Disseminated human immunodeficiency virus 1 (HIV-1) infection in SCID-hu mice after peripheral inoculation with HIV-1.

Abstract

SummaryA small animal model that could be infected with human immunodeficiency virus 1 (HIV-1) after peripheral inoculation would greatly facilitate the study of the pathophysiology of acute HIV-1 infection. The utility of SCID mice implanted with human fetal thymus and liver (SCIDhu mice) for studying peripheral HIV-1 infizction in vivo has been hampered by the requirement for direct intraimplant injection of H1V-1 and the continued restriction of the resultant HIV-1 infection to the human thymus and liver (hu-thy/liv) implant. This may have been due to the very low numbers of human T cells present in the SCID-hu mouse peripheral lymphoid compartment. Since the degree of the peripheral reconstitution 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 implanted under the renal capsule and implanted bu-thy/liv tissue under the capsules of both kidneys. This resulted in SCID-hu mice in which significant numbers of human T cells were detected in the peripheral blood, spleens, and lymph nodes. After intraimplant injection of HIV-1 into these modified SCID-hu mice, significant HIV-1 infection was detected by quantitative coculture not only in the hu-tby/liv implant, but also in the spleen and peripheral blood. This indicated that HIV-1 infection can spread from the thymus to the peripheral lymphoid compartment. More importantly, a similar degree of infection of the hu-thy/liv implant and peripheral lymphoid compartment occurred after peripheral intraperitoneal inoculation with HIV-1. Active viral replication was indicated by the detection of HIV-1 gag DNA, HIV-1 gag RNA, and spliced tat/rev KNA in the hu-thy/liv implants, peripheral blood mononudear cells (PBMC), spleens, and lymph nodes of these HIV-l-infected SCID-hu mice. As a first step in using our modified SCID-hu mouse model to investigate the pathophysiological consequences of HIV-1 infection, the effect of HIV-1 infection on the expression of human cytokines shown to enhance HIV-1 replication was examined. Significantly more of the HIV-l-infected SCID-hu mice expressed mKNA for human tumor necrosis factors c~ and/5, and interleukin 2 in their spleens, lymph nodes, and PBMC than did uninfected SCID-hu mice. This suggested that HIV-1 infection in vivo can stimulate the expression of cytokine mP, NA by human T cells. Our modified SCID-hu mice may provide an improved model for studying the pathophysiology of HIV-1 infection in vivo and for investigating the effects of anti-HIV interventions on the prevention of disseminated HIV-1 infection.

HIV-1 pathogenesis and therapeutic intervention in the SCID-hu Thy/Liv mouse: a model for primary HIV-1 infection in the human thymus

“…It has been reported that IL10, but not IL12, can inhibit HIV-1 replication in the SCID-hu Thy/Liv mouse. 25 …”

“…25 In this model, HIV-1 infection can be initiated by intraperitoneal inoculation. 44 However, the Lai/IIIB isolate appears to infect the Thy/Liv organ in this model and leads to thymus depletion.…”

Coming of age: reconstruction of heterosexual HIV-1 transmission in human ex vivo organ culture systems

“…Mice have been generated by transplantation technologies that maintain human adaptive immune system components including CD4 + T cells that support HIV-1 replication. 134 -136 SCID-hu mice (Severe Combined Immunodeficiency-humanized) 137,138 and BLT mice (Bone Marrow, Liver, Thymus) 139,140 are not necessarily optimal for transmission studies because they retain mouse mucosal and stromal components, and natural routes of HIV-1 transmission begin with mucosal exposure. Another interesting approach has seen the development of multi-layered stratified squamous epithelial membranes (MatTek, Boston, MA) that are derived in an ex vivo differentiation system, using human ectocervical epithelial cells 141,142 or vaginal epithelial cells.…”

Factors Contributing to HIV-1 Induced Pathogenesis in the Human Thymus

“…This hu-Thy/Liv-SCID model has been extensively used for the analysis of human hematopoiesis, especially T cells, and as an animal model of HIV infection (McCune, 1997). HIV-1 injection in the thymic implant of hu-Thy/Liv-SCID mice resulted in significant HIV-1 infection not only in the Thy/Liv implant, but also in the spleen and peripheral blood, which indicated that HIV-1 infection could spread from the thymus to the peripheral lymphoid compartment (Kollmann et al, 1994). The effect of HIV-1 infection on thymocyte maturation and depletion depended upon the strain of HIV-1 infecting the thymus (Kollmann et al, 1995).…”