CD4 down-modulation by human immunodeficiency virus type 1 Nef correlates with the efficiency of viral replication and with CD4(+) T-cell depletion in human lymphoid tissue ex vivo

The human immunodeficiency virus type 1 (HIV-1) Nef protein is an important virulence factor. Nef has several functions, including down-modulation of CD4 and class I major histocompatibility complex cell surface expression, e nhancement of virion infectivity, and stimulation of viral replication in p eripheral blood mononuclear cells. Nef also increases HIV-1 replication in human lymphoid tissue (HLT) ex vivo. We analyzed recombinant and primary ne f alleles with highly divergent activity in different in vitro assays to cl arify which of these Nef activities are functionally linked. Our results de monstrate that Nef activity in CD4 downregulation correlates significantly with the efficiency of HIV-1 replication and with the severity of CD4(+) T- celI depletion in HLT. In conclusion, HIV-1 Nef variants with increased act ivity in CD4 down-modulation would cause severe depletion of CD4(+) T cells in lymphoid tissues and accelerate AIDS progression.