CD4 + T cells from HIV‐1‐infected patients recognize wild‐type and mutant human immunodeficiency virus‐1 protease epitopes

Summary Human immunodeficiency virus (HIV)‐1 protease is a known target of CD8 + T cell responses, but it is the only HIV‐1 protein in which no fully characterized HIV‐1 protease CD4 epitopes have been identified to date. We investigated the recognition of HIV‐1 protease by CD4 + T cells from 75 HIV‐1‐infected, protease inhibitor (PI)‐treated patients, using the 5,6‐carboxyfluorescein diacetate succinimidyl ester‐based proliferation assay. In order to identify putative promiscuous CD4 + T cell epitopes, we used the TEPITOPE algorithm to scan the sequence of the HXB2 HIV‐1 protease. Protease regions 4–23, 45–64 and 73–95 were identified; 32 sequence variants of the mentioned regions, encoding frequent PI‐induced mutations and polymorphisms, were also tested. On average, each peptide bound to five of 15 tested common human leucocyte antigen D‐related (HLA‐DR) molecules. More than 80% of the patients displayed CD4 + as well as CD8 + T cell recognition of at least one of the protease peptides. All 35 peptides were recognized. The response was not associated with particular HLA‐DR or ‐DQ alleles. Our results thus indicate that protease is a frequent target of CD4 + along with CD8 + proliferative T cell responses by the majority of HIV‐1‐infected patients under PI therapy. The frequent finding of matching CD4 + and CD8 + T cell responses to the same peptides may indicate that CD4 + T cells provide cognate T cell help for the maintenance of long‐living protease‐specific functional CD8 + T cells.