HIV persistence and treatment response in Kaposi sarcoma

Kaposi sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi sarcoma (KS), which causes significant morbidity and mortality worldwide, particularly in people with HIV (PWH) and in sub-Saharan Africa (SSA) where KSHV seroprevalence is high. It is estimated that 80% of the KS burden in SSA, where the impact of KS is heaviest, is attributable to HIV infection. In our prospective KS cohort in Uganda (the “HIPPOS” study), we have observed that outcomes remain poor despite optimized treatment with antiretroviral therapy (ART) and chemotherapy, with an overall 1-year survival of 64% among the first 200 study participants. However, we have observed differential outcomes among participants, with 11% achieving a clinical complete response, 48% a partial response, 13% experiencing stable disease, and 25% progressive disease. Identifying the factors that contribute to these differences in outcome could inform the design of more effective KS therapies. Our ongoing studies of the HIPPOS KS cohort and findings from other investigators suggest that control of HIV is an important factor in KS response. First, among the initial 200 participants in our HIPPOS cohort, higher baseline plasma HIV viral loads were independently associated with increased mortality in HIV-associated KS. Second, RNA sequencing of pre-treatment KS tumors demonstrated high-level expression of HIV genes in KS tumors from PLWH. Third, transcriptionally active HIV and HIV Nef protein have been identified in treatment- refractory KS tumors, suggesting that KS tumors could be a reservoir for HIV that shapes the KS tumor microenvironment. Fourth, our studies of several KS cohorts have identified CD8+ T-cells specific for peptides derived from the HIV Gag/Pol, Vpr, and Nef gene products that persist in both KS tumors and peripheral blood of PWH with KS despite peripheral HIV suppression with ongoing ART. Collectively, these findings suggest that persistence of HIV in KS tumors of PWH might make an important contribution to treatment resistance. In this proposal we will test the hypothesis that intratumoral HIV persistence is associated with treatment resistance in PWH with KS through evaluation of: (i) HIV, KSHV, and host gene expression, and (ii) HIV and KSHV protein expression in serially acquired tumor biopsies from cohorts of PWH enrolled in three prospective KS therapeutic clinical trials. The first cohort comprises the HIPPOS study of newly diagnosed adults with KS treated with either bleomycin/vincristine or paclitaxel at the Uganda Cancer Institute in Kampala, Uganda. The second and third cohorts comprise adults with KS enrolled on two trials conducted by the NCI-sponsored Clinical Immunotherapy Trials Network (CITN) who were treated with a human IL-7 agonist (trial CITN-17) or with the PD-1-specific monoclonal antibody pembrolizumab (trial CITN-12). Central to all three clinical trials is the hypothesis that control of KSHV and HIV replication by KSHV- and HIV-specific T-cells combined with effective ART is essential for KS regression and resolution. The successful completion of these studies will contribute to improved outcomes for individuals with KS worldwide. Project Number: 1R21CA302296-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Edus Warren | Institution: FRED HUTCHINSON CANCER CENTER, SEATTLE, WA | Award Amount: $432,098 | Activity Code: R21 | Study Section: HIV Coinfections and HIV Associated Cancers Study Section[HCAC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11190522