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HIV-1 PERSISTENCE IN THE CNS: MECHANISMS OF LATENCY, PATHOGENESIS AND AN UPDATE ON ERADICATION STRATEGIES
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The presence of persistent latent virus in the brain might lead to cognitive impairment and neurodegeneration by continuous release of proinflammatory responses and altering gene expression. A study by Desplats et al. reports that patients with latent HIV-1 display cognitive deficits, neurodegenerative alterations, and neuroinflammatory changes indicating that the presence of latent virus in the brain represents a distinct condition that manifests with pathologic features (Desplats et al., 2013). Indeed, infection of the CNS by either latent or active HIV-1 has been long associated with neurologic conditions, such as HIV-associated dementia (HAD), HIV-associated neurocognitive disorders (HAND), HIV encephalitis (HIVE), etc. (Clifford and Ances, 2013; Fauci, 1988).
Comprehensive sequence and phylogenetic analyses on 14 individuals infected with HIV-1 who had been serially sampled in CSF and blood plasma before and after interruption of ART revealed that HIV-1 emerged from the CSF upon interruption of ART indicating that viral escape from the CNS is possible.
While antivirals designed to target the brain are known to cross the BBB, the presence of various transporter and efflux mechanisms leads to minimal accumulation and low concentration of the drug in the CNS than in the periphery (Ene et al., 2011). This suboptimal concentration of the antiretroviral is insufficient to inhibit HIV-1 transcription and replication, as a result of which the virus is able to maintain a low level of replication in the CNS.
Viral entry into the CNS can occur as early as within the first week of infection (Valcour et al., 2012). One of the popular theories that aim to explain the entry of HIV-1 into the CNS is the “Trojan horse theory” which proposes that the virus primarily enters the CNS through infected monocytes or CD4+T lymphocytes circulating in the plasma (Spudich and Gonzalez-Scarano, 2012). While the blood-brain barrier (BBB) tightly regulates the entry of foreign substances into the brain, many external and internal factors can alter its permeability, especially when physiological homeostasis is interrupted.
HIV-1 infected cells in the CNS (latent or active), if mobile, could theoretically travel out of this compartment and ‘reseed’ the systemic reservoir.
Normal neuronal function is disturbed by HIV-1 infection in the CNS. In the early stage of HIV-1 infection, complications in the CNS arise as a response to the detection of the virus in the form of multiple processes mediated by the immune system. In the intermediate stages, complications continue as an indirect consequence of the immune system dysfunction and the metabolic effects of the antiretroviral drugs. In later stages, the neurological complications exacerbate due to the development of opportunistic disorders in addition to the failing immune responses (Rojas-Celis et al., 2019)
Highlight
•HIV-1 latency in CNS reservoirs
•brain harbors HIV-1 regardless of its latent state
•the effect of eradication strategies on the CNS
Abstract
Despite -four decades of research into the human immunodeficiency virus (HIV-1), a successful strategy to eradicate the virus post-infection is lacking. The major reason for this is the persistence of the virus in certain anatomical reservoirs where it can become latent and remain quiescent for as long as the cellular reservoir is alive. The Central Nervous System (CNS), in particular, is an intriguing anatomical compartment that is tightly regulated by the blood-brain barrier. Targeting the CNS viral reservoir is a major challenge owing to the decreased permeability of drugs into the CNS and the cellular microenvironment that facilitates the compartmentalization and evolution of the virus.
Therefore, despite effective antiretroviral (ARV) treatment, virus persists in the CNS, and leads to neurological and neurocognitive deficits. To date, viral eradication strategies fail to eliminate the virus from the CNS. To facilitate the improvement of the existing elimination strategies, as well as the development of potential therapeutic targets, the aim of this review is to provide an in-depth understanding of HIV latency in CNS and the onset of HIV-1 associated neurological disorders.
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