Understanding the lineage differentiation of memory T cells is a central question in immunology. We investigated this issue by analysing the expression of the chemokine receptor CCR7, which defines distinct subsets of naive and memory T lymphocytes with different homing and effector capacities(1-3) and antiviral immune responses to HIV and cytomegalovirus. Ex vivo analysis of the expression of CD45RA and CCR7 antigens, together with in vitro analysis of the cell-division capacity of different memory CD8(+) T-cell populations, identified four subsets of HIV- and CMV-specific CD8(+) T lymphocytes, and indicated the following lineage differentiation pattern: CD45RA(+)CCR7(+) --> CD45RA(-) CCR7(+) --> CD45RA(-) CCR7(-) --> CD45RA(+) CCR7(-). Here we demonstrate through analysis of cell division (predominantly restricted to the CCR7(+) CD8(+) T-cell subsets) that the differentiation of antigen-specific CD8(+) T cells is a two-step process characterized initially by a phase of proliferation largely restricted to the CCR7(+) CD8(+) cell subsets, followed by a phase of functional maturation encompassing the CCR7(-) CD8(+) cell subsets. The distribution of these populations in HIV- and CMV-specific CD8(+) T cells showed that the HIV-specific cell pool was predominantly (70%) composed of pre-terminally differentiated CD45RA(-)CCR7(-) cells, whereas the CMV-specific cell pool consisted mainly (50%) of the terminally differentiated CD45RA(+) CCR7(-) cells. These results demonstrate a skewed maturation of HIV-specific memory CD8(+) T cells during HIV infection.