Molecular biology of KSHV in relation to AIDS-associated oncogenesis

Abstract

KSHV has been established as the causative agent of KS, PEL, and MCD, malignancies occurring more frequently in AIDS patients. The aggressive nature of KSHV in the context of HIV infection suggests that interactions between the two viruses enhance pathogenesis. KSHV latent infection and lytic reactivation are characterized by distinct gene expression profiles, and both latency and lytic reactivation seem to be required for malignant progression. As a sophisticated oncogenic virus, KSHV has evolved to possess a formidable repertoire of potent mechanisms that enable it to target and manipulate host cell pathways, leading to increased cell proliferation, increased cell survival, dysregulated angiogenesis, evasion of immunity, and malignant progression in the immunocompromised host. Worldwide, approximately 40.3 million people are currently living with HIV infection. Of these, a significant number are coinfected with KSHV. The complex interplay between the two viruses dramatically elevates the risk for development of KSHV-induced malignancies, KS, PEL, and MCD. Although HAART significantly reduces HIV viral load, the entire T-cell repertoire and immune function may not be completely restored. In fact, clinically significant immune deficiency is not necessary for the induction of KSHV-related malignancy. Because of variables such as lack of access to therapy noncompliance with prescribed treatment, failure to respond to treatment and the development of drug-resistant strains of HIV, KSHV-induced malignancies will continue to present as major health concerns.

Figure 1

KSHV genome and genes. The names of genes are labeled in color according to gene function (immunomodulation in blue, mitogenic and cell cycle in purple, antiapoptosis in green, and viral structure and replication in black). The blocks representing the ORFs are also labeled in color according to gene class (immediate-early in orange, early in light blue, late in red, latent in green, and unclassified in white). (See Color Plates)

Figure 2

Transcription of the latency-associated region of the KSHV genome. The KSHV latency-associated region encodes four proteins, indicated by black boxes, as well as 12 miRNAs (white boxes) and is flanked by lytic genes (gray boxes). Two latent promoters (white arrows), splice sites, and poly(A) addition sites are indicated. Sequence coordinates are derived from the prototype BC-1 KSHV genome (GenBank accession number NC_003409). Figure is modified from reference .