Molecular and pathologic insights from latent HIV-1 infection in the human brain

Abstract

Objective: We aimed to investigate whether HIV latency in the CNS might have adverse molecular, pathologic, and clinical consequences.Methods: This was a case-control comparison of HIV-1 seropositive (HIV1) patients with clinical and neuropathologic examination. Based on the levels of HIV-1 DNA, RNA, and p24 in the brain, cases were classified as controls, latent HIV CNS infection, and HIV encephalitis (HIVE). Analysis of epigenetic markers including BCL11B, neurodegeneration, and neuroinflammation was performed utilizing immunoblot, confocal microscopy, immunochemistry/image analysis, and qPCR. Detailed antemortem neurocognitive data were available for 23 out of the 32 cases.Results: HIV1 controls (n 5 12) had no detectable HIV-1 DNA, RNA, or p24 in the CNS; latent HIV1 cases (n 5 10) showed high levels of HIV-1 DNA but no HIV RNA or p24; and HIVE cases (n 5 10) had high levels of HIV-1 DNA, RNA, and p24. Compared to HIV1 controls, the HIV1 latent cases displayed moderate cognitive impairment with neurodegenerative and neuroinflammatory alterations, although to a lesser extent than HIVE cases. Remarkably, HIV1 latent cases showed higher levels of BCL11B and other chromatin modifiers involved in silencing. Increased BCL11B was associated with deregulation of proinflammatory genes like interleukin-6, tumor necrosis factor-a, and CD74. Conclusion:Persistence of latent HIV-1 infection in the CNS was associated with increased levels of chromatin modifiers, including BCL11B. Alteration of these epigenetic factors might result in abnormal transcriptomes, leading to inflammation, neurodegeneration, and neurocognitive impairment. BCL11B and other epigenetic factors involved in silencing might represent potential targets for HIV-1 involvement of the CNS.

Antiretroviral Therapy through Barriers: A Prominent Role for Nanotechnology in HIV-1 Eradication from Sanctuaries

“…A huge amount of HIV-1 DNA in the peripheral blood has been associated with severe neurocognitive impairment, independently of HIV-1 RNA plasma load [21]. In the setting of virologic suppression following ART, greater HIV-1 DNA levels contribute to persistent immune activation in tissues, including the brain [22], which in turn contributes to neurodegeneration and cognitive impairment [23]. Finally, there is evidence that the cerebrospinal pool of HIV-1 is one of the major obstacles to eradication [24] and therefore strategies to make ARVs overcome the BBB are urgently needed.…”

Progress and challenges in the use of latent HIV-1 reactivating agents

“…It interacts with bromodomains, exhibiting the highest specificity in Brd4. Recently, several lines of evidence indicated that JQ1 reactivates latent HIV in both the clonal and primary cell model of HIV latency, providing evidence for its multifunctional utility [22,36] . Specifically, it inhibits recognition of acetylated lysines relevant to actively transcribed chromatin by binding to the bromodomain-binding pocket.…”

“…An abundance of Sp3 relative to Sp1 in astrocytes can, in some part, explain the restriction of HIV-1 transcription within these cells [35] . In addition, Desplats and his colleagues reported that levels of BCL11B, heterochromatin protein 1 (HP1)α, methyl CpG binding protein 2 (MeCP2), and histone deacetylase 1 (HDAC1) were significantly increased in CNS cells latently infected with HIV-1, favoring the idea that epigenetic factors are involved in silencing mechanisms [36] .…”

The aliens inside human DNA: HERV-W/MSRV/syncytin-1 endogenous retroviruses and neurodegeneration

“…The neurodegenerative disease (neuroAIDS) progresses during chronic infection, with neurocognitive, behavioral, and motor impairments that can lead to full-blown HIV-associated dementia [58]. The mechanisms by which HIV causes neurodegeneration are not fully elucidated, and include both host and viral mechanisms [28,63]. Additional relevant contributions to neuroAIDS are caused by reactivation of bystander latent/persistent viruses with neurotropic potential such as EBV, cytomegalovirus, and JC polyomavirus, which can result in life-threatening CNS infections in immunocompromised hosts [28].…”