Naive CD4 T cells inhibit CD28-costimulated R5 HIV replication in memory CD4 T cells

Stimulation with antibodies to CD3 and CD28 coimmobilized on beads can be u sed to significantly expand T cells ex vivo. With CD4 T cells from HIV-infe cted patients, this expansion usually is accompanied by complete suppressio n of viral replication, presumed to be caused by down-regulation of the vir al coreceptor CCR5 and up-regulation of CCR5 ligands. Here we show that thi s suppression occurs in total CD4 T cells acutely infected with R5 HIV, but not in purified CD62L(-) memory CD4 T cells. The lack of complete suppress ion in these memory cells, typically comprising 10-40% of total CD4 T cells , occurs despite high levels of CCR5 ligand secretion and down-regulation o f CCR5. Significantly, adding back naive or CD62L(+) memory CD4 T cells inh ibits the viral replication in the CD62L(-) cells, with the naive cells cap able of completely repressing the virus. Although this inhibition was previ ously thought to be specific to bead-bound anti-CD3/CD28 stimulation, we sh ow that the same suppression is obtained with sufficiently strong antiCD3/B 7.1 stimulation. Our results show that inhibitory mechanisms, expressed pre dominantly by strongly stimulated naive CD4 T cells and mediated independen tly of CCR5-binding chemokines, play a role in the inhibition of R5 HIV rep lication in CD4 T cells upon CD28 costimulation.