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Page 8 of 14 Sahu et al. Neuroimmunol Neuroinflammation 2018;5:2 I http://dx.doi.org/10.20517/2347-8659.2017.43

Proviral role of autophagy in Japanese encephalitis virus and dengue virus infection
JEV is a mosquito-borne enveloped flavivirus with a positive-sense RNA genome, which causes acute
encephalitis with high mortality in humans. Autophagy has been shown to be induced in human natural
killer cells infected with an attenuated (RP-2ms) JEV strain, especially at the later stage, and to a lesser extent
with a virulent (RP-9) strain . In this study, the induction of autophagy by rapamycin was shown to enhance
[47]
JEV replication, whereas 3-methyadenine mediated inhibition of autophagy reduced viral replication for
both the strains of JEV. In addition, knockdown of ATG5 or Beclin 1 expression in cells also reduced JEV
replication, suggesting a proviral role of autophagy in JEV multiplication. It has been shown that following
endocytosis, the internalized JEV particles are targeted to preautolysosomal vacuoles (amphisomes) for viral
uncoating. It is also hypothesized that an enhanced autophagy would increase the synthesis of viral RNA,
leading to a raised viral protein expression level and yield of virus. In short, autophagy positively regulates
JEV replication .
[47]
Lately, the efficient dengue virus replication has been shown to be facilitated by an autophagy-dependent
lipid droplets processing. Free fatty acids release, augmented cellular beta- oxidation, and ATP generation
have provided energy and nutrient sources for viral production. It is noteworthy that dengue virus is also
one of the members of Flaviviridae family . In other words, therapeutic potential which inhibit autophagy
[58]
upon infection has bacteriostatic effect too .
[59]

Contradictory findings of interaction between autophagy and HIV 1 virus in central nervous
system infection
The autophagy in the brains of the HIV patients do not have any direct effect on neurons. However,
neuronal dysfunction due to inflammation and the massive involvements of macrophages in HIV-induced
encephalitis is apparent . Wilcox et al. reported a positive correlation of autophagy and apoptosis in
[61]
[60]
the viral infected regions of neonatal brains, compared to adult brains which showed a negative relation in
autophagy and apoptosis. This statement is supported by the observation made, that knock-out of ATG7
in neonates resulted in decreased apoptosis . Through this disconnection in the observations, it can be
[61]
inferred that autophagic processes may be age dependent, particularly in the developing brains.

HIV destabilizes autophagy to facilitate self-replication, affecting genes essential for HIV replication (ATG7,
MAP1LC3B, ATG12 and ATG16L2 involved in nucleation, and elongation of autophagosomes; CLN3 and
LAPTM5 involved in lysosomal functioning) which are identified using small RNAi screening [62,63] . Studies
elsewhere also demonstrated that replication of HIV is inhibited due to autophagy-associated silencing of
genes: BECN1 and ATG5 in macrophages and BECN1 and ATG7 in monocytes. BECN1 encodes for Beclin1
which is involved in regulation of autophagy in human body. HIV elicits autophagy activation but blocks
the process of late proteolysis .
[62]

Furthermore, in recent studies, HIV has been shown to inhibit autophagy in HIV-uninfected bystander
cells. Also HIV Tat is known to inhibit interferon-gamma (IFN-γ) induced autophagy in macrophages
that are uninfected by inhibiting STAT1 phosphorylation. As a consequence, immune effector mechanism
for targeted intracellular pathogens destruction is attenuated, and HIV patients are more susceptible to
infections such as tuberculosis and toxoplasmosis . In contrast to the effect of Tat on on non-infected
[62]
macrophages, HIV Env protein enhances apoptotic death of uninfected neurons and CD4+T cells, through
a mechanism that involves accumulation of BECN1 as well as autophagy induction .
[62]
In the postmortem examination of the frontal cortices of both HIV-infected patients and non-infected
individuals, autophagic markers were assessed by Western blotting and microscopy (confocal/electron).
Autophagic proteins Beclin1, autophagy-related genes ATG5, ATG7 and LC-II were observed to be significantly
activated in brains from HIV-1 encephalitis cases. Autophagosome development needs Beclin1 for nucleation,