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Page 4 of 6 Review Article

and directing their degradation by the proteasome. Therefore, it appears that the major effect of SMs on latently
The second mitochondria-derived activator of caspase infected T is to induce apoptosis rather than reactivate
CM
antagonises this activity, allowing the progression of the transcription.
apoptotic process. Several other IAPs are also inhibited by
41
SMAC, including the baculoviral IAP repeat-containing Furthermore, Campbell et al. demonstrated the mechanism
protein 2 (BIRC, also known as cellular IAP1). 41 of apoptosis on SM administration is dependent on the
induction (but not completion) of autophagy. Wortmannin
Viral proteins, in particular Tat and Nef, cause inhibition of (an inhibitor of early stages of autophagy) led to a
this intrinsic apoptosis pathway in latently infected cells. reduction in apoptosis despite the degradation of IAPs by
Tat upregulates host production of anti-apoptotic SMs. Further findings suggest that, following IAP
proteins including XIAP and Bcl2. The X-linked inhibitor degradation, autophagy proteins form a scaffold for the
42
of apoptosis inhibits caspase activity, as detailed earlier, assembly of a ripoptosome-like death-inducing signaling
whilst Bcl2 inhibits MOMP, thus preventing the release of complex (DISC), which can then initiate apoptosis via
43
cytochrome c and SMAC. Tat also inhibits the pro-apoptotic caspase 8 induction. This is an additional mechanism to
proteins p53 and the Bcl2-associated antagonist of cell the simple removal of IAP inhibition due to their
death (BAD). Nef causes p21-activated kinase activation, degradation and may explain the selectivity of SMs for
40
leading to phosphorylation of BAD, thus inhibiting its inducing death of HIV-T CM . Inhibitors of later stages of
pro-apoptotic activity (binding to and inhibition of Bcl2), autophagy did not reduce apoptosis, suggesting that the
44
and also inhibits caspase-8 and caspase-10. Conversely, in process of autophagy itself is not required for this
40
the CNS, it appears that Tat and Nef may induce mechanism of cell death. Induction of autophagy is
autophagy and apoptosis in HAND pathogenesis. 45,46 sufficient for apoptosis, as autophagy proteins allow
Expression and activation of anti-apoptotic proteins are DISC formation. IAPs are degraded by SMs in uninfected
therefore increased in latently infected cells, making this an T CM but this does not lead to the same degree of cell death
attractive therapeutic target. due to reduced autophagy induction and therefore
decreased probability of DISC formation. HIV-T CM are
Pro-apoptotic drugs more prone to autophagy induction than uninfected cells
as a result of the effects of viral proteins. Gag and Nef
Several classes of pro-apoptotic compounds have been interact with autophagy factors to increase autophagy
developed recently for cancer treatment, 47,48 as tumour cells induction, which in turn augments HIV yields in cells
often over-express or activate IAPs allowing the evasion of containing the actively replicating virus. Nef and Vif
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apoptosis, a key hallmark of cancer. Some of these have been inhibit later stages of autophagy to prevent HIV
shown to induce apoptosis of latent HIV infected cells in vitro, degradation. 53,54 Therefore, HIV-T CM are more prone to
leading to speculation that PADs may contribute to a future autophagy induction than uninfected cells, providing a
cure. potential explanation for the selective apoptosis observed
in latently infected cells on SM administration.
Second mitochondria-derived activator of caspase mimetics Over-expression or activation of IAPs in infected cells
(SMs) are a class of drugs which bind IAPs in a similar fashion may also contribute to the selectivity of SMs.
to the endogenous molecule. They cause caspase activation
48
49
via IAP binding and appear to reduce IAP activity through These findings present ex vivo evidence of the selective
both degradation and inhibition of the proteins, and killing of latently infected T by SMs, along with a
50
CM
therefore induce apoptosis. Second mitochondrias have convincing mechanism of how uninfected cells are spared.
recently been developed for cancer treatment, inducing Clinical trials in humans may now be justified, but should
48
apoptosis of tumour cells which over-express or activate be performed with caution as the side effects of these drugs
IAPs. The SMs birinapant, embelin and GDC-0152 were in people living with HIV are unknown. A number of
investigated for their efficacy to induce apoptosis in latently SMs have been used in phase I trials for various cancers,
51
infected T by Campbell et al. All were found to cause with a generally tolerable safety profile, although the
CM
rapid degradation of XIAP and BIRC2, which were occasional occurrence of cytokine release syndrome in
upregulated in the infected cells, and importantly showed patients is of some concern. In vitro and ex vivo findings
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selective killing of HIV-infected T compared to uninfected suggest SMs may be able to deplete the T reservoir in
CM CM
T , with the doses required for 90% clearance of HIV-infected vivo, and, whilst if 90% of latently infected cells are killed
CM
cells causing a small increase of T cell death, of 3.5% – 4.6% (as in the Campbell study) the patient will not be cured of
CM
above basal levels. This occurred in the absence of increased HIV, this eclipses reservoir clearance demonstrated by
virus production, despite findings in models of latency by current ‘Shock and Kill’ approaches. However, it is unclear
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Pache et al. suggesting that SMs may act as LRAs due to the if these drugs would induce apoptosis in non-T cell
reduction in BIRC2 leading to increased NFκβ signalling, reservoirs to the same degree, which may prevent the
resulting in an increased viral transcription. However, in development of a functional cure. Future in vitro and ex vivo
latent HIV-T from patients undergoing cART, the Pache studies of PADs using latently infected myeloid cells from
CM
study showed that SMs only caused latency reversal when people living with HIV would be advisable to further test
used in combination with an LRA such as vorinostat. their suitability.
http://www.sajhivmed.org.za 177 Open Access