This blog is the fifth in a series about the future of NIAID's HIV clinical research enterprise. For more information, please visit the HIV Clinical Research Enterprise page.

The outcomes of HIV clinical trials are often determined by precisely and accurately measuring how specific interventions work biologically in people. Whether tracking immune responses to a preventive vaccine candidate, monitoring changes to the amount of virus in the body, or screening for certain adverse events after administering a novel therapeutic, study teams routinely interact with clinical trial participants to safely obtain, store, transport, and analyze tissue and bodily fluid samples to answer important scientific questions about the impact of an HIV intervention in a laboratory. High quality, reliable laboratory infrastructure is critical to the accuracy and validity of clinical trial results. 

More than 150 NIAID-supported laboratories in 20 countries are addressing the diverse scientific programs of the four clinical trials networks in the Institute’s HIV clinical research enterprise. Since the start of HIV clinical research, laboratory capacities have grown in scope to support an increasing number of global clinical trials, emerging complexities in study protocol design and laboratory testing demands and evolving regulatory requirements for research and licensure.

NIAID is engaging research partners, community representatives, and other public health stakeholders in a multidisciplinary evaluation of its HIV clinical trials networks’ progress toward short- and long-term scientific goals. This process assesses knowledge gained since the networks were last awarded in 2020 to identify an essential path forward based on the latest laboratory and clinical evidence. Future NIAID HIV clinical research investments build on the conclusions of these discussions. 

In the next iteration of HIV clinical trials networks, laboratory functions will continue to evolve to align with scientific priorities and research approaches. Networks will support small early-phase trials, large registrational trials and implementation science research to examine preventive vaccine candidates and non-vaccine prevention interventions, antiviral treatments, HIV curative strategies, and therapies to improve the clinical outcomes of people affected by and living with HIV. Selected studies also will rely on high quality laboratory resources to examine interventions for tuberculosis, hepatitis, mpox and other infectious diseases. Clinical trial networks will need to employ a variety of laboratory types to achieve these objectives.  To increase flexibility and ensure the timeliness and the high quality standards the HIV field relies on for evidence that informs science, licensure and equitable practice, NIAID will have the ultimate authority for laboratory selection and approval.

Efficiency and Versatility 

Laboratory assays for HIV clinical trials continue to expand in quantity and complexity and require proportionate technical expertise and management. Future clinical research needs will include immunologic, microbiologic, and molecular testing, as well as standard chemistries and hematologic assays, with fluctuating volumes across a global collection of research sites. Balancing capacity, efficiency, scalability, and cost will require a mixed methods approach. These may include centralized laboratory testing where feasible and advantageous for protocol-specified tests; standardized processes for rapid assessment and approval of new network laboratories; and validated third-party outsourcing of routine assays to ensure timely turnaround when demands surge. 

Quality and Standardization

Ensuring consistent laboratory operations and high quality laboratory data will require continued compliance with the NIAID Division of AIDS Good Clinical Laboratory Practices and other applicable regulatory guidelines, ongoing external quality assurance monitoring, strong inventory management, importation and exportation expertise, and data and specimen management.

The research community plays an essential role in shaping NIAID’s scientific direction and research enterprise operations. We want to hear from you. Please share your questions and comments at NextNIAIDHIVNetworks@mail.nih.gov.

About NIAID’s HIV Clinical Trials Networks

The clinical trials networks are supported through grants from NIAID, with co-funding from and scientific partnerships with NIH’s National Institute of Mental Health, National Institute on Drug Abuse, National Institute on Aging, and other NIH institutes and centers. There are four networks—Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, the HIV Vaccine Trials Network, the HIV Prevention Trials Network, and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network.

More than one quarter of people with advanced HIV who had never taken antiretroviral therapy (ART) harbored antibodies that target the body’s own immune cells, and the presence of those antibodies was associated with slower immune system recovery once they initiated ART, according to an analysis of NIAID-sponsored studies. The antibodies, called anti-CD4 autoantibodies, target CD4+ T cells—a type of white blood cell essential for maintaining the body’s immune system—which are also the target of HIV. Typically, initiating ART helps to restore the body’s CD4+ T-cell count to a typical range. However, the analysis found that people with advanced HIV and anti-CD4 autoantibodies experienced limited CD4+ T-cell reconstitution through up to four years of observation after ART initiation, highlighting a potential immune effect of long-term unsuppressed HIV. The findings were published in Clinical Infectious Diseases.

The analysis included 210 people with advanced HIV—defined as having CD4+ T-cell counts of less than or equal to 100 cells per microliter (μL) of blood—who had never taken ART and were enrolled in one of two clinical studies examining the effects of HIV and ART on the immune system between December 2006 and June 2019. Study participants initiated ART and were clinically assessed for a median of 192 weeks after ART initiation at the NIH Clinical Center. 

Anti-CD4 autoantibodies were identified in the blood samples of 29% of participants with advanced HIV. The prevalence of anti-CD4 autoantibodies was four times higher in female participants compared to male participants. After initiating ART, the pace and extent of CD4+ T-cell recovery was lower in participants with anti-CD4 autoantibodies, who had a median CD4+ T cell count of 268 cells/µL after 192 weeks after ART, compared to 355 cells/µL in those without anti-CD4 autoantibodies. In a sub analysis, the investigators found that participants with anti-CD4 autoantibodies who were also incidentally taking clinically indicated immunosuppressive therapy such as corticosteroids experienced a significantly higher rate of CD4+ T-cell recovery and higher median CD4+ T-cell counts at week 192 than participants with autoantibodies and no immunosuppressive therapy. 

Researchers also examined blood samples from other study populations without advanced HIV, such as people with untreated HIV and CD4+ T-cell counts above 200 cells/μL, people who met criteria for designation as long-term non-progressors, people with autoimmune lymphoproliferative disease, people with idiopathic CD4 lymphocytopenia and healthy controls without HIV. Anti-CD4 autoantibodies were found in 9% of long-term non-progressors and 26% of people with untreated HIV and CD4+ T-cell counts above 200 cells/μL. Yet, the autoantibodies were absent in the other study groups, showing the strength of association between untreated HIV and the development of anti-CD4 autoantibodies. 

Overall, the findings show that untreated HIV is associated with the presence of anti-CD4 autoantibodies that could negatively impact CD4+ T-cell recovery in advanced disease. According to the authors, larger cohort studies are necessary to validate these findings, and further studies are needed to support the potential association seen with improved CD4+ T cell recovery in those with anti-CD4 autoantibodies who received immunosuppressive therapy. Authors also suggest large cohort studies can support the investigation of how sex disparities in anti-CD4 autoantibody prevalence relate to other sex-specific immunological mechanisms that predispose women to autoimmunity. 

Reference:

B Epling et al. Impact of Anti-CD4 Autoantibodies on Immune Reconstitution in People With Advanced Human Immunodeficiency Virus. Clinical Infectious Diseases DOI: 10.1093/cid/ciae562 (2024)