The effect of induction immunosuppression for kidney transplant on the latent HIV reservoir

Abstract

The HIV latent viral reservoir (LVR) remains a major challenge in the effort to find a cure for HIV. There is interest in lymphocyte-depleting agents, used in solid organ and bone marrow transplantation to reduce the LVR. This study evaluated the LVR and T cell receptor repertoire in HIV-infected kidney transplant recipients using intact proviral DNA assay and T cell receptor sequencing in patients receiving lymphocyte-depleting or lymphocyte-nondepleting immunosuppression induction therapy. CD4 + T cells and intact and defective provirus frequencies decreased following lymphocyte-depleting induction therapy but rebounded to near baseline levels within 1 year after induction. In contrast, these biomarkers were relatively stable over time in the lymphocyte-nondepleting group. The lymphocyte-depleting group had early TCRβ repertoire turnover and newly detected and expanded clones compared with the lymphocyte-nondepleting group. No differences were observed in TCRβ clonality and repertoire richness between groups. These findings suggest that, even with significant decreases in the overall size of the circulating LVR, the reservoir can be reconstituted in a relatively short period of time. These results, while from a relatively unique population, suggest that curative strategies aimed at depleting the HIV LVR will need to achieve specific and durable levels of HIV-infected T cell depletion.

HIV-Positive Liver Transplant Does not Alter the Latent Viral Reservoir in Recipients With Antiretroviral Therapy-Suppressed HIV

“…Studies have shown that kidney transplant patients who received lymphocyte nondepleting therapies had a slight reduction of CD4 + T-cell counts, and intact and defective provirus initially, but levels returned to baseline [ 5 ]. Liver transplant recipients in this study receiving lymphocyte nondepleting therapies show similar results.…”

“…IPDA was performed as previously described (Accelevir Diagnostics) [ 5 ]. Briefly, total CD4 + T cells were isolated from cryopreserved PBMCs via immunomagnetic selection, and genomic DNA was isolated.…”

“…All baseline and follow-up characteristics of the study population were summarized overall and by donor HIV status using descriptive statistics as previously described [ 5 ]. The primary outcomes evaluated included intact provirus, defective provirus, ratio of intact/defective provirus frequencies, and CD4 + T-cell counts per μL of blood stratified by donor allograft HIV status.…”

“…The primary outcomes evaluated included intact provirus, defective provirus, ratio of intact/defective provirus frequencies, and CD4 + T-cell counts per μL of blood stratified by donor allograft HIV status. The intact provirus and defective provirus frequencies were analyzed both by frequency per million CD4 + T cells and frequency per mL of blood, as previously described [ 5 ]. All values were log 10 transformed, except the ratio of intact/defective provirus frequencies, to approximate normal distributions.…”

“…Previous studies have monitored the LVR over time in kidney transplant recipients with HIV who received organs from donors with and without HIV [ 5 ]. In these kidney recipients, despite a dramatic initial reduction in the LVR size among those receiving lymphocyte-depleting induction therapy, the reservoir reconstituted within 1 year, and there were no differences in the LVR size among those receiving lymphocyte nondepleting immunosuppression induction therapy or by allograft donor HIV status [ 5 , 6 ]. However, one as yet unanswered question is whether the size of the LVR changes with liver transplantation from a donor with or without HIV into PWH.…”