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TELMISARTAN DECREASES HIV-1 RNA IN LYMPH NODES IN TREATED HIV INFECTION
Netanya S. Utay1, Jordan E. Lake1, Claire Deleage2, Douglas W. Kitch3, Eunice Yeh3, Karin L. Klingman4, Michael M. Lederman5, Carl Fichtenbaum6, Daniel Douek7, Judith S. Currier8, Jacob D. Estes2
1University of Texas at Houston, Houston, TX, USA,2Leidos Biomedical Research, Inc, Frederick, MD, USA,3Harvard University, Boston, MA, USA,4DAIDS, NIAID, Bethesda, MD, USA,5Case Western Reserve University, Cleveland, OH, USA,6University of Cincinnati, Cincinnati, OH, USA,7National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA,8University of California Los Angeles, Los Angeles, CA, USA
Chronic inflammation in HIV infection can lead to lymph node (LN) fibrosis and limit CD4+ T-cell recovery. Telmisartan, an angiotensin receptor blocker and PPAR-γ agonist, is anti-inflammatory and anti-fibrotic. We previously reported telmisartan did not decrease LN fibrosis (i.e. collagen I by immunohistochemistry (IHC)) more than ART alone. We hypothesized telmisartan would decrease macrophage infiltration and HIV-1 RNA+ cells and increase CD4+ T-cells in LN.
In this completed, randomized-controlled trial, adults with HIV-1 RNA <50 copies/mL on ART for ≥48 weeks received telmisartan plus ART for 48 weeks or ART alone. The number of LN HIV-1 RNA+ (vRNA+) cells was measured by RNAscope and % CD4+ T cells and CD68+CD163+ macrophages by IHC at weeks 0 and 48. Statistical testing used two-sided rank-sum, signed-rank tests and Spearman correlations (α=0.05).
Of 44 participants, 93% were male, 50% white non-Hispanic, median age 48 years, CD4+ T-cell count 588 cells/mm...3.... Week 0 median (IQR) number of vRNA+ cells/10...6... cells was 106 (67, 130; n=17) in the telmisartan arm and 75 (0, 118; n=13) for ART alone. By morphology, vRNA+ cells were lymphocytes. After 48 weeks, the number of vRNA+ cells/10...6... cells changed by -48 (-88, 0; P=0.004) in the telmisartan arm and +18 (-91, 45; P=0.70) with ART alone, with P=0.28 for the between-arm comparison. Median abundance of CD4+ T cells and macrophages in the B cell follicle (BCF) and T cell zone (TCZ) did not change significantly in either arm. With pooled treatment arms at Week 0, having less LN collagen I was associated with more CD4+ T cells in TCZ (r=-0.47, P=0.004). Having more vRNA+ cells was associated with fewer CD4+ T cells in BCF (r=-0.40, P=0.03) and fewer macrophages in BCF (r=-0.38, P=0.04) and TCZ (r=-0.35, P=0.04). While not associated at Week 0, 48-week increases in CD4+ T cells in TCZ were associated with decreases in macrophages in BCF (r=-0.60, P=0.0009) and TCZ (r=-0.60, P=0.0005) in a pooled analysis.
The number of LN HIV-1 RNA+ cells declined 45% with telmisartan added to suppressive ART. At Week 0, people with less LN fibrosis and fewer vRNA+ cells had more LN CD4+ T cells. Decreases in macrophages were accompanied by better LN CD4+ T cell recovery. Further characterization of these macrophages and the reservoir will clarify the interactions between HIV-1, LN immune cells, and their effects on fibrosis and the HIV reservoir.