Human immunodeficiency virus type 1 pathogenesis in SCID-hu mice correlates with syncytium-inducing phenotype and viral replication

Human immunodeficiency virus type I (HIV-I) patient isolates and molecular clones were used to analyze the determinants responsible for human CD4(+) t hymocyte depletion in SCID-hu mice, Non-syncytium-inducing, R5 or R3R5 HIV- 1 isolates from asymptomatic infected people showed little or no human CD4( +) thymocyte depletion in SCID-hu mice, while syncytium-indueing (SI), R5X4 or R3R5X4 HIV-1 isolates from the same individuals, isolated just prior to the onset of AIDS, rapidly and efficiently eliminated CD4-bearing human th ymocytes. We have mapped the ability of one SI HIV-1 isolate to eliminate C D4(+) human cells in SCID-hu mice to a region of the env gene including the three most amino-terminal variable regions (V1 to V3). We find that for al l of the HIV-1 isolates that we studied, a nonlinear relationship exists be tween viral replication and the depletion of CD4(+) cells. This relationshi p can best be described mathematically with a Hill-type plot indicating tha t a threshold level of viral replication, at which cytopathic effects begin to be seen, exists for HIV-1 infection of thymus/liver grafts in SCID-hu m ice. This threshold level is 1 copy of viral DNA for every 11 cells (95% co nfidence interval = 1 copy of HIV-I per 67 cells to 1 copy per 4 cells). Fu rthermore, while SI viruses more frequently achieve this level of replicati on, replication above this threshold level correlates best with cytopathic effects in this model system. We used GHOST cells to map the coreceptor spe cificity and relative entry efficiency of these early- and late-stage patie nt isolates of HIV-1. Our studies show that coreceptor specificity and entr y efficiency are critical determinants of HIV-1 pathogenesis in vivo.