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A phenotypic recessive, post-entry block in rabbit cells that results in aberrant trafficking of HIV-1.

ABSTRACT: Rabbit cells are poorly permissive to HIV-1 infection, but little is known about the nature of this block. Here, we show that the block to infection is mainly at the level of reverse transcription (RT), is independent of the cell receptor used by the virus for entry, cannot be effectively saturated with high doses of virus or virus-like particles, and has a recessive phenotype in human-rabbit heterokaryons. RT complexes (RTCs) extracted from human and rabbit cells have different densities but are both competent for RT in an in vitro endogenous assay. Cell fractionation showed that HIV-1 is trafficked in a different way in human and rabbit cells and that correct intracellular trafficking is linked to efficient RT and high infectivity in vivo. Viral DNA accumulated in rabbit cell nuclei only at a later stage and failed to associate with chromatin, suggesting a further block prior to integration. Our data point to the existence of cellular factors regulating the early stages of intracytoplasmic and possibly intranuclear HIV-1 trafficking.

SUBMITTER: Cutino-Moguel T

PROVIDER: S-EPMC1934423 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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A phenotypic recessive, post-entry block in rabbit cells that results in aberrant trafficking of HIV-1.

Cutiño-Moguel Teresa T Fassati Ariberto A

Traffic (Copenhagen, Denmark) 20060801 8

Rabbit cells are poorly permissive to HIV-1 infection, but little is known about the nature of this block. Here, we show that the block to infection is mainly at the level of reverse transcription (RT), is independent of the cell receptor used by the virus for entry, cannot be effectively saturated with high doses of virus or virus-like particles, and has a recessive phenotype in human-rabbit heterokaryons. RT complexes (RTCs) extracted from human and rabbit cells have different densities but ar ...[more]

PMID: 16882040

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Project description:Macrophages (MΦ) are increasingly recognized as HIV-1 target cells involved in the pathogenesis and persistence of infection. Paradoxically, in vitro infection assays suggest that virus isolates are mostly T-cell-tropic and rarely MΦ-tropic. The latter are assumed to emerge under CD4+ T-cell paucity in tissues such as the brain or at late stage when the CD4 T-cell count declines. However, assays to qualify HIV-1 tropism use cell-free viral particles and may not fully reflect the conditions of in vivo MΦ infection through cell-to-cell viral transfer. Here, we investigated the capacity of viruses expressing primary envelope glycoproteins (Envs) with CCR5 and/or CXCR4 usage from different stages of infection, including transmitted/founder Envs, to infect MΦ by a cell-free mode and through cell-to-cell transfer from infected CD4+ T cells. The results show that most viruses were unable to enter MΦ as cell-free particles, in agreement with the current view that non-M-tropic viruses inefficiently use CD4 and/or CCR5 or CXCR4 entry receptors on MΦ. In contrast, all viruses could be effectively cell-to-cell transferred to MΦ from infected CD4+ T cells. We further showed that viral transfer proceeded through Env-dependent cell-cell fusion of infected T cells with MΦ targets, leading to the formation of productively infected multinucleated giant cells. Compared to cell-free infection, infected T-cell/MΦ contacts showed enhanced interactions of R5 M- and non-M-tropic Envs with CD4 and CCR5, resulting in a reduced dependence on receptor expression levels on MΦ for viral entry. Altogether, our results show that virus cell-to-cell transfer overcomes the entry block of isolates initially defined as non-macrophage-tropic, indicating that HIV-1 has a more prevalent tropism for MΦ than initially suggested. This sheds light into the role of this route of virus cell-to-cell transfer to MΦ in CD4+ T cell rich tissues for HIV-1 transmission, dissemination and formation of tissue viral reservoirs.

Dataset Information

A phenotypic recessive, post-entry block in rabbit cells that results in aberrant trafficking of HIV-1.

Publications

A phenotypic recessive, post-entry block in rabbit cells that results in aberrant trafficking of HIV-1.

Similar Datasets

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