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Page 2 of 6 Review Article

be cleared in a patient’s lifetime. The T reservoir contains and Kill’ was that viral cytopathic effects and lysis, due to
CM
the majority of latent cells, but other reservoirs are also HIV replication, aided by cytotoxic T lymphocyte (CTL)-
present and form barriers to cure research. Several myeloid mediated killing of actively infected cells, would be sufficient
27
cell lines have been shown to harbour latent HIV in chronic to kill reactivated, formerly latent, cells. Shan et al. showed
infection and contribute to viral rebound on cART that the viral cytopathic effect alone is insufficient to kill
cessation. 14,15 There is evidence for the presence of latent cells, and the vigorous CTL response is lost in chronic HIV
reservoirs in tissue macrophages and microglial cells and infection. However, CTL stimulation increased latent cell
16
astrocytes in the central nervous system (CNS). 17,18 There is clearance, leading to the suggestion that some form of
no in vivo evidence of latently infected tissue dendritic cells immune stimulation may be required alongside latency
but infection has been shown in vitro, and it has been reversal to achieve a reduction in reservoir size. The CTL
19
proposed that this may be transferred to CD4 cells via a response to reactivated cells may be insufficient to reduce
+
20
virological synapse. Follicular dendritic cells have been reservoir size on latency reversal, due to 98% of latent T cells
28
shown to maintain a stable pool of virus on their surface carrying escape mutations to CTL killing and T cell
29
without being infected, providing a latent reservoir within exhaustion in chronic infection reducing the efficacy of the
secondary lymphoid tissue. Further reservoirs have been CTL response. Furthermore, LRAs may not affect non-T CM
21
30
suggested, such as within fibrocytes, but it is now reservoirs as macrophages are resistant to the cytopathic
20
apparent that the T reservoir is not the only source of effects of HIV, and dendritic cells do not integrate viral DNA,
CM
latently infected cells. Potential cures must, therefore, meaning that LRAs would be unable to cause viral
target all identified reservoirs to be successful. replication and subsequent targeting by the immune
system. It has also been proposed that continued cART may
Several approaches to clearing the latent reservoirs have not completely inhibit infection of further cells by virions
30
been investigated, with the ‘Shock and Kill’ combination produced from reactivated, formerly latent cells. Thus,
receiving particular interest. However, recent findings LRA administration may lead to infection of previously
seem to suggest this is unlikely to ever provide a cure uninfected cells. It is therefore clear that LRA administration
for HIV 22,23,24,25,26,27,28,29,30 and may have unresearched alone does not reduce reservoir size, due to a lack of viral
deleterious side effects. 31,32,33 An emerging class of cytopathic effects and lysis, insufficient CTL response and
drugs targeting the apoptosis pathways in latently the potential failure of cART to suppress replication. As such,
infected cells may allow reservoir depletion without stages 3 and 4 from Figure 1 are unlikely to be successful and
latency reversal, and therefore merit further research as a an additional killing agent is required to achieve the second
potential cure for HIV. goal of ‘Shock and Kill’. This may involve immune
stimulation, with natural killer (NK) cell stimulation showing
Shock and Kill some promise ex vivo or other agents, such as broadly
35
neutralising antibodies (bNAbs), which appear to mediate
A potential approach to clearing HIV latent reservoirs is
‘Shock and Kill’, in which the reservoir would be ‘shocked’
with latency-reversing agents (LRAs) to induce replication LRA An retroviral drug T cell receptor
MHC C1 with Ag
CD4 receptor
Viral protein
of the provirus. ‘Killing’ of the activated cells would then HIV virion CD8 receptor bNAb
+
be achieved through viral cytopathic effects, CD8 T cells,
cART or other agent, resulting in clearance of the latent 1
cells and curing the infection. This mechanism is outlined
in Figure 1. Several LRAs have been developed, many using
+
Yang’s in vitro model of latently infected CD4 T 34 to
CM
identify compounds that selectively induce viral replication
in latent cells. These include disulfiram and histone 4
22
deacetylase inhibitors (HDACIs) such as vorinostat and
panobionstat. Early in vivo studies were promising as 2
latency reversal was demonstrated with an increase in viral
gene expression in the resting cells observed with
disulfiram, 23,24 vorinostat and panbionstat administration.
26
25
However, the key caveat is that none of these studies 3
decreased reservoir size in vivo as the number of latent
cells did not decrease following latency reversal. Whilst
replication was induced in a proportion of the latent cells, 1. Latency reversing agents (LRAs) reactivate viral replication in latently infected cells.
2. Viral proteins are produced which are assembled into HIV virions. Antigen (Ag)
this did not lead to immune or viral-mediated killing of processing also occurs, leading to presentation on Major Histocompatibility Complex
Class 1 (MHC CI).
reactivated cells. 3. Combined antiretroviral therapy (cART) inhibits virion relase. Virions which are released
are unable to infect other cells due to cART.
4. Actively replicating cells are cleared by HIV-specific CD8*T cells (which may be
Several reasons have been proposed for the failure of LRAs pre-stimulated) or a killing agent such as a broadly neutralising antibody (bNAb).
alone to reduce reservoir size. The initial principle of ‘Shock FIGURE 1: Proposed mechanism of ‘Shock and Kill’.

http://www.sajhivmed.org.za 175 Open Access