Human Naive CD4 T-Cell Clones Specific for HIV Envelope Persist for Years In Vivo in the Absence of Antigenic Challenge

To study the persistence of HIV-specific human naive CD4-lymphocytes in vivo in the absence of antigenic stimulation, we identified 2 HIV-seronegative low-risk subjects carrying CD4-cells specific for gp120 that could be expanded in vitro. CD4 T-cell lines specific for gp120 were generated by stimulation cycles with antigen-pulsed antigen-presenting cells. Clonal analysis was performed by spectratyping and by sequencing of the CDR3 regions of the BV and AV-T-cell receptor (TCR) genes. HIV-specific T cells were expanded in vitro in 1989 and 2004. These lines were generated from naive precursors. Analysis of TCR-BV gene family use and sequencing of the TCR-BV22 hypervariable region revealed a BV22 clonotype in the 1989 line. The BV22-CDR3-based polymerase chain reaction primer confirmed that the 1989 and 2004 T-cell lines contained the same clonotype. In addition, the 1989 and 2004 T cells used the same TCR-AV38 gene family and identical CDR3-AV regions, confirming clonal identity. Similar data for a persistent clonotype defined by BV CDR3 sequencing were obtained from the second subject. In conclusion, naive CD4-cells specific for an HIV antigen not encountered in vivo persisted for more than 10 to 15 years. An extended lifespan, homeostatic proliferation, or the ability of the thymus to issue the same CD4 T-cell clone reiteratively might account for the phenomenon.