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The family did, however, continue to see the patient on occasion during his stay at the NIH; they were not here continuously. I gather from discussion with Dr. Nelson that the patient in large measure had been abandoned by his primary partner and other individuals who had been friendly with him in New York, and that no one visited this individual, who was in a critical and life-threatening condition, throughout his whole four-month stay.
Many individuals from clinical pathology began to recognize the importance of this syndrome. In general, they were very intrigued and excited by the intellectual and clinical challenges that this patient provided. John Misiti, as my clinical associate, spent an enormous amount of time with this patient to orchestrate the interaction with other groups. Unquestionably, our patient had AIDS. I appreciate your suggestion to try to validate that diagnosis with at least antibody assays on the serum. Tests of HIV viral integration by PCR on pathological tissues would be interesting.
As this disease became understood in its earliest phases, when it became very likely that it was caused by a retrovirus, but before the mode of spread of this retrovirus was defined, there was a certain level of anxiety in the people who had to deal with his body fluids. This was aggravated by the fact that three of our patients with the genetic, hereditary forms of immunodeficiency developed AIDS as well. Those individuals and this patient–because of his humoral immune deficiency–might not have been able to make antibodies to HIV. Because of their underlying genetic, hereditary immunodeficiency, the possibility of AIDS did not have to be entertained clinically; however it was confirmed by appropriate viral studies. Together these patients caused some concern in the people who dealt day-to-day with their blood. They did not convert at that time, or in succeeding years, to antibody positivity.
Rodrigues: It must have been very interesting for you, having spent so many years working on diseases of aberrations of the immune system, and then seeing these very rare cases. Was it surprising that a disease of immune deficiency could come along that would be a global pandemic?
Waldmann: It certainly was a challenge, and it presented a major question for our laboratory. We had to decide whether to drop everything else that we were studying and study AIDS, or to leave AIDS to others. There was no middle ground. At the time that this patient came, certain unique and dramatic observations were made in our laboratory independent of our study of immunodeficiency. We introduced, for the first time, the study of the rearrangement of the immunoglobulin and T-cell receptor genes for use in the diagnosis and monitoring of therapy of leukemias and lymphomas. Also we produced an antibody to the interleukin 2 receptor that we used to define the structure of this receptor and to initiate IL-2 receptor-directed therapy. We felt that these unique opportunities would contribute to our understanding of human T-cell lymphotrophic virus I (HTLV-I), which at that time was being defined in another patient within the broad NIH community at the NCI [National Cancer Institute] branch of the Navy Medical Research Center. Using that patient's cells led to the discovery of HTLV-I and the production by our laboratory of the monoclonal antibody to the IL-2 receptor, anti-Tac.
These aspects of T-cell activation are germane to AIDS, but not a direct study of AIDS. I decided to follow them because we were in a unique position in those areas to make a major contribution that would be relevant to retroviruses, malignancy, and immunodeficiency. I felt strongly that the etiology of AIDS would be an infectious agent, perhaps a virus, which was not in our area of expertise. We were not virologists, nor were we the kind of individuals who could make the fundamental AIDS breakthrough. Issues that relate to abnormal cellular interactions in AIDS, the sort of studies that Tony [Dr. Anthony] Fauci or Sam [Dr. Samuel] Broder perform, are very important. Sam Broder, who was my medical staff fellow, went on to do brilliant work in this area using techniques similar to those used on our branch. But I believed that the work that culminated in the demonstration of the HIV retrovirus was beyond our area of expertise and beyond our capacity for viral containment, since our laboratory has only P2 laminar flow hoods. There would have been no safe way for our technicians to have studied a virus that had an undefined mode of spread. The risk to the lab personnel would have been too great. A concern in this regard was expressed by the lab personnel themselves. Furthermore, one of the individuals working in the lab left, albeit to a higher administrative post, but the dominant reason was that we dealt with the virus HTLV-I, which is exceedingly difficult to spread. In contrast to HIV, HTLV-I had not been spread to health-care workers or to laboratory personnel. I don't know of lab personnel that have been infected with this virus.
Harden: In this context, could you talk a little more about how your own thinking about this disease evolved? What was being published in the literature? What was the time frame between the first patient and the issues of concern with viral transmission arose? When you saw this patient, what was your diagnosis and how did this evolve to the understanding of a contagious disease, a retroviral disease?
Waldmann: It would be easy to reconstruct history knowing its outcome. I don't know if I can get a fair picture, especially since we're asking the classical, “What did you know and when did you know it?” type of question. As the patient came in, we recognized that this patient was of that category that had three decades of normal immune function and then something very critical happened. There are a few causes for that. It is typical of me to not force things into an old, established cause but to try to think about new syndromes. When I started at the NIH, we would find clinical disorders that others could somehow force into a pattern but we would describe as new syndromes. We described the previously undescribed intestinal lymphangiectasia as well as allergic gastroenteropathy. These diseases were defined by us when we forced ourselves to think about them as something new. When our patient entered the NIH, it was known that there is an X-linked immunodeficiency state, essentially in males, that emerges in individuals who have a normal ability to fight infections, but following exposure to Epstein-Barr virus [EBV], develop immunodeficiency. [Drs.] Provisor and Portillo had shown these individuals could die of the virus EBV, which for most of us causes infectious mononucleosis but nothing more. These patients could also develop lymphoid tumors, or could become hypogammaglobulinemic and immunodeficient for the rest of their lives. We were studying the mechanism of the hypogammaglobulinemia of such patients. We knew that when one of us got infectious mononucleosis, our B cells would be infected with EBV and our T cells would react to those B cells and would shut off the B-cell proliferation. That bubble boy in Texas, who lacked T cells developed B cells that were uncontrolled when he received Epstein-Barr virus in a marrow transplant from his sister. The EBV drove the B cells to proliferate, but there were no T cells around to provide a brake on their proliferation. So we had the precedent of EBV being a potential cause of lymphoma and of immunodeficiency after a period of normal function.
Hepatitis virus was also appearing in some of our patients. We were aware that the patient and other homosexual men were using drugs that could conceivably have impaired the immune system. However, drug use as the etiology of AIDS was soon made very unlikely when blood transfusions were shown to cause a similar syndrome. It then appeared that an infectious agent was the cause. There were other infectious agents, such as the one that caused Legionnaire's disease, that were not easy to define, yet were not a retrovirus. It became an issue of whether an infectious cause was present. Early on if we thought it was likely to be a chemical, we might have done further studies of this syndrome, seeking other patients. The fact that we thought it was a virus, and that there were virologists around that would be the ones to discover that and not us, altered our thinking. We did not sense that what was present in five patients at the CDC and one patient at the NIH, was going to be a global problem.
One aspect that affected our decision was the difficulty in taking care of the patient. The medical staff fellows on our service spend 10 percent of any given period of time dealing with patient care and the rest of their time in the laboratory working on cellular immunology, receptor peptides, cloning new genes, etc. To them clinical care obligations, although a learning experience, were onerous. We did not have a cadre of individuals like the medical staff fellows on other services, completely dedicated to patient care over a period of time. If you were in NIAID [National Institute of Allergy and Infectious Disease] or the Medicine Branch of the NCI, physicians had 100 percent of their time dedicated to patient care, let us say, for a year, and then 100 percent of their time, with the exception of their clinics, in the laboratory. We always had shared patient care/laboratory experience. We had for the whole branch about three medical staff fellows a year, so I personally would have one new fellow every other year. One medical staff fellow worked with me. It would have been overwhelming to have even one patient with AIDS. One couldn't do science in the laboratory on the one hand and intense patient care on the other. This affected what we were going to do in the end.
Our first choice concerning etiology was that this was some virus with a pattern that was different from the viruses that had been defined. EBV caused B-cell tumors and B-cell antibody deficiency. AIDS, as exemplified by our patient, had different kinds of infections than those observed with B-cell deficiency. The patient had a low number of lymphocytes, a reduced number of T-cells, and skin anergy, which is a cell-mediated immune defect. There was not a counterpart virus known at that time that inhibited cell-mediated immunity. Thus it seemed unlikely to be Epstein-Barr virus or the hepatitis virus.
Obviously, there were retroviruses emerging that had a preference for the T cell. There were individuals, such as Bob [Dr. Robert] Gallo, who recognized that there was an array of retroviruses that could cause both immunodeficiency and malignancy. The human T-cell lymphotrophic virus I (HTLV-I), a virus that we were studying, not only caused adult T-cell leukemia but a profound immunodeficiency as well. It may not be as broadly known as HIV. Patients with adult T-cell leukemia and HTLV-I infection have anergy, delayed hypersensitivity defects, Pneumocystis infections of the lungs, an array of infections, and they cannot make antibodies, including antibodies to our monoclonal antibody from the mouse. Thus, they have an array of T-cell abnormalities. This may reflect the action of a lymphokine made by these cells.
One of the candidates for AIDS being presented to the community was HTLV-I, and parallels between patients with HTLV-I and those with AIDS were brought forth. HTLV-I was endemic, one could see transmission of HTLV-I by blood, involvement of CD4 cells, an immunodeficiency leading to infections with this virus.
What was discordant between HTLV-I and AIDS was the regions in which AIDS was appearing. HTLV-I is endemic in Japan, in the Caribbean, including Haiti, and in sub-Saharan Africa. It was not endemic in San Francisco or in New York at the time of the onset of the AIDS epidemic. The Caribbean and sub-Saharan Africa are common to both of these viruses and these diseases. But Japan, at that time, had a great deal of HTLV-I, yet it did not have AIDS at all. It was a problem epidemiologically. It could have reflected variations in the virus. We must recognize there could be differences in responsiveness to a virus related to the HLA groups of infected individuals. Those of us who are immunologists constantly focus on the contribution made by the transplanation antigens to the host response. People who get the neurological disease called tropical spastic paraparesis [TSP] or HAM [HTLV-I associated myelopathy], which is distantly analogous to multiple sclerosis, share an HLA type more frequently than would have been anticipated by chance alone. The observation suggests that this disease is caused by the combination of a virus and perhaps the host's response to that virus. The host T-cell response to that virus unfortunately causes the brain to be the loser, because the T cell proliferates in response to the virus but unfortunately recognizes and damages the neurological tissue. In these patients with AIDS, the issue is if it is due to a virus alone, the combination of certain drugs and the virus, or if there is a connection with the patients’ HLA type. Furthermore, early on there were suggestions that Kaposi's sarcoma patients had a predominant HLA type. Now we recognize that one does not need any particular HLA type to get AIDS.
Rodrigues: You talked about the contributions that studying certain types of immune deficiency diseases could have on experiments of nature. Could you give any insights into how this works?
Waldmann: I didn't allow you to ask a question but I'd like to...it may be classic of Washington, give you a particular answer no matter what the question happens to be. That is to try to help you see what was known concerning the immune system when I was going to medical school compared to what is now known–how much insights relevant to AIDS have increased in these thirty years since I went to medical school in the early fifties.
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