Disseminated and Sustained HIV-Infection in CD34+ Cord Blood Cell Transplanted Rag2−/−gc−/− Mice.

Abstract

HIV research has been hampered due to the lack of assessable animal models that mirror infection in humans. HIV is a human-specific virus, and consequently laboratory rodents as mice or rats are not susceptible to infection. Although non-human primates as chimpanzees can be infected, they do not develop HIV-associated immunodeficiency, while sooty mangabeys, rhesus macaques, and baboons are only susceptible to HIV related simian-immunodeficiency virus. Efforts to genetically engineer rodents to become HIV targets have largely failed; even if infection in vitro was achieved, HIV replication in vivo was limited or absent. Thus, substitute xeno-chimeric models have been developed by transplanting immunodeficient mice with either human peripheral blood leukocytes (hu-PBL-SCID), or pieces of human fetal tissues containing hematopoietic cells (SCID-hu). Both hu-PBL-SCID and SCID-hu mice sustain HIV infection and replication in vivo. However, in hu-PBL-SCID mice xeno-reactivity and successive loss of human leukocytes limit infection to a relatively short time frame. In SCID-hu mice, HIV infection can be observed for extended times; however, availability of transplantable human fetal organs is restricted for practical and ethical reasons, and HIV pathology in these mice is mainly limited to tissue implants. Given these limitations hu-PBL-SCID and SCID-hu mice did not fully match the demand for a small animal model that closely mirrors infection in humans.Recently, we found that injection of human cord blood CD34+ cells into newborn Rag2−/−gc−/− mice leads to development of human T, B, and dendritic cells, successive formation of primary and secondary lymphoid organs in situ, and some in vivo immune responses. We here tested these mice as a model system for in vivo HIV-1 infection. Mice with a PB CD45+ and CD4+ cell chimerism of 29.4±18.2% and 2.7±3.0%, respectively, were infected i.p. with either CCR5-tropic YU-2 (n=15), or CXCR4-tropic NL4–3 (n=19) HIV-strains at 10–28 weeks of age. Independent of viral strains used, HIV-RNA levels peaked two to six weeks after infection, with up to about 2x10E6 copies/ml plasma, while thereafter viremia mostly stabilized at lower levels, and was maintained for up to 190 (YU-2) and 120 (NL4–3) days, the longest time followed. A marked relative CD4+ T cell depletion in peripheral blood occurred in CXCR4-tropic strain infected mice, while this was less pronounced in CCR5-tropic strain infected animals. Thymus infection, as determined by p24 immunohistochemistry, was almost exclusively observed in CXCR4-tropic strain infected mice, while spleen and lymph node HIV infection occurred irrespective of co-receptor selectivity, consistent with respective co-receptor expression on human CD4+ T-cells. P24 expressing, and thus productively HIV infected non-T cells such as CD68+ macrophages were only occasionally detected as expected in a non-inflammatory in vivo setting. In summary, the here presented data establishes newborn human CD34+ cell transplanted Rag2−/−gc−/− mice as a new tool to study HIV infection and pathogenesis in vivo, closely resembling HIV infection in humans. This straight-forward to generate, cost-effective, ethically unproblematic, and easy to monitor new in vivo model should thus be valuable to study virus-induced pathology, as well as pharmacologic or genetic approaches aiming to prevent or treat HIV infection.