Ana Kim

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

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.

Decreased susceptibility of peripheral blood mononuclear cells from individuals heterozygous for a mutant CCR5 allele to HIV infection.

OBJECTIVE Individuals homozygous for a deletion in the CCR5 gene (CCR5delta32/CCR5delta32) are resistant to HIV infection, indicating that this particular chemokine receptor plays a crucial role in the initiation of in vivo HIV infection. We investigated the effect of the heterozygote genotype (CCR5/CCR5delta32) on susceptibility of peripheral blood mononuclear cells (PBMC) to HIV infection. DESIGN Sensitivity to HIV infection of PBMC from volunteers with either the CCR5/CCR5, CCR5/CCR5delta32, or CCR5delta32/CCR5delta32 genotypes was examined by challenging their PBMCs with serial titers of HIV isolates with different cellular tropisms. The genotype of the PBMCs was correlated with the lowest viral inoculum required to initiate productive infection with either three M-tropic HIV-1 isolates, (92RW009A, HIV-1ada, and HIV-1(59)), one dual-tropic HIV-1 isolate (92BR021), or two T-tropic HIV-1 isolates (92UG021 and 92UG029). RESULTS PBMCs from the CCR5/CCR5delta32 group required a significantly higher inoculum (p value from .036 to .003) to become infected with these three M-tropic HIV-1 isolates than did PBMC from the CCR5/CCR5 group, but became infected after exposure to an inoculum of T-tropic HIV-1 isolates that was comparable to that which infected PBMCs from the CCR5/CCR5 individuals. CONCLUSIONS The decreased susceptibility of PBMCs from individuals heterozygous for the CCR5 deletion to HIV infection by M-tropic HIV-1 isolates may provide a mechanistic explanation for the delayed progression of disease in some CCR5/CCR5delta32 individuals.

Receptor-mediated maternofetal transfer of immunoglobulins. Inhibition of transport of anti-HIV-1 immunoglobulin by generic immunoglobulins in the in vitro perfused placenta.

Objectives: The passage of immunoglobulin G (IgG) across the placenta is thought to involve Fc’ receptors on the syncytiotrophoblast. To confirm the receptor dependency of this process we have studied the changes in the tissue content and transfer kinetics of immunoglobulins and hyperimmune serum to HIV (HIVIG) during in vitro dual placental perfusion. Methods: Isolated lobules of term placentae from normal pregnancies were perfused in a model of maternal and fetal circulation. The perfused tissue was compared to fresh tissue samples from the same placenta for the content of IgG, IgG subclasses, IgM, cytokeratin, human placental lactogen and SP1 antigen by immunohistochemistry and by protein elution. Results: The immunoglobulin staining faded by an average of 40% during the 1st hour of perfusion. In contrast, staining for cytokeratin, human placental lactogen and SP1 remained unchanged. During a 4-hour recycling of endogenous immunoglobulins in the maternal circulation, IgG and HIVIG crossed to the fetal side in a steady rate. The transport of HIVIG could be inhibited by preperfusion with an intravenous gammaglobulin preparation (IVIG). Discussion: The transfer of IgG across the placenta occurs in a steady state rate consistent with a receptor-mediated mechanism. Furthermore, inhibition of HIVIG maternofetal transfer by IVIG further establishes the receptor-mediated transfer of immunoglobulins through the placenta.