HIV-1: a look back from 20 years.

191 IN ONE SENSE, if AIDS had to come, the timing of the epidemic was fortuitous. Only a few years earlier (mid-1970s) the prevailing views in the scientific community were that viruses played no role in human cancer, that retroviruses did not infect humans (some even argued that it was not possible!), and that serious epidemics were no longer a problem for “us.” Additionally, some of the critical technology was not available. However, by 1981, when AIDS was first recognized, viruses were linked to over 20% of all human cancers, retroviruses of humans were discovered, and one, HTVL-1, was demonstrated to be a cause of an unusual leukemia as well as a fatal neurological disease. HIV/AIDS quickly became one of the greatest epidemics in medical history. Thus, the overconfidence and biases of the 1970s were destroyed. Additionally, techniques to grow primary human blood cells in liquid suspension culture were developed by the late 1970s, especially T-cells mediated by the discovery of what was first called T-cell mitogenic factor (1976), then T-cell growth factor, and finally interleukin-2 (IL-2). Also essential were the development of rapid, sensitive, and specific assays for reverse transcriptase developed during the 1970s. Thus, the discovery of HIV did not come “out of the blue.” Essential technological and conceptual advances preceded it. Work with HTLV-1 and HTLV-2 contributed to the HIV discovery by stimulation of the idea of a retrovirus cause and by providing experience working with immortalized CD4 T-cell lines. However, it was a double-edged sword in that it held me about 6 months too long to the view that the retrovirus of AIDS would be in the HTLV family. The lessons of the above history are clear enough, and include the need for recognition that microbes, including viruses, are here to stay, that we cannot predict sudden emergence of new epidemics, that no class of virus can be precluded as a candidate human pathogen, and that (for the HTLV link) one should not get overly specific in predicting nature’s behavior. For me, there is still another lesson, and that is the need for multiple Centers of Excellence in Virology (CEV), which in total, would include sophistication in every class of virus. I draw this conclusion because except the CDC, no one or group was responsible for solving the AIDS epidemic, and the CDC can not have adequate depth for each virus type except in their capacity for monitoring new epidemics. I know it was simply chance interest that we first became involved, and it was at a time when few virologists had experience in T-cell culturing, and many institutions had forbidden receipt of any specimens from AIDS patients. Some things addressing this problem have been done. NIAID has formed Centers studying candidate microbes of biological warfare, and have included new emerging infections in this program. However, I do not believe this completely answers the need; first, because the major function of these centers is in preparation against those microbes most likely used for terroristic acts, and most of these are bacterial; and second, these centers are regional, and hence, with political overtones; third, it is unlikely that they will foster sufficient breadth or depth in virology or that they will be able to bring in a sufficient number of “new faces.” Finding HIV was one thing, and demonstrating it to be the causative agent was quite another. HIV and AIDS, of course, were uniquely problematic compared to other viral diseases of the past or the recent SARS outbreak in two fundamental ways. First, signs of AIDS are only manifest years after infection. This had immensely complicated the epidemiology until a test was developed. Second, when AIDS did manifest itself the patient was riddled with numerous other infections. Picking out and showing the role of the correct agent was a challenge. A key breakthrough was continuous cell line production of the virus achieved with six different isolates by early 1984. This led directly to the blood test, which almost immediately gave us three major advances: (1) it made the blood supply safe again; (2) it allowed us to follow the epidemic for the first time; (3) it provided clear linkage of HIV to AIDS as its causative agent. Although numerous (48) isolates were reported by our group by early 1984, and one earlier by L. Montagnier and co-workers, this was difficult for most investigators to reproduce because of the inexperience in T-cell culture, and because of the institutional restrictions on AIDS specimens. However, the blood test was rapid, inexpensive, simple, safe, and could be quickly made available all over the world.