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Increase in Breadth and Frequency of CTL Responses after Structured Therapy Interruptions in Individuals Treated with HAART during Acute HIV-1 Infection M. ALTFELD*, E. S. ROSENBERG, R. L. ELDRIDGE, S. POON, J. S. MUKHERJEE, M. PHILLIPS, P. J. GOULDER, and B. D. WALKER.
AIDS Res. Ctr., Massachusetts Gen. Hosp. and Harvard Med. Sch., Boston Objective: To characterize HIV-1 specific CTL responses in individuals treated with HAART prior to HIV-1 seroconversion and during structured therapy interruptions (STI).
Methods: Acute HIV-infection was diagnosed in 15 persons prior to seroconversion and treated immediately with HAART. After at least 1 year of treatment 7 patients underwent STI. HIV-RNA levels and CD4-cell counts were quantified weekly during STI. CTL responses against optimal HLA class I-restricted epitopes and comprehensive overlapping GAG, ENV, RT and NEF peptides were quantified by ELISPOT assays and CD8+ T-cell dependence of the responses was confirmed by CD8-cell depletion and generation of CTL clones.
Results: Mean viral load at the time of diagnosis was 13.8 x 106 copies HIV-1 RNA/ml. HIV-RNA became undetectable in all patients on average 10 weeks (4 - 19 weeks) after institution of HAART and remained undetectable during the entire period of treatment. Low magnitude CTL responses directed against 1 to 4 epitopes were detected in 10 of 15 subjects at time of diagnosis, and persisted at lower frequencies during therapy. Therapy was then interrupted in seven persons. All had a rebound in virus within 1 to 8 weeks and HAART was reintroduced. This was accompanied by a boost in CTL responses in all patients, resulting in an increase in the number of recognized epitopes by a median of 2 (range 0 to 3) and an augmentation of the magnitude of responses to previously recognized epitopes. The two persons with no CTL responses both developed CTL following STI. Additional increases in CTL responses were observed in the two persons who underwent additional STI, resulting in total CTL frequencies 5040 and 7240/million PBMC, respectively.
Conclusion: CTL responses are detectable during acute HIV-1-infection prior to seroconversion, but are narrowly directed at a few epitopes. These responses persist at lower levels during HAART. Structured treatment interruptions results in a persistent augmentation in the frequency and breadth of CTL responses in these subjects, which can be further boosted by additional controlled interruptions in therapy.
Key Words: acute HIV-infection, CTL, therapy interruption
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