Dataset Information

A macaque model of HIV-1 infection.

ABSTRACT: The lack of a primate model that utilizes HIV-1 as the challenge virus is an impediment to AIDS research; existing models generally employ simian viruses that are divergent from HIV-1, reducing their usefulness in preclinical investigations. Based on an understanding of species-specific variation in primate TRIM5 and APOBEC3 antiretroviral genes, we constructed simian-tropic (st)HIV-1 strains that differ from HIV-1 only in the vif gene. We demonstrate that such minimally modified stHIV-1 strains are capable of high levels of replication in vitro in pig-tailed macaque (Macaca nemestrina) lymphocytes. Importantly, infection of pig-tailed macaques with stHIV-1 results in acute viremia, approaching the levels observed in HIV-1-infected humans, and an ensuing persistent infection for several months. stHIV-1 replication was controlled thereafter, at least in part, by CD8+ T cells. We demonstrate the potential utility of this HIV-1-based animal model in a chemoprophylaxis experiment, by showing that a commonly used HIV-1 therapeutic regimen can provide apparently sterilizing protection from infection following a rigorous high-dose stHIV-1 challenge.

SUBMITTER: Hatziioannou T

PROVIDER: S-EPMC2657417 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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A macaque model of HIV-1 infection.

Hatziioannou Theodora T Ambrose Zandrea Z Chung Nancy P Y NP Piatak Michael M Yuan Fang F Trubey Charles M CM Coalter Vicky V Kiser Rebecca R Schneider Doug D Smedley Jeremy J Pung Rhonda R Gathuka Mercy M Estes Jacob D JD Veazey Ronald S RS KewalRamani Vineet N VN Lifson Jeffrey D JD Bieniasz Paul D PD

Proceedings of the National Academy of Sciences of the United States of America 20090302 11

The lack of a primate model that utilizes HIV-1 as the challenge virus is an impediment to AIDS research; existing models generally employ simian viruses that are divergent from HIV-1, reducing their usefulness in preclinical investigations. Based on an understanding of species-specific variation in primate TRIM5 and APOBEC3 antiretroviral genes, we constructed simian-tropic (st)HIV-1 strains that differ from HIV-1 only in the vif gene. We demonstrate that such minimally modified stHIV-1 strains ...[more]

PMID: 19255423

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Project description:In the present study, we investigated whether colony-stimulating factor 1 receptor (CSF1R) is expressed on brain macrophages and microglia in the human and macaque brain and whether it is upregulated and activated after lentivirus infection in vivo and contributes to development of encephalitic lesions. We examined, using multi-label and semi-quantitative immunofluorescence microscopy, the protein expression level and cellular localization of CSF1R in brain tissues from uninfected controls and SIV-infected adult macaques with or without encephalitis and also from uninfected controls, HIV-infected encephalitic subjects and virally suppressed subjects. In the normal uninfected brain, CSF1R protein was detected only on microglia and brain macrophages but not on neurons, astrocytes or oligodendrocytes. Microglia constitutively expressed CSF1R at low levels, and its expression was largely unchanged in non-encephalitic and encephalitic animals. Brain macrophages, including perivascular macrophages (PVMs), expressed higher levels of CSF1R compared to microglia. Interestingly, we found significantly increased expression of CSF1R on the infected PVMs and lesional macrophages in the brains of encephalitic macaques. Moreover, the per cell expression of CSF1R determined by its mean pixel intensity (MPI) correlated positively with the MPI of SIV Gag p28 in SIV-infected PVMs. Using phosphorylated CSF1R at tyrosine residue 723 and phosphorylated signal transducer and activator of transcription 5 at tyrosine reside 694 as markers for CSF1R activation, we found selective activation of CSF1R signaling in infected brain macrophages in encephalitis. We also found colocalization of CSF1R and its ligand CSF1 in PVMs and lesional macrophages in the brains of encephalitic macaques and humans. Notably, elevated brain CSF1R expression was found in virally suppressed subjects. These findings point to opportunities for developing a specific approach targeting infected brain macrophages, with several brain-penetrant CSF1R inhibitors that are available now, in order to eliminate central nervous system macrophage reservoirs, while not affecting resting uninfected microglia and PVMs that show no CSF1R activation.

Dataset Information

A macaque model of HIV-1 infection.

Publications

A macaque model of HIV-1 infection.

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