Background:
Combination antiretroviral therapy (cART) reduces the incidence of HIV-associated nephropathy (HIVAN), but people living with HIV (PLWH) remain at high risk for later developing chronic kidney disease (CKD), with a poorly defined etiology. HIV acquisition is associated with reduced plasma all-trans-retinoic acid (atRA) and increased pro-fibrotic galectin (Gal)-3. Clinical trials investigating atRA receptor agonists and Gal-3 antagonists to ameliorate HIVAN/CKD were completed but discontinued after phase 2, necessitating new strategies to restore kidney function. FDA-approved vedolizumab (anti-α4β7) is well-tolerated for inflammatory bowel diseases. Here, we query whether anti-α4β7 can improve renal function in a rhesus macaque (RM) infection model.
Methods:
Nine RMs were CD8-depleted and inoculated with SIVmac251. Daily cART was begun at week two, along with infusions (anti-α4β7 mAb: n=5; IgG controls: n=4) every three weeks until week 23. cART was discontinued (ATI) at week 14. Longitudinal plasma measurements were performed for serum chemistry, retinoids determined by HPLC-UV, and Gal-3 by Luminex. atRA metabolism and podocyte differentiation gene expression were determined by qPCR in kidney samples collected at necropsy and compared to uninfected RMs (n=4).
Results:
Anti-α4β7 treated RMs had lower measures of urea nitrogen (BUN) and BUN:Creatinine ratio than IgG RMs following therapy and ATI (P=0.0159; P=0.0250), despite comparable measures at baseline. Acute infection was associated with reduced (~35% less) atRA in both groups (P=0.0046; P=0.0014). While atRA remained low in IgG RMs, it increased in anti-α4β7 RMs during cART (P=0.0012) and ATI (P=0.0004), resulting in differences between groups (P=0.0101; P=0.037). atRA precursor retinyl ester (RE) was higher in IgG RMs (P=0.0139) than anti-α4β7 RMs after ATI. RE was positively correlated with BUN:Creatinine (P=0.0152). Anti-α4β7 RMs had greater atRA synthesis (ALDH1A1, ALDH1A3) while IgG RMs had higher atRA catabolism (CYP26A1) gene expression than uninfected RMs. IgG (but not anti-α4β7) RMs also had lower SYNPO and RARRES expression. IgG RMs had lower Gal-3 than anti-α4β7 RMs (P=0.004) after ATI. Gal-3 levels associated negatively with SYNPO expression (P=0.0299) and positively with RE (P=0.0275) and BUN:Creatinine (P=0.044).
Conclusions:
Our data provide a rationale for repurposing vedolizumab for HIVAN/CKD to restore retinoid signaling, podocyte differentiation, and glomerular filtration thereby improving quality of life in PLWH.