Effects of human immunodeficiency virus type 1 on CD4 lymphocyte subset activation

The pathogenesis of the decline of CD4 lymphocyte counts accompanying the t ypical course of HIV-1 infection is not completely defined and might be rel ated to a differential susceptibility of naive and memory cells to HIV-1 ex posure. Here, we examined the effects induced by heat-inactivated HIV-1 vir ions on these lymphocyte populations. Exposure of CD45RA naive T cells to i nactivated viral particles induced a marked decrease of both mitogenic resp onses and activation-induced apoptosis. Conversely, the growth of CD45RO ce lls was less severely restrained. Analysis of intracellular levels of cell cycle regulatory proteins revealed an arrest at the G1/S restriction point of the naive but not memory subset. This effect was associated with alterat ions in phosphotyrosine profile and with a marked decrease of ERK and NJK k inase activation. Finally, up-regulation of the cAMP-dependent protein kina se A (PKA) activity induced by mitogens was not affected by virus. Altogeth er, these findings show that interaction of HIV-1 with the T cell surface i s sufficient to inhibit the proliferative response of the CD4CD45RA subset by disturbing proximal TCR signaling, This mechanism would affect renewal o f naive lymphocytes, contributing in such a way to the impairment of T cell turnover during the course of HIV-1 infection.