Apoptosis and Immune Recognition in Kaposi’s Sarcoma

Updated September 17, 2021

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At its peak, Kaposi sarcoma occurred in people at a rate of 47 million people per year (“Key Statistics”). This potentially deadly tumor causing virus has now slowed to an infection rate of 6 million cases per year, but it is still an important disease to find new treatments for (“Key Statistics”, Sathish and Yuan 10934).

Kaposi’s sarcoma-associated herpesvirus evades the host’s innate immune response by performing on several protein signaling pathways typically involved in the detection and elimination of viral infections. Some methods it uses is the evasion of apoptosis, a latent period, and evading methods of immune recognition by the cell.

Evading Apoptosis

Background information

Apoptosis is programmed cell death. Apoptosis “is thought to be an evolutionary ancient defense mechanism against infection by viruses” (Tabtieng and Gaglia 1).

Many viruses have evolved mechanisms to protect their host cells from apoptosis (Belanger et al. 63).

Caspases are a family of proteases (Tabtieng and Gaglia 1). A protease is an enzyme that breaks down other proteins and peptides. Enzymes are substances that catalyze reactions in living organisms. Peptides are two or more amino acids linked with a special type of bond called a peptide bond.

KSHV vFLIP inhibits Fas-mediated apoptosis

Belanger et al. found that cells transfected with vFLIP remained visually viable after treatment with a Fas-receptor antibody that clearly caused apoptosis in control cells (Belanger et al. 67).

They then confirmed this result using an Annexin-V apoptosis assay. This assay involves reading the cells with Annexin-V and Propidium Iodide in a flow cytometer (Belanger et al. 67). This quantitative assay showed again that cells expressing vFLIP experienced a statistically significantly lower level of apoptosis than the control cells (Belanger et al. 68).

Viral Bcl-2 homologs escape conversion into proapoptotic proteins by caspase

Bcl-2 is a gene regularly expressed in healthy cells and is vital to the normal function o the immune system (Bellows et al. 5024). Before cleavage by caspase-3, Bcl-2 acts as an antiapoptotic protein. (Bellows et al. 5024).

Bellows et al. found that viral homologs of the Bcl-2 gene also have antiapoptotic activity (5025). They found that the viral homolog lacks a cleavage site, and therefore cannot be cleaved by caspase-3 to produce the proapoptotic fragments (Bellows et al. 5026).

The Latent Period and Activation of the Lytic Cycle

Background Information

The lytic cycle is the method by which viruses replicate within cells. It involves the injection of genetic material and other proteins into the cell, and eventually results in the destruction of the cell.

Before entering the lytic cycle, KSHV maintains a stage of latency where the virus is not actively replicating. During latency, the number of genes that are transcribed is limited, which helps the virus evade immune detection (Ye et al. 4235).

One of the few genes transcribed during latency is vFLIP (Ye et al. 4235). vFLIP has been established to activate the NF-kappaB pathway by many studies in the last decade (Ye et al. 4235).

Caspases are linked to the reactivation of KSHV into the lytic cycle caused by the induction of apoptosis

KSHV ordinarily enters the lytic cycle by means of the RTA protein, which is a product of the ORF50 gene (Prasad et al. 4405). RTA activates eight other genes that lead to the replication cycle.

Prasad et al. found that after knocking down the ORF50 gene, KSHV still entered the lytic cycle after the induction of apoptosis (4409). They then inhibited the caspases via a general inhibitor and found “a clear dose-response relationship between the concentration of the general caspase inhibitor…and both the inhibition of apoptosis and inhibition of KSHV replication” (Prasad et al. 4412). This shows that apoptosis and KSHV replication are linked by the caspases. They then found that caspase-3 directly activates KSHV replication.

vFLIP regulates cell survival and lytic replication

Ye et al. found that overexpression of vFLIP inhibits the expression of RTA (4237). RTA is generally necessary for the entering of KSHV into the lytic cycle (Prasad et al. 4405, Ye et al. 4237). Therefore, vFLIP can inhibit the entrance of KSHV into the lytic cycle.

Ye et al. found that vFLIP regulates RTA through the activation of the NF-kappaB pathway, which regulates the AP-1 pathway (4243). This chain shows that the performance of vFLIP on NF-kappaB can lead to several other performances which ultimately leads to one on the promotor of RTA.

Plasma cell differentiation is linked to KSHV’s reactivation from latency

Wilson et al. found that the overexpression of X Box Binding Protein 1 activates RTA expression (13581). XBP-1 is a protein necessary to the differentiation of B cells.

Wilson et al. then found that RTA expression catalyzed by XBP-1 “is sufficient to initiate the full KSHV lytic cycle” (13582). This finding puts together the fact that a protein made during the normal differentiation of human immune cells can transition KSHV into its lytic cycle.

Evading Immune Recognition

The immune system can be broken up into two branches: innate and adaptive immunity (Lee et al. 3). The innate immune system is involved with the recognition of pathogens (Lee et al. 3). The adaptive immune system is the response to the innate immune system, typically by immune cells (Lee et al. 9) KHSV has evolved several ways to thwart both the innate and adaptive immune system.

vFLIP regulates antigen presentation

For the adaptive immune system to be fully activated, antigen presentation is required. Lagos et al. finds that the surface presentation of KLEC antigens is “significantly compromised” (1553).

Lagos et al. also showed that KSHV can inhibit MHC-1 transcription by showing that interferon treatment only increased the expression of MHC-1 by 1.5-fold in infected cells, while it increased by 3-fold in control cells (1554).

KSHV antagonizes type 1 interferon (IFN) pathways

Toll like receptors primarily use two adapter proteins to activate interferon regulatory factors. “These include the TIR domain-containing adaptor-inducing interferon (TRIF/TICAM-1) protein and the myeloid differentiation primary response protein 88 (MyD88) (Sathish et al. 10935).

During de novo infection, the tegument protein ORF45 is binds to IRF-7 (Sathish et al. 10937). This acts to inactivate IRF-7, an IRF that is specifically involved in T immune cell response (Sathish et al. 10937).

KSHV regulation of the complement system

The complement system is one of the most commonly known methods of immune recognition. It involves the binding of antibodies to the pathogen (Spiller et al. 592).

KCP is the protein encoded by the KSHV ORF4 gene (Spiller et al. 595). Spiller et al. found that KCP regulates the C3, a complement protein, deposition on the cell surface (596). This shows that KSHV regulates the ability of the complement system to function properly in cells infected with it.


KSHV has multiple means of evading both the innate and adaptive immune responses. It evades apoptosis that would typically be triggered by an infection, its latent period makes it harder to be detected by the cell, and it has several pathways that serve the sole purpose of avoiding detection by the immune system.

Although many mechanisms of KSHV immune evasion have been found, there are undoubtably many more waiting to be discovered.

Works Cited

  1. Belanger, Carole et al. “Human herpesvirus 8 viral FLICE-inhibitory protein inhibits Fas-mediated apoptosis through binding and prevention of procaspase-8 maturation.” Journal of human virology, vol 4, no. 2, Mar 2001, pp. 62-73.
  2. Bellows, D S et al. “Antiapoptotic herpesvirus Bcl-2 homologs escape caspase-mediated conversion to proapoptotic proteins” Journal of virology, vol. 74, no. 11, Jun 2000: 5024-5031
  3. “Key Statistics About Kaposi Sarcoma.” American Cancer Society, 19 Apr. 2018, www.cancer.org/cancer/kaposi-sarcoma/about/what-is-key-statistics.html.
  4. Lagos, Dimitrios et al. ‘Kaposi sarcoma herpesvirus–encoded vFLIP and vIRF1 regulate antigen presentation in lymphatic endothelial cells.’ Blood, vol. 109, no. 4, Feb 2007, pp. 1550-1558.
  5. Lee, Hye-Ra et al. “Immune evasion by Kaposi’s sarcoma-associated herpesvirus” Future microbiology, vol. 5, no. 9, Sep 2010, pp. 1349-1365.
  6. Prasad, Alka et al. “An Alternative Kaposi’s Sarcoma-Associated Herpesvirus Replication Program Triggered by Host Cell Apoptosis” Journal of Virology, vol. 86, no. 8, Mar 2012, pp. 4404-4419.
  7. Sathish, Narayanan and Yan Yuan. “Evasion and subversion of interferon-mediated antiviral immunity by Kaposi’s sarcoma-associated herpesvirus: an overview” Journal of virology, vol. 85, no. 21, Oct 2011, pp. 10934-10944.
  8. Spiller, O Brad et al. “Complement regulation by Kaposi’s sarcoma-associated herpesvirus ORF4 protein” Journal of virology, vol. 77, no. 1 Jan 2003, pp. 592-599.
  9. Tabtieng, Tate et al. “Emerging Proviral Roles of Caspases during Lytic Replication of Gammaherpesviruses.” Journal of Virology, vol. 92, no. 19, July 2018, pp. 1011-1017
  10. Wilson, Sam J et al. “X box binding protein XBP-1s transactivates the Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF50 promoter, linking plasma cell differentiation to KSHV reactivation from latency” Journal of virology, vol. 81, no. 24, Dec 2007, pp. 13578-13586.
  11. Ye, Feng-Chun et al. “Kaposi’s sarcoma-associated herpesvirus latent gene vFLIP inhibits viral lytic replication through NF-kappaB-mediated suppression of the AP-1 pathway: a novel mechanism of virus control of latency” Journal of virology, vol. 82, no. 9, Feb 2008, pp. 4235-4249.
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