Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag2−/−γc−/− (RAG-hu) mice

Abstract

Studies on HIV-1 mucosal transmission to evaluate early events in pathogenesis and the development of effective preventive/prophylactic methods have thus far been hampered by the lack of a suitable animal model susceptible to HIV-1 infection by either vaginal and/or rectal routes. In this regard, while primate-SIV/SHIV and cat-FIV models provided useful surrogate platforms to derive comparative data, these viruses are distinct and different from that of HIV-1. Therefore an optimal model that permits direct study of HIV-1 transmission via mucosal routes is highly desirable. The new generation of humanized NOD/SCID BLT, NOD/SCIDgammac(-/-), and Rag2(-/-)gammac(-/-) mouse models show great promise to achieve this goal. Here, we show that humanized Rag2(-/-)gammac(-/-) mice (RAG-hu) engrafted with CD34 hematopoietic progenitor cells harbor HIV-1-susceptible human cells in the rectal and vaginal mucosa and are susceptible to HIV-1 infection when exposed to cell-free HIV-1 either via vagina or rectum. Infection could be established without any prior hormonal conditioning or mucosal abrasion. Both R5 and X4 tropic viruses were capable of mucosal infection resulting in viremia and associated helper T cell depletion. There was systemic spread of the virus with infected cells detected in different organs including the intestinal mucosa. R5 virus was highly efficient in mucosal transmission by both routes whereas X4 virus was relatively less efficient in causing infection. HIV-1 infection of RAG-hu mice by vaginal and rectal routes as shown here represents the first in vivo model of HIV-1 transmission across intact mucosal barriers and as such may prove very useful for studying early events in HIV-1 pathogenesis in vivo, as well as the testing of microbicides, anti-HIV vaccines/therapeutics, and other novel strategies to prevent HIV-1 transmission.

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

“…In an attempt to evaluate the humanized mouse model as an appropriate model for HIV transmission studies, two independent groups were able to demonstrate transmission of HIV via mucosal routes of infection. Utilizing the NOD/scid or BALB/c-DKO-hu models it was shown that sites of mucosal transmission were populated by HIV target cells and were capable of transmitting virus [125,126]. Thus, it appears that the humanized mouse model is a robust model for the study of HIV infection.…”

Links between Progressive HIV-1 Infection of Humanized Mice and Viral Neuropathogenesis

“…Long-term functional engraftment of a human immune system was achieved in immune deficient mice reconstituted with human hematopoietic stem cells (HSC) in divergent genetic backgrounds: NOD/scid-IL-2R␥ c null (NSG), [7][8][9][10] BALB/c-Rag2 Ϫ/Ϫ ␥ c Ϫ/Ϫ (BRG), [11][12][13][14][15] and NOD/ scid mice reconstituted with fetal thymus/liver and HSC (BLT). 16,17 Despite rapid research advances made in these rodent animal models on HIV-1 disease pathobiology, their importance for studies of HIV-1-related complications, including neuroAIDS, have not been explored.…”

Use of Animal Models for Anti-HIV Drug Development

“…The animals could be infected with HIV-1 and had detectable viremia for more than 27 weeks (Baenziger et al, 2006). Like the BLT model, Rag2 -/-C -/-mice also had CD4 + target cells in mucosal tissues and could be infected intrarectally or intravaginally (Berges et al, 2008). With a wide array of simian and murine models of HIV/AIDS, it is difficult to know which one to use to answer a scientific question.…”