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Review
. 2014 Jul 10;10(7):e1004154.
doi: 10.1371/journal.ppat.1004154. eCollection 2014 Jul.

Molecular and cellular mechanisms of KSHV oncogenesis of Kaposi's sarcoma associated with HIV/AIDS

Lucas E Cavallin  1 , Pascal Goldschmidt-Clermont  1 , Enrique A Mesri  1
Affiliations
Review

Molecular and cellular mechanisms of KSHV oncogenesis of Kaposi's sarcoma associated with HIV/AIDS

Lucas E Cavallin et al. PLoS Pathog. .
No abstract available

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. KSHV pathobiology in healthy and HIV/AIDS patients.
(A) In a healthy host, KSHV infection of a KS progenitor is not oncogenic, since it leads to latent infection or to cytopathic lytic replication. Reactivation leading to oncogenic lytic gene expression is under immunological control. (B) Scenario for AIDS-KS pathogenesis according to the Paracrine Oncogenesis and Abortive Lytic Hypotheses. In HIV/AIDS, decreased immunosurveilance, inflammatory cytokines and HIV Tat lead to KSHV reactivation and reinfection. This leads to increased, uncontrolled, early lytic oncogenic gene expression, with concomitant risk of cell transformation by somatic host cell oncogenic alterations. Upon transformation, cells shut down early lytic oncogenes. Latently infected transformed cells are stimulated in a paracrine manner by angiogenic and proliferative factors released from lytically infected or abortive lytic cells (paracrine oncogenesis, see details in Figure 2). In addition, lytically infected cells provide a constant source of virions for reinfection, while angiogenesis and inflammation recruit target KS progenitors. ART inhibits KSHV reactivation and lytic replication through immune reconstitution and decreased levels of HIV viral loads. Gancyclovir inhibits viral replication and lytic gene expression.
Figure 2
Figure 2. Molecular mechanisms, therapeutic targets, and clinically tested drugs in AIDS-KS paracrine viral oncogenesis.
In KS spindle cells lytically infected with KSHV cells or latently infected spindle cells expressing early lytic genes, KSHV genes such vGPCR, K1, and ORF45 constitutively trigger signaling cascades, leading to mTOR and ROS activation, which induce transcription and translation of PDGF and VEGF. These secreted growth factors can act in a paracrine manner to activate the same signaling cascades in latently infected cells expressing VEGF and PDGF receptors to drive KS cell proliferation and angiogenesis. Rapamycin (RAPA), which inhibits mTOR, and Imatinib (IMA), which inhibits PDGFR, can interrupt this paracrine loop to target KSHV tumorigenesis. Both drugs have shown efficacy in AIDS-KS clinical trials.
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