# Pathogenesis of the cART unresponsive Kaposi’s sarcoma tumor niche

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $566,972

## Abstract

Abstract
Kaposi's Sarcoma (KS) is the most common AIDS-defining cancer. Combined anti-retroviral therapy (cART) has
greatly reduced KS-associated mortality among AIDS patients; however, a serous clinical problem exists in that
up to 50% of HIV+KS+ patients in the United States and 61% in Sub-Saharan Africa never achieve complete
remission even with chemotherapy and a reduction in HIV viral loads. No definitive study has identified if there
are tumor-associated features or mechanisms are associated with cART-progressive KS (progressors) vs. the
responder (responders) phenotype. Our study utilizes a robust pre-cART KS tissue collection (n = 224) from the
ACSR that originated from the Antiretrovirals for Kaposi's Sarcoma (ARKS) clinical trial. 36% of ARKS
participants experienced continued progression of KS despite a reduction in viral loads and restored T-cell
counts, in contrast to the rest of the cohort who experienced a reduction or elimination of tumors by the 1-year
trial endpoint. This application poses several hypotheses concerning the progressor phenotype: 1) prior to the
initiation of cART, an increase in HIV and/or KSHV-infected immune cells enhances a stimulatory immunological
profile in the progressor phenotype, 2) there are significant differences in the upregulation of KSHV lytic and
immunomodulation genes, which stimulate increased immune cell recruitment into the pre-cART tumor
microenvironment and promote tumor progression through cytokine-signaling inflammatory processes enhanced
in part by the cART-revitalized immune system, 3) the highly inflammatory nature of KS tumors, comprising a
complex mixture of immune cells with which to interact, selects for unique and/or elusive HIV genotypes, distinct
from plasma HIV, that promote stimulatory processes to continue in the progressor phenotype. Our Specific
Aims address these hypotheses using a combination of advanced immunohistochemistry, virus specific cellular
localization (DNA and RNAscope), high-throughput gene expression analysis (RNAseq), and a novel deep
sequencing approach applied to HIV. Innovations include the unprecedented amount pre-cART KS tumor
material available for the study, advanced imagining technologies, in vivo KS tumors gene expression studies,
the use of the newer PacBio SMRT sequencing approach applied to HIV, and machine-learning approaches that
can define non-linear associations in complex data sets. This project will define the largest well-characterized
set of combinatorial features related to cART-associated KS outcomes derived directly from KS-associated
biomaterial. Identifying clinically relevant immune factors in the tumor niche pre-cART will pave the way for the
development of future mechanistic studies on the functions of both viral and cellular genes that are involved in
cART resistant tumor progression.

## Key facts

- **NIH application ID:** 10669148
- **Project number:** 5R01CA239263-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** MICHAEL Shannon MCGRATH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $566,972
- **Award type:** 5
- **Project period:** 2019-09-18 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10669148

## Citation

> US National Institutes of Health, RePORTER application 10669148, Pathogenesis of the cART unresponsive Kaposi’s sarcoma tumor niche (5R01CA239263-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10669148. Licensed CC0.

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