1. Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV 
Youry Kim, Jenny L. Anderson, Sharon R. Lewin 
Cell Host & Microbe 
Volume 23, Issue 1, Pages (January 2018)
DOI: /j.chom
Copyright © 2017 Elsevier Inc. Terms and Conditions

2. Figure 1
Shock and Kill Strategy to Eliminate HIV Latently Infected Cells
The “shock and kill” strategy uses LRAs to increase HIV transcription, protein expression, and virion production. The cell may potentially die through virus-mediated cytopathic events or immune-mediated clearance. LRAs, latency reversing agents; ART, antiretroviral therapy.
Cell Host & Microbe  , 14-26DOI: ( /j.chom )
Copyright © 2017 Elsevier Inc. Terms and Conditions

3. Figure 2
Classes of LRAs
LRAs can act on different pathways, resulting in an increase in HIV transcription and/or virion production. P-TEFb, positive transcription elongation factor b; TLR, Toll-like receptor; mTOR, mechanistic target of rapamycin; STAT5, signal transducer and activator of transcription 5; IL-15, interleukin-15.
Cell Host & Microbe  , 14-26DOI: ( /j.chom )
Copyright © 2017 Elsevier Inc. Terms and Conditions

4. Figure 3
Effects of HIV Proteins on Apoptosis and Compounds to Foster Apoptosis of Cells
When stress stimuli induce the intrinsic mitochondrial pathway, the Bak or Bax members of the B cell lymphoma 2 (Bcl-2) family are activated to promote apoptosis. However, activation of the PI3K pathway promotes cell survival by preventing steps in the apoptosis pathway. PI3K activation leads to conversion of phosphatidylinositol 4,5-biphosphate (PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3). This step is also negatively regulated by phosphatase and tensin homolog (PTEN). The conversion of PIP2 to PIP3 leads to the activation of Akt protein. Akt can inhibit the forkhead box protein O1 (FOXO1) transcription factor from translocating into the nucleus to induce pro-apoptotic target genes, preventing apoptosis. Additionally, Akt inhibits the pro-apoptotic protein Bad from inhibiting anti-apoptotic Bcl-2 members like Bcl-2 and Bcl-XL, which in turn is inhibited from activating Bak or Bax, thereby also preventing apoptosis.
(A) Pathways leading to cell survival. Anti-apoptotic HIV proteins (shown in red) expressed early in the virus life cycle that can promote cell survival include Nef, Tat, and Vpr. Nef can bind PI3K proteins to increase the conversion of PIP2 to PIP3. This leads to an increase in Akt protein that subsequently leads to inhibition of pro-apoptotic molecules such as Bad from activating apoptosis, thereby promoting cell survival. Additionally, Nef can prevent p53 from activating the pro-apoptotic molecule PUMA, which directly inhibits Bcl-2 to prevent apoptosis. HIV Tat protein can inhibit PTEN, thereby promoting the PI3K/Akt pathway to promote cell survival. Tat can also directly inhibit FOXO1 transcription factors to prevent the transcription of pro-apoptotic genes, preventing apoptosis. Tat also prevents the pro-apoptotic molecule PUMA from inhibiting Bcl-2. HIV Vpr can lead to the increase of anti-apoptotic molecule Bcl-2 in addition to inhibiting the pro-apoptotic Bak molecule.
(B) Pathways leading to cell death. When activated, Bax proteins form pores in the mitochondrial membrane, leading to the release of cytochrome c and Smac into the cytosol. Cytosolic cytochrome c leads to the formation of the apoptosome that activates caspase-9. Caspase-9 then cleaves pro-caspase-3 and -7 into their active caspase-3 and caspase-7 forms, which lead to apoptosis. Multiple HIV proteins (shown in green) can interact with the members of the apoptosis pathway later in the viral life cycle, leading to increased apoptosis. Nef can inhibit the anti-apoptotic molecules Bcl-2 and Bcl-XL. Higher expression of HIV Vpr can bind and lead to the upregulation of Bak to initiate apoptosis. Higher expression of Tat also leads to the upregulation of Bax, resulting in the release of cytochrome c from the mitochondria and subsequent activation of the caspase cascade. HIV Env protein can inhibit the anti-apoptotic protein Bcl-2 to favor apoptosis. The HIV protease protein also cleaves caspase-8 to the pro-apoptotic Casp8p41 peptide to promote apoptosis. It is likely that the balance of pro-apoptotic versus anti-apoptotic cellular and viral proteins decides the fate of infected cells.
(C) Modulation of apoptosis pathways using compounds. Compounds (in light blue) that act on different cellular proteins in these pathways could potentially be used to tip the balance toward apoptosis of HIV-infected cells. PI3K inhibitors block the conversion of PIP2 to PIP3, decreasing active Akt within a cell to stop Akt from inhibiting apoptosis. Akt inhibitors directly decrease active Akt to prevent Akt from inhibiting apoptosis to ultimately induce apoptosis. Bcl-2 inhibitors such as Venetoclax inhibit anti-apoptotic Bcl-2 to sensitize the cells toward apoptosis. Smac mimetics competitively bind inhibitors of apoptosis proteins like X-linked inhibitor of apoptosis (XIAP) to promote apoptosis. RIG-I detects viral RNA and activates pro-apoptotic Bak/Bax proteins, leading to apoptosis. In addition to viral RNA, RIG-I inducer compounds like the RA derivative acitretin can also trigger apoptosis.
Cell Host & Microbe  , 14-26DOI: ( /j.chom )
Copyright © 2017 Elsevier Inc. Terms and Conditions