Gag-specific CTL epitopes are valuable for control of HIV C-clade infection and underline the importance of Gag-specific T-helper responses in the maintenance of the CTL response.

Keywords: T helper response; CTL; HIV