Pathogenesis of HIV-associated nephropathy in children and adolescents: taking a hard look 40 years later in the era of gene-environment interactions.

HIV-associated nephropathy (HIVAN) is a kidney disease that affects mainly people of African ancestry with a high HIV-1 viral load. New antiretroviral therapies (ART) have been highly efficient in preventing and improving the outcome of HIVAN. However, providing chronic ART to children and adolescents living with HIV (CALWH) remains a significant challenge all over the world. More than 2.5 million CALWH, including those living in Sub-Saharan Africa, continue to be at high risk of developing HIVAN. Much of our understanding of the pathogenesis of HIVAN is based on studies conducted in transgenic mice and adults with HIVAN. However, CALWH may experience different health outcomes, risk factors, and susceptibilities to HIVAN in comparison to adults. This article reviews the progress made over the last 40 years in understanding the pathogenesis of HIVAN in CALWH, focusing on how the HIV virus, alongside genetic and environmental factors, contributes to the development of this disease. The landmark discovery that two risk alleles of the apolipoprotein-1 (APOL1) gene play a critical role in HIVAN has significantly advanced our understanding of the disease's pathogenesis. However, we still need to understand why renal inflammation persists despite ART and determine whether the kidney may harbor HIV reservoirs that need to be eliminated to cure HIV permanently. For these reasons, we emphasize reviewing how HIV-1 infects renal cells, affects their growth and regeneration, and discussing how inflammatory cytokines and APOL1 affect the outcome of childhood HIVAN.