RAG2 ^−/− γ _c ^−/− Mice Transplanted with CD34 ⁺ Cells from Human Cord Blood Show Low Levels of Intestinal Engraftment and Are Resistant to Rectal Transmission of Human Immunodeficiency Virus

Abstract

Rectal transmission is one of the main routes of infection by human immunodeficiency virus type 1 (HIV-1).To efficiently study transmission mechanisms and prevention strategies, a small animal model permissive for rectal transmission of HIV is mandatory. We tested the susceptibility of RAG2 ؊/؊ ␥ c ؊/؊ mice transplanted with human cord blood hematopoietic stem cells to rectal infection with HIV. We rectally exposed these humanized mice to cell-free and cell-associated HIV. All mice remained HIV negative as assessed by plasma viral load. The same mice infected intraperitoneally showed high levels of HIV replication. In the gut-associated lymphatic tissue, we found disproportionately smaller numbers of human cells than in other lymphoid organs. This finding may explain the observed resistance to rectal transmission of HIV. To increase the numbers of local HIV target cells and the likelihood of HIV transmission, we treated mice with different proinflammatory stimuli: local application of interleukin-1␤, addition of seminal plasma to the inoculum, or induction of colitis with dextran sodium sulfate. These procedures attracted some human leukocytes, but the transmission rate was still very low. The humanized mice showed low levels of human engraftment in the intestinal tract and seem to be resistant to rectal transmission of HIV, and thus they are an unsuitable model for this application.

No SEVI-mediated enhancement of rectal HIV-1 transmission of HIV-1 in two humanized mouse cohorts

“…HIV-1 JR-CSF was incubated with SEVI or a negative control peptide prior to inoculation and mice were inoculated once daily for three days with mixtures containing 9 x 10 4 tissue-culture infectious units (TCIU) (high dose) HIV-1 incubated with either SEVI or the negative control peptide. Humanized mice are relatively resistant to intrarectal inoculation of HIV at low doses (Hofer et al, 2008), but the enhancing effect of SEVI might be most evident at low virus concentrations as has been demonstrated in vitro (Munch et al, 2007). To test whether SEVI would enhance infection with lower doses of HIV-1, one group was also infected with a lower dose (1 x 10 4 TCIU) of HIV-1 JR-CSF that had been incubated with SEVI.…”

Evolution of the HIV-1 env Gene in the Rag2 −/− γ C −/− Humanized Mouse Model

“…However, the MLN in this model, which is populated by human T cells, may represent a different environment than that seen in healthy humans or wild-type mice. The GALT has been shown to be underdeveloped in this model (37), indicating that the MLN may not be populated by the same CD4 ϩ T-cell subsets present in this tissue in a normal individual. Further exploration is required to assess more fully the cellular subsets populating this and other compartments in this model and the effects that they have on the selection of viruses with different phenotypes.…”

Animal models for HIV/AIDS research

“…Several studies have used this model to demonstrate the effectiveness of antiretroviral therapy in suppressing viraemia, to test new therapeutic approaches and to investigate the effects of viral replication on the immune system 61–63 . However, humoral responses to HIV-1 are generally not detectable 59,60 , and there are conflicting reports regarding the ability to infect these animals by mucosal inoculation 64–66 .…”