High Natural Permissivity of Primary Rabbit Cells for HIV-1, with a Virion Infectivity Defect in Macrophages as the Final Replication Barrier

Abstract

An immunocompetent, permissive, small-animal model would be valuable for the study of human immunodeficiency virus type 1 (HIV-1) pathogenesis and for the testing of drug and vaccine candidates. However, the development of such a model has been hampered by the inability of primary rodent cells to efficiently support several steps of the HIV-1 replication cycle. Although transgenesis of the HIV receptor complex and human cyclin T1 have been beneficial, additional late-phase blocks prevent robust replication of HIV-1 in rodents and limit the range of in vivo applications. In this study, we explored the HIV-1 susceptibility of rabbit primary T cells and macrophages. Envelope-specific and coreceptor-dependent entry of HIV-1 was achieved by expressing human CD4 and CCR5. A block of HIV-1 DNA synthesis, likely mediated by TRIM5, was overcome by limited changes to the HIV-1 gag gene. Unlike with mice and rats, primary cells from rabbits supported the functions of the regulatory viral proteins Tat and Rev, Gag processing, and the release of HIV-1 particles at levels comparable to those in human cells. While HIV-1 produced by rabbit T cells was highly infectious, a macrophage-specific infectivity defect became manifest by a complex pattern of mutations in the viral genome, only part of which were deamination dependent. These results demonstrate a considerable natural HIV-1 permissivity of the rabbit species and suggest that receptor complex transgenesis combined with modifications in gag and possibly vif of HIV-1 to evade species-specific restriction factors might render lagomorphs fully permissive to infection by this pathogenic human lentivirus.

Animal models for HIV/AIDS research

“…However, none of these models supports robust viral replication or the development of disease 8–10 . It is now evident that cells from these animals do not provide essential cofactors for HIV-1 replication and might also express proteins that inhibit HIV-1 infection 11–13 . These findings also limit the utility of transgenic mice expressing HIV-1 proviruses 14,15 .…”

Macaque-tropic human immunodeficiency virus type 1: breaking out of the host restriction factors

“…Although many efforts were performed in small animals, HIV-1 did not infect rodents, such as mice and rats, due to a number of restrictions, including the inability of HIV-1 Env to use the surface molecules in these animals as binding and entry receptors (Atchison et al, 1996) and the defect of murine cyclin T1 protein to associate with HIV-1 Tat (Kwak et al, 1999). Although rabbits were once expected to show susceptibility to HIV-1 infection (Filice et al, 1988; Kulaga et al, 1989), the reproducibility of this model remains to be elucidated (Reina et al, 1993; Speck et al, 1998; Tervo and Keppler, 2010). In an attempt to overcome the limitation in using these animals, several versions of humanized mice such as SCID-hu-PBL (severe combined immunodeficiency-human peripheral blood lymphocytes) mice (Mosier et al, 1988), Rag2 - / - γc - / - mice (Traggiai et al, 2004), NOG (NOD/Shi-scid/IL-2Rγ null) mice (Ito et al, 2002), NSG (NOD scid gamma) mice (Shultz et al, 2005), and NOD/SCID-hu BLT mice (Melkus et al, 2006), have been generated (reviewed in Berges and Rowan, 2011).…”

Humanized mice for HIV and AIDS research

“…HIV cannot infect mice, rats, rabbits, or macaques [6–10]. The species-specificity of HIV is not limited to its interactions with its receptor CD4 and co-receptors CXCR4 or CCR5 on host cells.…”