Human immunodeficiency virus type 1 strains R5 and X4 induce different pathogenic effects in hu-PBL-SCID mice, depending on the state of activation differentiation of human target cells at the time of primary infection

In a previous study, we had found that the extent of T-cell dysfunctions in duced by a T-tropic strain of human immunodeficiency virus type 1 (HIV-1) i n SCID mice reconstituted with human peripheral blood lymphocytes (hu-PBLs) (hu-PBL-SCID mice) was related to the in vivo state of activation of the h uman lymphocytes. In this article, we compared the effect of infection of h u-PBL-SCID mice with either T-tropic (X4) or M-tropic (R5) strains of HIV-1 by performing virus inoculation at either 2 h or 2 weeks after the hu-PBL transfer, when the human T cells exhibited a marked activation state or a p redominant memory phenotype, respectively. A comparable level of infection was found when hu-PBL-SCID mice were challenged with either the SF162 R5 or the IIIB X4 strain of HIV at 2 h postreconstitution, while at 2 weeks, the R5 virus infection resulted in a higher level of HN replication than the X 4 virus. The R5 strain induced a marked human CD4(+) T-cell depletion along with a drop in levels of human immunoglobolin M in serum and release of so luble factors at both infection times, while the X4 virus induced severe im mune dysfunctions only at 2 h. Of interest, injection of hu-PBLs into SCID mice resulted in a marked up-regulation of CCR5 on human CD4(+) T cells. Th e percentage of CXCR4(+) cells did not change after transplantation, even t hough a significant decrease in antigen expression was observed. Comparativ e experiments with two molecular clones of HIV-1 (X4 SF2 and R5 SF162) and two envelope recombinant viruses generated from these viruses showed that R 5 viruses (SF162 and the chimeric env-SF162-SF2) caused an extensive deplet ion of human CD4(+) T cells in SCID mice at both 2 h and 2 weeks after reco nstitution, while the X4 viruses (SF2 and the chimeric env-SF2-SF162) induc ed CD4 T-cell depletion only when infection was performed at the 2-h recons titution time. These results emphasize the importance of the state of activ ation/differentiation of human CD4(+) T cells and gp120-coreceptor interact ions at the time of primary infection in determining HIV-1 pathogenicity in the hu-PBL-SCID mouse model.