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Genetic Knockouts Suggest a Critical Role for HIV Co-Receptors in Models of HIV gp120-Induced Brain Injury

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Abstract

Infection with HIV-1 frequently affects the brain and causes NeuroAIDS prior to the development of overt AIDS. The HIV-1 envelope protein gp120 interacts with host CD4 and chemokine co-receptors to initiate infection of macrophages and lymphocytes. In addition, the virus or fragments of it, such as gp120, cause macrophages to produce neurotoxins and trigger neuronal injury and apoptosis. Moreover, the two major HIV co-receptors, the chemokine receptors CCR5 and CXCR4, serve numerous physiological functions and are widely expressed beyond immune cells, including cells in the brain. Therefore, HIV co-receptors are poised to play a direct and indirect part in the development of NeuroAIDS. Although rodents are not permissive to infection with wild type HIV-1, viral co-receptors - more than CD4 - are highly conserved between species, suggesting the animals can be suitable models for mechanistic studies addressing effects of receptor-ligand interaction other than infection. Of note, transgenic mice expressing HIV gp120 in the brain share several pathological hallmarks with NeuroAIDS brains. Against this background, we will discuss recently completed or initiated, ongoing studies that utilize HIV co-receptor knockout and viral gp120-transgenic mice as models for in vitro and in vivo experimentation in order to address the potential roles of HIV gp120 and its co-receptors in the development of NeuroAIDS.

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Acknowledgments

M.K. is supported by grants from the National Institutes of Health, MH087332, DA026306 and DA029480.

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The authors state that they have no conflict of interest.

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Authors and Affiliations

  1. Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Ricky Maung, Kathryn E. Medders, Natalia E. Sejbuk & Marcus Kaul

  2. Neuroscience, Aging and Stem Cell Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Maya K. Desai, Rossella Russo & Marcus Kaul

  3. Department of Pharmacobiology, University of Calabria, 87036, Arcavacata di Rende, Italy

    Rossella Russo

  4. Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Marcus Kaul

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Correspondence to Marcus Kaul.

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Maung, R., Medders, K.E., Sejbuk, N.E. et al. Genetic Knockouts Suggest a Critical Role for HIV Co-Receptors in Models of HIV gp120-Induced Brain Injury. J Neuroimmune Pharmacol 7, 306–318 (2012). https://doi.org/10.1007/s11481-011-9328-x

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