Abstract
Kaposi’s sarcoma (KS) is an angioproliferative tumor showing an increased frequency and aggressiveness in HIV-infected subjects (AIDS-KS), due to the combined effects of inflammatory cytokines (IC), angiogenic factors, and the HIV-1 Tat protein. While the introduction of effective combined antiretroviral regimens greatly improved AIDS-KS incidence and course, it continues to be an incurable disease and the development of new rational targeted therapies is warranted. We used the BKV/Tat transgenic mouse model to evaluate the effects of IC and anti-Tat antibodies (Abs) treatment on KS-like lesions arising in BKV/Tat mice. We demonstrated here that IC-treatment increases the severity and delays the regression of KS-like lesions. Further, anti-Tat Abs reduced KS-like lesion severity developing in IC-treated mice when anti-Tat Abs were administered at an early-stage of lesion development as compared to more advanced lesions. Early anti-Tat Abs treatment also accelerated KS-like lesion regression and reduced the rate of severe-grade lesions. This effect was more evident in the first weeks after Ab treatment, suggesting that a longer treatment with anti-Tat Abs might be even more effective, particularly if administered just after lesion development. Although preliminary, these results are encouraging, and the approach deserves further studies for the development of anti-Tat Ab-based therapies for AIDS-KS. Clinical studies specifically addressing the effect of anti-Tat antibodies in treating AIDS-KS are not yet available. Nevertheless, the effectiveness of anti-Tat antibodies in controlling HIV/AIDS progression, likely due to the neutralization of extracellular Tat activities, is suggested by several cross-sectional and longitudinal clinical studies, indicating that anti-Tat Ab treatment or Tat-based vaccines may be effective to treat AIDS-KS patients or prevent the tumor in individuals at risk.
Highlights
Kaposi’s sarcoma (KS) is an angioproliferative tumor first described in elderly men of the Mediterranean Eastern-European areas and observed in patients treated with chronic immunosuppressive therapy, especially in organ transplant recipients, and in children and young/adults of subequatorial Africa (African KS) [1]
We have shown here that treatment with the same inflammatory cytokines (IC) that are increased in lesions and blood of KS patients or in subjects at risk of disease development enhances the severity and delays the regression of KS-like lesions arising in BK virus (BKV)/Tat transgenic mice
This is because IC induce production and release of angiogenic factors such as basic fibroblast growth factor and vascular endothelial growth factor (VEGF), which are highly expressed in all forms of KS and synergize in promoting angiogenesis, matrix-metalloproteases expression and activation, vascular permeability, and edema [13,37–43] as observed in human KS lesions [1,15]
Summary
Kaposi’s sarcoma (KS) is an angioproliferative tumor first described in elderly men of the Mediterranean Eastern-European areas (classical KS) and observed in patients treated with chronic immunosuppressive therapy, especially in organ transplant recipients (iatrogenic KS), and in children and young/adults of subequatorial Africa (African KS) [1]. In the group of mice in which the anti-Tat Ab treatment was started at an early stage, the lesion score tended to be lower as compared to the group of mice in which the anti-Tat Abs were given at a more advanced stage (Figure 3A), while no difference was observed in the lesion course of control mice (Figure 3B). One out of seven animals treated at an early stage showed progression to a score ≥3 as compared to those treated later (14% versus 75%, respectively), while the early-stage and late-stage mice treated with control Abs showed a similar progression rate (40% versus 60%, respectively) (Table S1) These results indicate that anti-Tat Ab treatment may be effective against KS-like lesions of BVK/Tat transgenic mice when administered at early-stages of lesion development
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