Background: CTL escape has been demonstrated numerous times, yet it is not clear which epitopes are protective and to what extent escape mutations play a role in host pathogenesis. We hypothesized that responses maintained during chronic infection are directed against more conserved proteins than are responses observed in early infection.

Methods: We analyzed responses appearing early in infection as well as in chronic infection to the most variable of HIV-1 proteins (Vif, Vpr, Vpu, Tat, Rev, and Env) and compared these with responses to conserved proteins (Gag, Pol, and Nef). Nef is categorized as such since it is conserved at regions targeted by CD8⁺ T-cells. Frozen PBMCs taken early in infection (< 1 yr) from 20 patients (pts) and in more chronic infection from 70 (selected from the REACH study of the Adolescent Medicine HIV/AIDS Research Network and the UAB HIV clinic) were stimulated with subtype B peptides spanning all HIV-1 proteins. Responses were measured in an IFN-g ELISpot assay.

Results: Overall, early in infection 18/20 (90%) pts had HIV-1 specific T-cell responses to one or more variable proteins (Rev 30%, Vif 20%, Vpr 25%, Tat 5 %, Vpu 5%, and Env 55%). These were significantly different from responses of chronically infected subjects 37/70 (53%) (p = 0.004 by Fischer’s exact) (Rev 10%, Vif 9%, Vpr 10%, Tat 3%, Vpu 1%, and Env 39%). Responses to the conserved proteins Gag, Pol, and Nef occurred at similar rates in early infection (15/20 [75%]; Gag 50%, Pol 30%, and Nef 60%) and in chronic infection (56/70 [80%]; Gag 65%, Pol 54%, and Nef 64%). Additionally, immunodominant (ID) responses were targeted to the variable proteins for 9/20 (45%) during early infection compared with 8/70 (11%) during chronic infection (p = 0.007). We also evaluated CTL responses longitudinally in the 1 acutely infected pt who had discontinued ART. Although Vif represented the ID response early (with subdominant responses in Nef), the Vif response declined during the course of infection while new responses were seen against Gag and Pol (the latter becoming ID). Responses in Nef remained unchanged.

Conclusions: CD8⁺ T-cells targeted variable proteins early in HIV-1 infection, yet these responses did not appear to be maintained during chronic disease. This finding may be due to the accumulation of escape mutations in variable proteins. The role of variable proteins as protective antigens for use in candidate HIV-1 vaccines should be carefully assessed.