An HIV drug that suppresses the activity of the CCR5 receptor—a collection of proteins on the surface of certain immune cells—was associated with better renal function in kidney transplant recipients with HIV compared to people who took a placebo in a randomized trial. Study participants taking the drug, called maraviroc, also experienced lower rates of transplant rejection than those taking placebo, but the difference was not statistically significant due to lower-than-expected rejection rates across the entire study population. The findings of the NIAID-sponsored trial were presented today at the 2024 American Transplant Congress in Philadelphia. 

The CCR5 receptor helps HIV enter CD4+ T cells. Some people have a genetic mutation that prevents the CCR5 receptor from working, and either cannot acquire HIV or experience slower HIV-related disease progression if living with the virus. It has separately been observed that people with the same CCR5 genetic mutation have better outcomes following kidney and liver transplantation. The CCR5 antagonist class of antiretroviral drugs was developed to mimic the naturally occurring CCR5 mutation and is a well tolerated component of HIV treatment, but the drugs have not been evaluated as an intervention to improve transplantation outcomes in people. Furthermore, transplant recipients with HIV more frequently experience transplant rejection and elevated CCR5 activity than transplant recipients without HIV.

A research team led by the University of California San Francisco conducted a U.S.-based Phase 2 trial to assess the safety and tolerability of the CCR5 antagonist maraviroc given daily from the time of transplant onward among kidney transplant recipients, and to compare renal function of people taking daily maraviroc to those taking a placebo one year (52 weeks) post-transplant. All study participants were living with HIV and were virally suppressed on antiretroviral therapy (ART) regimens. The study randomized 97 participants to receive maraviroc or a placebo in addition to their continued ART regimens post-transplant. Of them, only 27 participants were able to complete all necessary study examinations through 52 weeks due to logistical complications from the SARS-CoV-2 pandemic. At one-year post-transplant, the mean estimated glomerular filtration rate—a measure of how well kidneys were working—was significantly higher in participants receiving maraviroc in addition to their ART regimen compared with participants receiving ART and placebo (59.2 versus 49.3 mL/min/1.73m²). The drug was safe and well tolerated. 

Four of the 49 participants taking maraviroc and 6 of the 48 participants taking placebo experienced transplant rejection, but this difference was not statistically significant given the relatively small sample size. Transplant rejection rates were lower than expected across both study groups, which the study team suggests may be a favorable outcome of the ART regimens most participants were taking. 

The addition of maraviroc significantly improved renal function in kidney transplant recipients with HIV compared to placebo. According to the authors, these findings warrant further exploration of the benefit of CCR5 antagonists in all kidney transplant recipients regardless of HIV status.

For more information about this study, please visit ClinicalTrials.gov and use the identifier NCT02741323.

Reference:

Brown et al. Beneficial Impact of CCR5 Blockade in Kidney Transplant Recipients with HIV. American Transplant Congress in Philadelphia, Pennsylvania. Tuesday, June 4, 2024.

The presence of antibodies that target one of the body’s own proteins was associated with severe infections that typically only occur when a person’s immune system is suppressed, based on a multi-cohort study of blood samples from more than 1,000 people. This study suggests autoimmune processes could be involved in the development of immunodeficiency in adulthood. The research was led by scientists in the Immunopathogenesis Section of NIAID’s Laboratory of Clinical Immunology and Microbiology (LCIM) and published in the New England Journal of Medicine.

Antibodies play a critical role in the body’s response to infection and injury, but some people have “autoantibodies” that target the body’s own cells and organs, resulting in autoimmune diseases and conditions. This study centered on the role of antibodies that target the body’s own inflammatory cytokines, proteins that communicate with other cells to prompt the body to fight infection. Only a few anti-cytokine autoantibodies have previously been implicated in promoting enhanced susceptibility to certain severe infections. Interleukin-12 and interleukin-23 are related cytokines that share a common structural feature and function similarly to influence the generation of interferon-gamma (IFN-gamma), a protein involved in immune system responses. Interleukin-23 is known to control inflammation in tissues such as the skin, lung, gastrointestinal tract, joints, and brain. Prompted by an observation that a person with Burkholderia gladioli—a rare bacterial infection—had detectable antibodies to both interleukin-12 and interleukin-23, scientists investigated the prevalence of anti-interleukin-23 antibodies in people with known anti-interleukin-12 antibodies, only half of whom experienced opportunistic infections, meaning infections that tend to affect only compromised immune systems. They found anti-interleukin-23 antibodies among the half that experienced opportunistic infections.

Subsequently the team examined the blood from people participating in several cohort studies for the presence of anti-interleukin-23 antibodies, examining its association with thymoma (a tumor in the thymus associated with autoimmunity and immune deficiency), rare mycobacterial, bacterial and fungal infections versus common viral infections. The presence of anti-interleukin-23 antibodies was associated with severe, persistent opportunistic mycobacterial, bacterial, and fungal infections, but not with COVID-19. The strongest association to such infections was found in people who also had thymoma.

According to the authors, a comprehensive approach to autoantibodies against cytokines is needed to understand their role in both the source and the severity of infections. An editorial accompanying the publication suggests that these findings should prompt the design of new diagnostic tests and therapeutic approaches based on anti-interleukin-23 antibodies for people with rare and severe infections of unknown cause. This research represents an advance in the core mission of the LCIM Immunopathogenesis Section, which has contributed key evidence about the role of IFN-gamma in human immunity for decades.

References:

Cheng, A et al. Anti–Interleukin-23 Autoantibodies in Adult-Onset Immunodeficiency. New England Journal of Medicine. DOI 10.1056/NEJMoa2210665 (2024).

Netea, MG et al. Anti–Interleukin-23 Autoantibodies and Severe Infections. New England Journal of Medicine. DOI 10.1056/NEJMe2400475 (2024)