Longitudinal analysis of viral dynamics in HIV+-to-HIV+ HOPE Act kidney-transplant recipients

Abstract

BACKGROUNDThe HIV Organ Policy Equity (HOPE) Act allows individuals living with HIV to accept organs from donors with HIV. This practice widens the pool of available organs, but also presents important virological issues, including the potential for HIV superinfection of the recipient, viral persistence in the kidney, and loss of virological control.METHODSWe addressed these issues by performing in-depth longitudinal viral sequence analyses on urine, blood, and urine-derived renal epithelial cells from 12 recipients of HIV+ kidney allografts.RESULTSWe amplified donor-derived HIV-1 env sequences in 5 out of 12 recipients after transplant. These donor-derived env sequences were amplified from recipient urine, urine-derived renal epithelial cells, and plasma between 12 and 96 hours after transplant and remained detectable up to 16 days after transplant. Env sequences were also detected in kidney biopsies taken from the allografts before implantation in 6 out of the 12 transplant cases, indicating the presence of donor virus within the organ. One recipient had a viremic episode 3.5 years after transplantation as a result of antiretroviral therapy (ART) interruption. Only recipient strain viral sequences were detected in blood, suggesting that the donor virus, if still present, was not reactivated during the temporary ART withdrawal.CONCLUSIONSThis study demonstrates that the HIV env sequences in a donor kidney can be amplified from biopsies taken from the allograft before implantation and can be detected transiently in blood and urine samples collected from the organ recipients after transplantation.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant number R01DK131497.

Keywords: AIDS/HIV; Chronic kidney disease; Organ transplantation; Transplantation.

Figure 1. Phylogenetic tree analysis of HIV env sequences amplified from Hope 1 recipient before and up to 5 years after kidney transplant.

(A) Neighbor-joining phylogenetic tree that includes all of the HIV envelope sequences amplified from blood, urine, and LN samples obtained from the kidney-transplant recipient with HIV before and up to 5 years after transplantation of a kidney from a donor with HIV. Two separate viral lineages (lineages 1 and 2) were identified in the recipient up to 16 days after transplantation. Bootstrap values over 80% are indicated. (B) All the HIV quasispecies in lineage 1 that were amplified from the recipient’s urine (solid blue triangles for cell-free viral RNA and green squares for viral DNA associated with RTE cells) and plasma (solid orange circles) between 12 hours and 16 days after transplantation are genetically related to the donor virus (open shapes) and genetically distant from the viral sequences amplified from the recipient’s PBMCs, plasma, LNs, and urine-derived RTE cells before transplantation. Several HIV env sequences were also amplified from the kidney biopsy taken from the allograft before implantation (open pink diamonds), the majority of which were compartmentalized from the rest of samples analyzed (P value of 0.016 using a codon-based test of positive selection). The asterisk demarks a group of HIV envelope sequences amplified from either donor urine or recipient urine collected after transplantation that clustered separately from blood-derived sequences.

Figure 2. Phylogenetic tree analysis of HIV env sequences amplified from Hope 4 recipient before and up to 3.25 years after kidney transplant.

(A) Neighbor-joining phylogenetic tree that includes all of the HIV envelope sequences amplified from blood and urine samples obtained from the kidney-transplant recipient with HIV before and up to 3.25 years after transplantation of a kidney from a donor with HIV. Two separate viral lineages (lineages 1 and 2) were identified in the recipient up to 7 days after transplantation. Bootstrap values over 80% are indicated. (B) All the HIV quasispecies in lineage 1 that were amplified from the recipient’s urine (solid blue triangles for cell-free viral RNA) and plasma (solid orange circles) between 12 hours and 7 days after transplantation are genetically related to the donor virus (open shapes) and genetically distant from the viral sequences amplified from the recipient’s PBMCs and plasma before transplantation. All the urine sequences (73/73) were predicted to use CCR5 coreceptors (CCR5 false-positive rate <10%).

Figure 3. Phylogenetic tree analysis of HIV env sequences amplified from Hope 11 recipient before and up to 9 months after kidney transplant.

(A) Neighbor-joining phylogenetic tree that includes all of the HIV envelope sequences amplified from blood and urine samples obtained from the kidney-transplant recipient with HIV before and up to 9 months after transplantation of a kidney from a donor with HIV. Donor virus was detected in this recipient’s plasma 24 hours after transplantation. (B) Two HIV env sequences in lineage 1 that were amplified from the recipient’s plasma (solid orange circles) at 24 hours after transplantation are genetically related to the donor virus (open shapes). Additionally, several HIV env sequences were amplified from the kidney biopsy (open pink diamonds) taken from the allograft before implantation. Bootstrap values over 80% are indicated. All the donor- and recipient-derived sequences were predicted to use CCR5 coreceptors (CCR5 false-positive rate <10%).

Figure 4. Phylogenetic tree analysis of HIV env sequences amplified from Hope 14 recipient before and up to 1 month after kidney transplant.

(A) Neighbor-joining phylogenetic tree that includes all of the HIV envelope sequences amplified from blood and urine samples obtained from the kidney-transplant recipient with HIV before and up to 1 month after transplantation of a kidney from a donor with HIV. Two separate viral lineages (lineages 1 and 2) were identified in the recipient up to 4 days after transplantation in both urine and plasma. Bootstrap values over 80% are indicated. (B) All the HIV quasispecies in lineage 1 that were amplified from the recipient’s urine (solid blue triangles for cell-free viral RNA) and plasma (solid orange circles) between 30 hours and 4 days after transplantation are genetically related to the donor virus (open shapes). No HIV env sequences could be amplified from urine and blood samples collected from the recipient before transplantation. All the donor-derived HIV sequences were predicted to use CCR5 coreceptors, while the urine-derived HIV sequence shown in lineage 2 (recipient HIV) was predicted to use CXCR4 (CCR5 false-positive rate <10%),

Figure 5. Phylogenetic tree analysis of HIV env sequences amplified from Hope 15 recipient before and up to 1 year after kidney transplant.

(A) Neighbor-joining phylogenetic tree that includes all of the HIV envelope sequences amplified from blood and urine samples obtained from the kidney-transplant recipient with HIV before and up to 1 month after transplantation of a kidney from a donor with HIV. Two separate viral lineages (lineages 1 and 2) were identified in the recipient 30 hours after transplantation in both urine and plasma. (B) All the HIV quasispecies in lineage 1 that were amplified from the recipient’s urine (solid blue triangles for cell-free viral RNA) and plasma (solid orange circles) at 30 hours after transplantation are genetically related to the donor virus (open shapes). Only donor plasma and allograft biopsy samples were available for analysis. Bootstrap values over 80% are indicated.