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Cross-Clade Envelope Gp160, Gag p55 and Pol Specific CD8+ CTL Responses Early Following HIV-1 Clade-B Infection Objective: To evaluate the breadth of HIV-1 intra- and interclade env gp160 (BLAI vs. BMN, A and C), gag p55 and pol (A and BLAI) CTL reactivity in recently HIV-1 clade B-infected individuals. Methods: PBMC were isolated from recently HIV-1 clade B-infected individuals (10 weeks to 24 months post seroconversion) and stimulated in vitro using autologous PBMC infected with a vaccinia vectors expressing either a multigene cocktail comprised of HIV-1 env gp160LAI, gag p55LAI, polLAI(vAbT-408-6-1) and nefLAI (vAbT-23-5-1), or a multigene complex containing env gp120MN linked to the transmembrane portion of gp41LAI, gag p55LAI and proteaseLAI antigens (vP1291). At day 9-12 CTL reactivity against a panel of targets was assess using a standard 4-h chromium release assay. The target panel was comprised of autologous EBV-BCL infected with vaccinia vectors expressing env gp160 (BLAI, BMN, A92UG037 and C92BR025), gag p55 BLAI A92UG037 and E91CAR402, or pol BLAI and A92UG037. Results: All 13 of the 19 recent seroconverters who elicited positive gp160 BLAI CTL responses also showed comparable CTL reactivity against gp160 C92BR025, nine of these individuals also demonstrated CTL cross recognition of gp160 A92UG037. In addition, 18/22 (82%) donors elicited positive gag p55 BLAI CTL reactivity, with 16/22 (73%) and 10/13 (77%) showing CTL cross-recognition of gag p55 A92UG037 and gag p55 E91CAR402 respectively. Interestingly, four donors examined showed significantly greater CTL response against clade A92UG037 and/or E91CAR402 gag p55 infected targets than BLAI. Of a total of 18 donors tested for pol-specific CTL reactivity, 16/17 (94%) responded to pol BLAI with only 8/17 (53%) showing pol A92UG037 CTL cross-reactivity. All CTL reactivity was found to be mediated by CD8+ effectors. Conclusion: This study indicates that there is a considerable degree of CTL cross-recognition of the highly divergent HIV-1 env gp160 subtypes during early phases of HIV-1 infection, as well as the more conserved gag p55 and pol proteins. Such findings suggest that a HIV-1 vaccine based on a single isolate that can induce extensive cross-clade immunity could potentially demonstrate significant universal utility. Susan Wilson
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