Disseminated and sustained HIV infection in CD34⁺cord blood cell-transplanted Rag2^−/−γ_c^−/−mice

Abstract

Because of species selectivity, HIV research is largely restricted to in vitro or clinical studies, both limited in their ability to rapidly assess new strategies to fight the virus. To prospectively study some aspects of HIV in vivo, immunodeficient mice, transplanted with either human peripheral blood leukocytes or human fetal tissues, have been developed. Although these are susceptible to HIV infection, xenoreactivity, and short infection spans, resource and ethical constraints, as well as biased HIV coreceptor tropic strain infection, pose substantial problems in their use. Rag2 ؊/؊ ␥c ؊/؊ mice, transplanted as newborns with human CD34 ؉ cells, were recently shown to develop human B, T, and dendritic cells, constituting lymphoid organs in situ. Here we tested these mice as a model system for HIV-1 infection. HIV RNA levels peaked to up to 2 ؋ 10 6 copies per milliliter of plasma early after infection, and viremia was observed for up to 190 days, the longest time followed. A marked relative CD4 ؉ T cell depletion in peripheral blood occurred in CXCR4-tropic strain-infected mice, whereas this was less pronounced in CCR5-tropic strain-infected animals. Thymus infection was almost exclusively observed in CXCR4-tropic strain-infected mice, whereas spleen and lymph node HIV infection occurred irrespective of coreceptor selectivity, consistent with respective coreceptor expression on human CD4 ؉ T cells. Thus, this straightforward to generate and cost-effective in vivo model closely resembles HIV infection in man and therefore should be valuable to study virus-induced pathology and to rapidly evaluate new approaches aiming to prevent or treat HIV infection.

Viral infections in mice with reconstituted human immune system components

“…Accordingly, they are compromised in their ability to make humoral immune responses and primarily IgM antibodies against viruses can be found after infection. This was reported for huNSG, huBRG and BLT mice after HIV, HSV-2, adeno-, EBV, dengue and JC virus infection [16,40,43,62,66,77,78]. Consistent with these findings, the B cell areas of secondary lymphoid tissues of HIS mice do not show germinal center development [79], but can develop these structures after prolonged or repeated immunization [75,80].…”

“…However, many more hurdles have to be overcome [27,28,88], the manipulation of human immune system components will generate potent preclinical models for relevant human diseases, which might yield results that can be more easily translated into the clinic. Hepatitis B virus (HBV) Liver disease [41] Herpes simplex virus 2 (HSV-2) Inflammation at mucosal infection site [16] Human cytomegalovirus (HCMV) GM-CSF mediated reactivation from myeloid cells [17] Epstein Barr virus (EBV) Tumor formation, hemophagocytic lymphohistiocytosis, erosive arthritis [89] Kaposi Sarcoma associated herpesvirus (KSHV) Persistent infection in B cells [39] Adenovirus Liver disease [40] Human immunodeficiency virus (HIV) CD4 + T cell depletion [43] Human T cell leukemia virus 1 (HTLV-1)…”

“…Therefore, I will just concentrate on some high-lights from the studies of HIV infection in HIS mice. Both CCR5-and CXCR4-tropic HIV-1 strains have been found to replicate in HIS mice and cause CD4 + T cell depletion [43,44]. To some extent, especially BLT mice on the NOD-scid background also allow rectal infection via mucosal transmission [9,45].…”

HIV-1 infection and pathogenesis in a novel humanized mouse model

“…First, the mouse supports efficient and stable development of human T, B, and myeloid cells in central and peripheral lymphoid organs. 11,12 Second, HIV-1 infection leads to high and persistent HIV-1 viremia in PB and in lymphoid organs (this report and a recent report 24 ). Third, human CD4 ϩ T cells are depleted by HIV-1 in a dose-and virus-dependent fashion.…”

“…However, the human antibody or T-cell response is weak in the DKO-hu HSC mouse (L.Z. and L.S., unpublished results and Baenziger et al 24 ). In a recent report, NOD/SCID/ IL2R␥-null mice humanized by cord blood-derived CD34 ϩ cells have been shown to support HIV-1 infection with both CCR5-and CXCR4-tropic HIV-1 isolates for more than 40 days.…”