Abstract
For any study involving human subjects, we acknowledge the study participants for their willingness to provide specimens and sometimes very personal medical details that allow us to carry out the research we perform. We refer to these individuals as study subjects, participants, patients, cohorts, for example, but these are people. In an effort to de-identify them, perhaps we somewhat de-humanize them when we tell their stories. These individuals are people, people we may have met, people who are often sick, often vulnerable. These people have entered an agreement of trust with us, often for very little or no personal gain, that directly enables us to do the research we want to do.
In recent years, there has been a shift toward involving the study participants more and more in the research. These days, study participants even can be involved in the planning of the research from the start. This is particularly important when study populations involve vulnerable groups. We try to do research “with people” instead of “on them.” In many cases, principal investigators may never meet the people who provide specimens or scientific data, but this is not always the case. In other studies, enrollment into a study has translated to decades of collaboration and personal interaction where the people in the study have gotten to know the researchers very well. The loss then that can be felt when a study subject passes can be as hard as losing a friend.
Below is a tribute, written by my mentor, friend, and colleague, Dr. Michael Grant, about the first person he enrolled in his first research study almost 30 years ago.
I
Over a period of 27 years, 001's plasma was pipetted into thousands of ELISA plates to release information on their evolving antibody repertoire, circulating cytokine milieu and immune activation status. Their plasma recorded a diverse and challenging history of antiretroviral drug treatment and was sourced for early drug resistance genotyping. It marked infected cells for targeting by natural killer (NK) cells and yielded viruses for sequence analysis. Their lymphocytes were equally valuable and informative. B lymphocytes were transformed into a permanent cell line for autologous targets of cytotoxic T cells (CTL) and T lymphocytes were screened for reactivity against recombinant viruses, viral peptides, and unknown antigens on a variety of targets. The adaptive phenotypic and functional properties of their T lymphocytes, dictated by aging with HIV infection, were captured in ELISPOT, cytotoxicity, and flow cytometry assays spanning 27 years.
Trainees, staff, and colleagues came and went, while 001's samples flowed regularly to my lab, at widening intervals as antiretroviral therapy and HIV clinical care matured towards the standard enjoyed by people living with HIV (PLWH) today. The early days of treatment with the “D” drugs with their mitochondrial toxicity, followed by the lipodystrophy and lipoatrophy emerging during the time of protease inhibitors, took a toll on many PLWH. Increased incidence of type II diabetes, renal disease and accelerated aging emerged as new issues, but 001's resilience over that period symbolized that of their community. The transformation brought about by effective combination antiretroviral therapy is faithfully reflected in 001's laboratory records over their 99 visits. Their CD4+ T cell counts rebounded from 51/μL to 840/μL, plasma virus load fell from >500,000 to <30 copies/mL and plasma β2 microglobulin dropped from 11.3 μg/mL to 2.4 μg/mL. Through the many experiments enabled by sequential blood donations, 001 was a constant contributor to research publications and a part of almost all my grant proposals and presentations.
My first graduate student used 001's CD8+ T cells to characterize autoreactivity against uninfected CD4+ T cells and to describe a novel form of activation-induced cell death (Kottilil et al., 2001; Kottilil et al., 2000). One of the first studies to link HIV reservoir size with immunological and clinical outcomes used 001's CD4+ T cells (Russell et al., 2001). Their CD8+ T cell's genomes helped to demonstrate T cell repertoire preservation despite falling numbers and the functional and phenotypic attributes of their CD8+ T cells outlined relationships between HIV disease progression, immune memory, immune reconstitution, antiretroviral treatment, and viral suppression (Gamberg et al., 2004a; Gamberg et al., 2004b; Gamberg et al., 1999; Mason et al., 2004).
During the H1N1 influenza pandemic, their response to vaccination formed part of a data set illustrating issues relevant to PLWH vaccination (Kelly et al., 2012). Their HIV-specific CTL responded favorably to checkpoint inhibitors, helping to usher in a new era of ideas for immunotherapy and their NK cells were positioned by case history within a rare subset critical for addressing the role of NK cell adaptation in HIV infection (Adegoke et al., 2015; Holder et al., 2021).
I have no doubt we all appreciate the efforts made by volunteer study subjects to contribute to our research, as without them, progress is literally impossible. However, while reflecting on the contributions 001 made over the past 27 years, I realized how much more useful, meaningful, and abundant those contributions were than I was generally aware. The gift that research study subjects give is seldom directly returned and they often remained silent partners supporting my progress and that of a growing series of trainees. I owe a debt of gratitude to all the volunteers who participated in our research studies as PLWH have always been enthusiastic participants, but the breadth of impact that 001 has had strikes home most deeply.
I had the good fortune to meet subject 001 several times during my career and was struck by their broad compassion and gentle giving nature. The individual was an advocate for PLWH, an animal lover, a politician, and a craftsperson, and lived through the transformative era in HIV care, while willingly contributing more than was asked, touching myself, my colleagues, and many lab members in the process. Far exceeding the bounty of experimental data, I am left the lasting gift of the memory of a person who gave of themselves readily, extensively, and selflessly, and I learned more than I dared hope in ways I never expected. I take this opportunity to thank you and all the other volunteers contributing samples for scientific research. Your legacy is progress.