HIV Promotes Neurocognitive Impairment by Damaging the Hippocampal Microvessels

Mol Neurobiol. 2022 Aug;59(8):4966-4986. doi: 10.1007/s12035-022-02890-8. Epub 2022 Jun 4.


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.

Keywords: HIF-1α; Mitochondria; Oxidative stress; Tat; VEGF.

MeSH terms

  • Animals
  • Endothelial Cells / metabolism
  • HIV Infections* / complications
  • HIV Infections* / metabolism
  • Hippocampus / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mice
  • Microvessels
  • Vascular Endothelial Growth Factor A / metabolism


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Vascular Endothelial Growth Factor A