Abstract
Despite improvements in antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in subjects undergoing therapy. HAND significantly affects individuals’ quality of life, as well as adherence to therapy, and, despite the increasing understanding of neuropathogenesis, no definitive diagnostic or prognostic marker has been identified. We investigated transcriptomic profiles in frontal cortex tissues of Simian immunodeficiency virus (SIV)-infected Rhesus macaques sacrificed at different stages of infection. Gene expression was compared among SIV-infected animals (n = 11), with or without CD8+ lymphocyte depletion, based on detectable (n = 6) or non-detectable (n = 5) presence of the virus in frontal cortex tissues. Significant enrichment in activation of monocyte and macrophage cellular pathways was found in animals with detectable brain infection, independently from CD8+ lymphocyte depletion. In addition, transcripts of four poly (ADP-ribose) polymerases (PARPs) were up-regulated in the frontal cortex, which was confirmed by real-time polymerase chain reaction. Our results shed light on involvement of PARPs in SIV infection of the brain and their role in SIV-associated neurodegenerative processes. Inhibition of PARPs may provide an effective novel therapeutic target for HIV-related neuropathology.
Highlights
The advent of combination antiretroviral therapy resulted in a 50% decline in rates of AIDS-related deaths and a 40–50% decrease in the incidence of human immunodeficiency virus (HIV)-associated dementia (HAD) (Maschke et al 2000)
We focused our analysis on characterizing the transcriptome profiles of the frontal cortex, as severity of cognitive impairment has been previously associated with the degree of frontal cortex neurodegeneration (Moore et al 2006; Woods et al 2009), and based on our previous work showing that greater level of both proviral DNA and viral RNA in the frontal cortex of SIVinfected macaques with SIV-associated encephalitis (SIVE), as compared with other brain tissues, as well as the emergence of specific viral neurotropic sub-populations in animals with SIVE (Rife et al 2016)
Our previous work showed that the frontal cortex of SIVinfected macaques with SIVE has higher level of both proviral DNA and viral RNA compared with other brain tissues (Rife et al 2016)
Summary
The advent of combination antiretroviral therapy (cART) resulted in a 50% decline in rates of AIDS-related deaths and a 40–50% decrease in the incidence of human immunodeficiency virus (HIV)-associated dementia (HAD) (Maschke et al 2000). Even in HIV-infected individuals on combined anti-retroviral therapy (cART), low-level viral replication persists in the central nervous system (CNS) (Spudich 2016). Persistent CNS infection and inflammation may contribute to the development of HAND (Valcour et al 2012), which remains a major cause of morbidity among HIV-infected individuals. If therapy is interrupted, viral rebound is going to occur (Andrade et al 2020; Palmisano et al 2007; SaezCirion et al 2013), and because HIV is able to replicate in the CNS, brain-specific viral variants are found at rebound after interruption of cART (Gianella et al 2016)
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