DISSEMINATED HUMAN-IMMUNODEFICIENCY-VIRUS-1 (HIV-1) INFECTION IN SCID-HU MICE AFTER PERIPHERAL INOCULATION WITH HIV-1

A small animal model that could be infected with human immunodeficienc y virus 1 (HIV-1) after peripheral inoculation would greatly facilitat e the study of the pathophysiology of acute HIV-1 infection. The utili ty of SCID mice implanted with human fetal thymus and liver (SCID-hu m ice) for studying peripheral HIV-1 infection in vivo has been hampered by the requirement for direct intraimplant injection of HIV-1 and the continued restriction of the resultant HIV-1 infection to the human t hymus and liver (hu-thy/liv) implant. This may have been due to the ve ry low numbers of human T cells present in the SCID-hu mouse periphera l lymphoid compartment. Since the degree of the peripheral reconstitut ion of SCID-hu mice with human T cells may be a function of the hu-thy /liv implant size, we increased the quantity of hu-thy/liv tissue impl anted under the renal capsule and implanted hu-thy/liv tissue under th e capsules of both kidneys. This resulted in SCID-hu mice in which sig nificant numbers of human T cells were detected in the peripheral bloo d, spleens, and lymph nodes. After intraimplant injection of HIV-1 int o these modified SCID-hu mice, significant HIV-1 infection was detecte d by quantitative coculture not only in the hu-thy/liv implant, but al so in the spleen and peripheral blood. This indicated that HIV-1 infec tion can spread from the thymus to the peripheral lymphoid compartment . More importantly, a similar degree of infection of the hu-thy/liv im plant and peripheral lymphoid compartment occurred after peripheral in traperitoneal inoculation with HIV-1. Active viral replication was ind icated by the detection of HIV-1 gag DNA, HIV-1 gag RNA, and spliced t at/rev RNA in the hu-thy/liv implants, peripheral blood mononuclear ce lls (PBMC), spleens, and lymph nodes of these HIV-1-infected SCID-hu m ice. As a first step in using our modified SCID-hu mouse model to inve stigate the pathophysiological consequences of HIV-1 infection, the ef fect of HIV-1 infection on the expression of human cytokines shown to enhance HIV-1 replication was examined. Significantly more of the HIV- 1-infected SCID-hu mice expressed mRNA for human tumor necrosis factor s alpha and beta, and interleukin 2 in their spleens, lymph nodes, and PBMC than did uninfected SCID-hu mice. This suggested that HIV-1 infe ction in vivo can stimulate the expression of cytokine mRNA by human T cells. Our modified SCID-hu mice;may provide an improved model for st udying the pathophysiology of HIV-1 infection in vivo and for investig ating the effects of anti-HIV interventions on the prevention of disse minated HIV-1 infection.