Immunological profiles of HIV-positive recipients of liver transplant

Highlights

• Limited data are available about immune profiles in HIV-positive recipients of liver transplant (HIV-LT)

• Healthy controls showed increased numbers of B cell subsets and decreased T effector subpopulations compared to HIV-LT.

• Altered frequencies of B, T, and NK cell populations were shown in HIV-LT compared to healthy controls.

• Knowledge of immune cell proportions may help stratify HIV-LT requiring additional monitoring after transplantation

Abstract

Background

Scarce data are available about immune cell frequencies in HIV-positive recipients of liver transplant. Alterations in immune subsets can lead to persistent immune activation and disease progression or reduced HIV-specific responses. In liver transplantation, impaired immune tolerance can lead to organ rejection.

Methods

HIV-positive subjects with undetectable HIVRNA and CD4 > 100/mm³ were included. Control groups were non-transplanted HIV-positive patients with similar immunovirological parameters and healthy subjects. B cells (memory, transitional, and mature subsets), T cells (effector TH1, nonclassic TH1, TH17, TH1/17; T regulatory naïve and effector subsets and CD8⁺ T regulatory cells), and NK cells (CD56^dim and CD56^bright subsets) were analyzed by flow cytometry.

Results

A total of 56 patients, including 14 HIV-positive transplant recipients (HIV-LT), 14 HIV-positive controls, and 28 healthy controls were included. Median age of HIV-LT patients was 54.9 years with median time from transplant of 7.6 years. Eleven (79%) were HIV/HCV coinfected. Compared to nontransplanted patients, HIV-LT displayed significantly increased frequency of T CD8⁺ cells, lower percentage of T CD4+ cell, and lower number of nonclassic TH1, TH1/17 cells and naïve T CD4⁺ regulatory cells (Tregs). Healthy controls showed increased numbers of B cell subsets and decreased percentage of T effector subpopulations compared to HIV-LT. Compared to HIV-positive patients, healthy controls had higher B cells, NK cells, CD4⁺ T cells, naïve CD4+ Tregs but lower CD8⁺ T cells, effector Tregs, CD8⁺ Tregs, and all T effector cell subsets.

Conclusions

Immune cell subpopulations potentially associated with HIV progression and organ rejection were detected in HIV-positive transplant recipients. We confirmed altered frequencies of B, T, and NK cell populations in HIV-positive liver transplant recipients compared to healthy controls. The imbalance among immune cell subsets deserves further studies to identify markers of transplant outcome and potential therapeutic targets.

Introduction

Prior to the introduction of HAART, HIV positivity was an absolute contraindication for solid organ transplantation (SOT) [1] due to the reduced life expectancy of HIV-infected patients and the concern that immunosuppressants could have favored post-transplant opportunistic infections (OI). Prolonged survival due to HAART, however, has increased the prevalence of non-OI related causes of death. Among these, end-stage liver disease related to HCV coinfection and drug toxicity caused an increase in the demand for liver transplant (LT) among HIV-infected individuals [2,3]. SOT currently represents a valid therapeutic option for HIV patients with stable viral infection and end-stage organ disease [4]. In this cohort, mortality rates comparable to non-HIV patients and limited occurrence of OI have been reported, especially for renal transplant recipients [4,5]. Conversely, clinicians managing HIV-positive liver transplant recipients (LTR) have faced worse outcomes compared to the HIV-negative counterpart, especially among coinfected HIV/HCV patients [[4], [5], [6], [7]].

The immune system plays a pivotal role in graft survival, causing organ rejection if not controlled or, on the other side, favoring the occurrence of infections. In HIV-positive individuals, T cell alterations such as reduction of CD4⁺ T cell absolute number and decreased CD4:CD8 ratio appear to be key immune disorders for disease progression [8]. Although the distribution of B, T, and NK cells has been extensively studied in HIV-positive patients and in HIV-negative transplant recipients, the analysis of immunological profiles in HIV-positive LTR has not been previously documented. Data on T cell function and cytokine production among HIV-positive patients undergoing SOT are also limited to few reports [[9], [10], [11]].

Among T cell populations, decreased T regulatory cell (Tregs) absolute counts have been described in HIV-patients and could be linked to immune hyper-activation [12]. Natural killer (NK) cells could play an important role in controlling viral expansion through cell antibody-dependent cell cytotocity, but their number and function is often impaired, especially among viremic HIV-patients [13]. Finally, B-cell abnormalities that are still not completely clarified, including defects of IgM⁺ memory B cells and paucity of HIV-specific IgA responses, likely prevent the occurrence of an effective antibody response against HIV [14].

We have analyzed the frequencies of peripheral subpopulations of lymphocytes by flow cytometry in a cohort of stable HIV-positive LTR and compared them with non-transplanted HIV-positive patients and healthy controls to observe if numerical alterations were present.