CCR5- and CXCR4-tropic HIV-1 are equally cytopathic for their T-cell targets in human lymphoid tissue

A rapid decline in T-cell counts and the progression to AIDS is often assoc iated with a switch from CCR5-tropic (R5) HIV-1 to CXCR4-tropic (X4) HIV-1 or R5/X4 HIV-1 variants(1,2) Experimental infection with R5 HIV-1 causes le ss T-cell depletion than infection with X4 or R5/X4 variants in T-cell cult ures(3), in ex vivo infected human lymphoid tissue(4,5) and in SCID/hu mice (6), despite similar replication levels. Experimental genetic changes in th ose sequences in gp120 that transform R5 HIV-1 variants into otherwise isog enic X4 viruses make them highly cytopathic(6,7). Thus, it is now believed that R5 variants are less cytopathic for T cells than are X4 variants. Howe ver, it is not known why CCR5-mediated HIV-1 infection does not lead to a m assive CD4(+) T-cell depletion, as occurs in CXCR4-mediated HIV-1 infection . Here we demonstrate that R5 HIV-1 isolates are indeed highly cytopathic, but only for CCR5(+)/CD4(+) T cells. Because these cells constitute only a small fraction of CD4(+) T cells, their depletion does not substantially ch ange the total CD4(+) T-cell count. These results may explain why the clini cal stage of HIV disease correlates with viral tropism.