Mechanisms of HIV persistence in the kidney

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.

Grant Number: 5R01DK131497-04
NIH Institute/Center: NIH
Principal Investigator: Maria Blasi