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Diverse Repertoire of HIV-1 p24-Specific, IFN--Producing CD4⁺ T Cell Clones Following Immune Reconstitution on Highly Active Antiretroviral Therapy¹

Eli Boritz^*, Brent E. Palmer, Brian Livingston, Alessandro Sette and Cara C. Wilson^2,*,

Departments of ^* Immunology and Medicine, University of Colorado Health Sciences Center, Denver, CO 80262; and Epimmune, San Diego, CA 92121

HIV-1 Ag-specific CD4⁺ T cell proliferative responses in human subjects with advanced, untreated HIV-1 disease are often weak or undetectable. Conversely, HIV-1-specific CD4⁺ T cell proliferation is occasionally detected following suppression of HIV-1 replication with highly active antiretroviral therapy (HAART). These observations suggest that unchecked HIV-1 replication may lead to depletion or dysfunction of HIV-1-specific CD4⁺ T cells, and that these defects may be partially corrected by viral suppression and subsequent immune reconstitution. However, the impact of this immune reconstitution on the repertoire of HIV-1-specific CD4⁺ T cells has not been thoroughly evaluated. To examine the HIV-1-specific CD4⁺ T cell repertoire in this clinical setting, we established HIV-1 p24-specific CD4⁺ T cell clones from a successfully HAART-treated subject whose pretreatment peripheral CD4 count was 0 cells/µl. Eleven different p24-specific CD4⁺ T cell clonotypes were distinguished among 13 clones obtained. Most clones produced both IFN- and IL-4 upon Ag stimulation. Clones targeted eight distinct epitopes that varied in their conservancy among HIV-1 strains, and responses were restricted by one of three MHC II molecules. Clones showed a range of functional avidities for both protein and peptide Ags. Additional studies confirmed that multiple HIV-1 p24-derived epitopes were targeted by IFN--producing CD4⁺ cells from subjects first treated with HAART during advanced HIV-1 disease (median, 4.5 peptides/subject; range, 3–6). These results suggest that in HAART-treated subjects whose peripheral CD4⁺ T cell pools were once severely depleted, the HIV-1-specific CD4⁺ T cell repertoire may include a diverse array of clonotypes targeting multiple HIV-1 epitopes.

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