MICE TRANSGENIC FOR HUMAN CD4 AND CCR5 ARE SUSCEPTIBLE TO HIV-INFECTION

HIV entry into human cells is mediated by CD4 acting in concert with o ne of several members of the chemokine receptor superfamily. The resis tance to HIV infection observed in individuals with defective CCR5 all eles indicated that this particular chemokine receptor plays a crucial role in the initiation of in vivo HIV infection. Expression of human CD4 transgene does not render mice susceptible to HIV infection becaus e of structural differences between human and mouse CCR5. To ascertain whether expression of human CD4 and CCR5 is sufficient to make murine T Lymphocytes susceptible to HIV infection, the lck promoter was used to direct the T cell-specific expression of human CD4 and CCR5 in tra nsgenic mice. Peripheral blood mononuclear cells and splenocytes isola ted from these mice expressed human CD4 and CCR5 and were infectible w ith selected M-tropic HIV isolates. After in vivo inoculation, HIV-inf ected cells were detected by DNA PCR in the spleen and lymph nodes of these transgenic mice, but HIV could not be cultured from these cells. This indicated that although transgenic expression of human CD4 and C CR5 permitted entry of HIV into the mouse cells, significant HIV infec tion was prevented by other blocks to HIV replication present in mouse cells. In addition to providing in vivo verification for the importan t role of CCR5 in T lymphocyte HIV infection, these transgenic mice re present a new ill vivo model for understanding HIV pathogenesis by del ineating species-specific cellular factors required for productive in vivo HIV infection. These mice should also prove useful for the assess ment of potential therapeutic and preventative modalities, particularl y vaccines.