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Decreased neurotropism of nef long terminal repeat (nef/LTR)-deleted simian immunodeficiency virus
Katherine A Thompson1, Stephen J Kent, Michelle E Gahan
1Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia.
Abstract:
Simian immunodeficiency virus (SIV) infection of macaques results in neurological abnormalities similar to those of human immunodeficiency virus (HIV)-associated dementia in humans and is a valuable system for the identification of viral neurotropic and neurovirulence factors. The authors recently established an SIV-macaque model where macaques can be infected with wild-type or nef/LTR-deleted SIVmac239 via administration of purified proviral DNA. In this study, the ability of wild-type and nef/LTR-deleted SIV infections to enter the cerebral spinal fluid (CSF) and brain was analyzed. In situ polymerase chain reaction (PCR) readily detected SIV gag DNA-positive cells in the mid-frontal gyrus and basal ganglia of the wild-type SIV-infected macaques, but not in nef/LTR-deleted SIV-infected or SIV-uninfected macaques. PCR on extracted DNA confirmed the in situ results, with multiple brain regions of the wild-type SIV-infected macaques positive for both gag and wild-type nef, whereas in the nef/LTR-deleted SIV-infected macaques, nef/LTR and gag DNA were undetectable. Further, macaques infected with nef/LTR-deleted SIV, which later became superinfected with wild-type SIV, also remained negative for SIV DNA in the brain by both in situ and extracted DNA techniques, despite having high levels of SIV RNA both in the CSF and plasma. This study provides evidence of the inability of nef/LTR-deleted SIV to initiate central nervous system (CNS) infection and suggests that, in the brain regions examined, nef/LTR-deleted viruses have either diminished neurotropism or insufficient systemic viral replication for entry into the CNS.
Insights
The nef/LTR-deleted simian immunodeficiency virus (SIV) cannot infect the central nervous system (CNS) in macaques. This suggests this SIV variant has reduced neurotropism or insufficient replication for CNS entry.
Area of Science:
- Neurovirology
- Immunology
- Primate Models
Background:
- Simian immunodeficiency virus (SIV) infection in macaques mimics human immunodeficiency virus (HIV)-associated dementia.
- Identifying viral neurotropic and neurovirulence factors is crucial for understanding HIV-associated dementia.
- A novel SIV-macaque model using purified proviral DNA was established.
Purpose of the Study:
- To analyze the central nervous system (CNS) entry of wild-type and nef/LTR-deleted SIV.
- To investigate the neurotropism and neurovirulence of SIV variants in a macaque model.
- To determine if nef/LTR-deleted SIV can establish CNS infection.
Main Methods:
- Infection of macaques with wild-type or nef/LTR-deleted SIVmac239 via proviral DNA.
- In situ polymerase chain reaction (PCR) to detect SIV gag DNA in brain tissue.
- PCR on extracted DNA from multiple brain regions to confirm viral presence.
- Analysis of SIV RNA in cerebrospinal fluid (CSF) and plasma.
Main Results:
- Wild-type SIV gag DNA was detected in the mid-frontal gyrus and basal ganglia of infected macaques.
- Nef/LTR-deleted SIV-infected macaques showed undetectable gag and nef/LTR DNA in brain tissue.
- Even after superinfection with wild-type SIV, macaques infected with nef/LTR-deleted SIV remained negative for SIV DNA in the brain.
- High levels of SIV RNA in CSF and plasma did not correlate with CNS infection for nef/LTR-deleted SIV.
Conclusions:
- Nef/LTR-deleted SIV is unable to initiate central nervous system (CNS) infection in the studied macaque model.
- The nef/LTR-deleted SIV variant exhibits diminished neurotropism or insufficient systemic replication for CNS entry.
- This finding is significant for understanding SIV/HIV neuroinvasion and developing therapeutic strategies.
