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Sahu et al. Neuroimmunol Neuroinflammation 2018;5:2 I http://dx.doi.org/10.20517/2347-8659.2017.43 Page 9 of 14

whereas covalent binding of ATG5 to ATG12 regulates vesicle elongation, following a pathway catalyzed by
ATG7 and ATG10 . In other words, the level of autophagy is likely increased in encephalitis caused by HIV.
[64]
Additionally, autophagic protein levels and autophagosome formation are reported to be increased in the
neurons of those treated with CXCR4- or CCR-tropic HIV-1 gp 120. In contrast, no increase in the extent of
autophagic death is observed in the brains of non-encephalitic HIV patients compared to HIV-uninfected
subjects. Therefore, the above study suggested that although autophagy could help neurons to sustain survival,
the enhancement in autophagic death contributes to encephalitis and so also to cognitive impairment. Hence,
the above study suggested that by combining drugs that reduce autophagic activity alongside anti-retroviral
medications, the neurological deficits associated with HIV-1 infection could be prevented or reversed, since
dysregulation of autophagy is highly correlated with pathogenesis of neurological HIV infection. Experiments
in the future are needed to investigate further whether the process of autophagy leads to completion in the
brains, or if there is any accumulation of autophagic proteins without autophagy-related degradation [62,65] .

Sindbis virus infection of central nervous system induces autophagy
In this study, it has been demonstrated that Sindibis virus (SIN) infection induces autophagy in virally
infected neurons in vivo, and viral antigen colocalizes with autophagosomes in neurons. It is important to
note that ATG gene ATG5 encodes an essential component of ATG5-ATG12-ATG16 conjugation system,
[66]
and is required for formation of autophagosomes .
The role of the autophagy gene ATG5 is very essential for providing protection against infection with lethal
SIN in the mouse CNS. Inactivating ATG5 in SIN-infected murine neurons results in a late viral protein
clearance, an increased accumulation of adaptor protein p62, and enhanced neuronal death, however the
viral replication levels remain unaffected. In vitro, the cellular protein p62 interacts with capsid protein
of SIN and is required for capsid targeting to the autophagosome. Genetic deficiency of p62 blocks the
targeting of viral capsids to autophagosomes, accelerates viral capsid aggregation, and thereby increases
virus-induced cell death without hampering virus multiplication. In other words, increased SIN-induced
animal mortality is not due to a direct role of neuronal ATG5 in the control of viral replication or regulation
of innate immune signaling. Rather, the disruption of neuronal ATG5 function leading to neuronal death
was actually associated with impaired SIN protein clearance. In this study, one plausible explanation is that
in post mitotic cells such as neurons, the failure to properly clear viral proteins by autophagy results in
cellular toxicity and increased animal lethality .
[67]
Transmissible spongiform encephalopathies associated pathological implications of autophagy
Though the autophagy process of cell death has been identified in scrapie (experimental infections) for
[68]
quite some time this has only recently been reevaluated as a possible cell death process in prion diseases .
However, apoptosis is generally assumed to be the cause of neuronal death in transmissible spongiform
encephalopathies (TSE) [69,70] . These pathologies of TSE, and many other neurodegenerative conditions, are
characterized by the accumulation of aggregated and misfolded proteins in the brain; autophagy may be
playing a protective role by removing such “toxic” protein aggregates [71,72] .

The scrapie responsive gene 1 (Scrg1) encodes a cysteine-rich protein that is highly conserved and expressed
primarily in the CNS. This protein is targeted to the Golgi apparatus as well as large dense-core secretory
granules in neuronal cells . It has been recently demonstrated that the Scrg1 protein is induced widely in
[68]
scrapie-infected murine neurons, suggesting that Scrg1 plays a role in the neuronal death and/or the host
response to stress. The consistent association of autophagic structures (typical of scrapie) with Scrg1 is in
agreement with the recruitment of Golgi-specific proteins during this process of degradation, and therefore
it is suggested that Scrg1 might be used as a specific probe to identify the process of neuronal autophagy in
TSE .
[68]