How does HAART lead to the resolution of Kaposi's sarcoma?

Abstract

As highly active antiretroviral therapy (HAART) is available for less than one million individuals worldwide, Kaposi's sarcoma (KS) remains a common complication of infection with the human immunodeficiency virus (HIV). Use of HAART has reduced the incidence of KS and, in affected individuals, HAART alone can lead to KS resolution. Pos- sible mechanisms include general improvements in immune function including the specific generation of anti-KS responses, the inhibition of HIV-1 cofactors that are thought to be important in tumour development and inhibitory effects on angiogenic growth factors and cytokines that promote KS formation. The relative contributions of these mechanisms will be discussed. Infection with HIV-1 is associated with a significant and increased risk of developing KS, a tumour that remains a significant cause of morbidity and mortality. 1-3 Its aetiologic agent is Kaposi's sarcoma-associated herpesvirus (KSHV), 4 a γ-herpesvirus that is widely prevalent in immunosuppressed populations, associated with all the clinico-epidemiological forms of KS and levels of which appear predictive of its devel- opment. 3 The introduction of HAART with combinations of nucleoside analogue reverse transcriptase inhibitors and protease inhibitors (PIs) or non-nucleoside reverse tran- scriptase inhibitors (NNRTIs) has altered survival associated with HIV 5 and there is increasing evidence that the incidence of KS in the HIV-seropositive population is declining; 6 this fall coincides with the increasing use of HAART. 2 The epide- miological evidence is supplemented by observations that individual KS lesions resolve with HAART 7 and KSHV loads decrease during this resolution. 8 The lower incidence and regression of KS observed with HAART may result from a variety of effects. These include one or more of the following: (i) immune reconstitution fol- lowing initiation of HAART; (ii) the inhibition of HIV-1 replication and the resultant decrease in its 'angiogenic' Tat protein; and (iii) the reduction in intracellular cytokine pro- duction, which triggers the production of angiogenic factors and KSHV reactivation, and, related to this, direct anti- angiogenic effects of HAART on KS. The potential role of each of these is discussed below.