Mechanisms of HIV persistence in the kidney

点击翻译按钮获取中文摘要

ABSTRACT Despite the dramatic improvement in HIV-associated morbidity and mortality with combination antiretroviral therapy (ART), HIV remains a chronic disease. The major barrier to HIV cure is the long-term persistence of multiple, latent viral reservoirs capable of reactivation in the absence of ART. Any effort to eradicate these reservoirs as part of a cure initiative requires understanding of the dynamics and control of HIV reactivation and replication in tissues and cells harboring the virus long-term. Our work has focused on understanding the mechanisms and implications of HIV infection of the kidney. We demonstrated that HIV infects renal tubule epithelial cells (RTEs) in vitro via direct contact with HIV-infected T cells and macrophages. Viral nucleic acid sequence analysis from in vivo derived RTEs compared to blood derived sequences demonstrated that the kidney represents a unique viral compartment. Furthermore, we showed that people with HIV (PWH) shed viral RNA in urine, and we have optimized approaches to detect and amplify HIV sequences from fresh and archived urine specimens. We found that some urine-derived HIV sequences were closely related to HIV sequences amplified from RTEs, supporting those cells as one of the sources of urine viruses. Viral detection in the urine allows for repeated sampling of the kidney compartment, which can be particularly useful in viral rebound studies. Additionally, in all of the PLWH we have analyzed so far, we amplified several identical HIV-1 sequences in urine, raising the possibility of clonal expansion of infected renal cells. Indeed, we recently reported that proliferation is one of the cellular fates observed in both actively and latently infected RTEs in vitro, together with hypertrophy and cell-death. Whether proliferation of infected renal epithelial cells contributes to HIV persistence in the kidney is unknown. The studies proposed here will define: 1) the long-term persistence of HIV in the kidney through the analysis of samples collected prospectively from PWH undergoing HIV+ to HIV+ kidney transplantation; 2) the reactivation potential of HIV in urine following ART interruption in terminally ill PWH who have consented to prospective follow-up as part of a rapid autopsy protocol; 3) the ability of patient-derived renal epithelial cells to carry replication competent virus; 4) the role of APOL1 kidney disease risk variants in RTE and podocyte infection; and 5) how HIV infection influences individual cell fate and potential for clonal expansion of infected RTEs. We hypothesize that renal epithelial cells serve as a long-term reservoir for HIV. Understanding the mechanisms of HIV persistence and reactivation in the kidney will inform cure strategies and further define renal pathogenesis in PLWH.