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HIV Promotes Neurocognitive Impairment by Damaging the Hippocampal Microvessels

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Abstract

Current evidence suggests that mild cerebrovascular changes could induce neurodegeneration and contribute to HIV-associated neurocognitive disease (HAND) in HIV patients. We investigated both the quantitative and qualitative impact of HIV infection on brain microvessels, especially on hippocampal microvessels, which are crucial for optimal O2 supply, and thus for maintaining memory and cognitive abilities. The results obtained using cultured human brain microvascular endothelial cells (HBMEC) were reproduced using a suitable mouse model and autopsied human HIV hippocampus. In HBMEC, we found significantly higher oxidative stress-dependent apoptotic cell loss following 5 h of treatment of GST-Tat (1 µg/ml) compared to GST (1 µg/ml) control. We noticed complete recovery of HBMEC cells after 24 h of GST-Tat treatment, due to temporal degradation or inactivation of GST-Tat. Interestingly, we found a sustained increase in mitochondrial oxidative DNA damage marker 8-OHdG, as well as an increase in hypoxia-inducible factor hypoxia-inducible factor-1α (HIF-1α). In our mouse studies, upon short-term injection of GST-Tat, we found the loss of small microvessels (mostly capillaries) and vascular endothelial growth factor (VEGF), but not large microvessels (arterioles and venules) in the hippocampus. In addition to capillary loss, in the post-mortem HIV-infected human hippocampus, we observed large microvessels with increased wall cells and perivascular tissue degeneration. Together, our data show a crucial role of Tat in inducing HIF-1α-dependent inhibition of mitochondrial transcriptional factor A (TFAM) and dilated perivascular space. Thus, our results further define the underlying molecular mechanism promoting mild cerebrovascular disease, neuropathy, and HAND pathogenesis in HIV patients.

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Data Availability

The datasets generated from this study is included in this manuscript and are also available from the corresponding author on reasonable request.

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Acknowledgements

Human tissue specimens were obtained from the NIH NeuroBioBank: University of Maryland Brain and Tissue Bank (A Brain and Tissue Bank Reposition of the NIH NeuroBioBank) and NIH Brain & Tissue Repository-California, Human Brain & Spinal Fluid Resource Center, VA West Los Angeles Medical Center, Los Angeles, California, which is supported in part by National Institutes of Health and the US Department of Veterans Affairs.

Funding

Research reported in this publication was funded by the National Institutes of Health, an R01, R01AG058884, from National Institute on Aging to JH and an R01, R01DA041746, National Institute on Drug Abuse to MT.

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  1. Department of Medicine, Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, 1020 Locust Street, Jefferson Alumni Hall, PA, 19107, Philadelphia, USA

    Adhikarimayum Lakhikumar Sharma, Huaixing Wang, Zongxiu Zhang, Guetchyn Millien, Mudit Tyagi & Jarin Hongpaisan

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  1. Adhikarimayum Lakhikumar Sharma
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  2. Huaixing Wang
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Contributions

A.L.S., H.W, Z.Z., G.M., and J.H. performed the experiments; J.H. and M.T. analyzed the data and wrote the first draft of the manuscript; J.H., A.L.S., and M.T. reviewed and edited the manuscript; J.H. and M.T. supervised the project; J.H. and M.T. acquired the funding. All authors read and approved the final version of the manuscript.

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Correspondence to Mudit Tyagi or Jarin Hongpaisan.

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The present work was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. All patients (or relatives/representatives who had the power of attorney) signed informed consent forms.

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Sharma, A.L., Wang, H., Zhang, Z. et al. HIV Promotes Neurocognitive Impairment by Damaging the Hippocampal Microvessels. Mol Neurobiol 59, 4966–4986 (2022). https://doi.org/10.1007/s12035-022-02890-8

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