thy/liv‐SCID‐hu Mice: A System for Investigating the In Vivo Effects of Multidrug Therapy on Plasma Viremia and Human Immunodeficiency Virus Replication in Lymphoid Tissues

Abstract

Modified, human immunodeficiency virus (HIV)-inoculated thy/liv-SCID-hu mice were used to evaluate the in vivo efficacy of antiretroviral drugs. Ritonavir treatment alone initially suppressed plasma viremia, but the viremia recurred with the appearance of ritonavir-resistant HIV isolates. Multidrug therapy suppressed plasma HIV RNA to undetectable levels; however, plasma viremia returned after therapy was stopped, showing that the therapy did not completely suppress HIV infection in the thymic implant. When thy/liv-SCID-hu mice were treated with a combination of zidovudine, lamivudine, and ritonavir immediately after inoculation with HIV, cocultures of the thymic implants remained negative for HIV even 1 month after therapy was discontinued, suggesting that acute treatment can prevent the establishment of HIV infection. Thus, these modified thy/liv-SCID-hu mice should prove to be a useful system for evaluating the effectiveness of different antiretroviral therapies on acute and chronic HIV infection.

Reconsidering targeted toxins to eliminate HIV infection: You gotta have HAART

“…There are several experimental paradigms in which this question can be examined, including comparison of CD4-PE40 hepatotoxicity in uninfected vs. chronically HIV-infected severe combined immunodeficient-hu mice or SIV-infected rhesus macaques. Perhaps more important is to use these systems to compare animals with the normal high viral loads occurring during chronic infection vs. the reduced loads achieved with potent antiviral therapy, e.g., HAART in HIV-infected severe combined immunodeficient-hu mice (32) or reverse transcriptase inhibitor therapy in SIV-infected macaques (33). A related analysis would compare in chronically infected animals the effects of hybrid toxins targeted to gp120 (e.g., CD4-PE40 and gp120-targeted immunotoxins) versus those targeted to gp41; according to our model, the latter agents would not produce hepatotoxicity even in animals with high virus load because gp41 is not released spontaneously from the membrane.…”

CCR8 on Human Thymocytes Functions as a Human Immunodeficiency Virus Type 1 Coreceptor

“…However, effective inhibition of viral replication was achieved when multidrug therapy was initiated immediately after infection of the thymic implant (26). Since the thymic microenvironment preserves its ability to support endogenous progenitor cell differentiation following exposure to HIV-1 (39), it is important to identify which coreceptors within the thymus should be targeted by inhibitors in combination with multidrug therapy to ensure control of viral replication.…”

Gene Therapy Using a Simian Virus 40–Derived Vector Inhibits the Development of In Vivo Human Immunodeficiency Virus Type 1 Infection of Severe Combined Immunodeficiency Mice Implanted with Human Fetal Thymic and Liver Tissue

“…The level of HIV-1 infection of the human thymic implants was determined by quantifying the number of HIV-1-infected thymocytes present in the graft, using limiting dilution quantitative cocultures, as described elsewhere [11,12]. This technique was used because it measures the number of cells capable of producing infectious HIV-1 [14].…”

“…The HIV-1-susceptible animal model we used is the thy/liv-SCID-hu mouse, which is constructed by implanting human fetal thymus and liver tissue under the murine kidney capsules, where the implanted tissue grows into a graft that closely resembles normal human thymus, exhibits long-term human T cell differentiation, and displays susceptibility to infection with HIV-1 [11]. We used this system to evaluate the in vivo capacity of anti-HIV-1 therapies to inhibit HIV-1 replication by examining their effects on the number of HIV-1-infected thymocytes in the human thymic graft [12]. Therefore, we postulated that we could evaluate the in vivo therapeutic efficacy of candidate anti-HIV-1 genes delivered by this vector using our thy/liv-SCID-hu mouse system [13].…”