Among the first results of that effort was the finding that the new virus (which was named lymphadenopathy associated virus. or LAV) grew in T4 cells but not in related cells called T8; that finding was made by David Klatzmann and Jean-Claude Gluckman of the Salpetriere Hospital in collaboration with the Pasteur group. It was shown that the virus could kill T4 cells or inhibit their growth. Electron micrographs of the new virus were different from those of HTLV-I and resembled those of a retrovirus of horses. A viral protein called P25 (or P24) that is not present in HTLV-I was identified. In collaboration with virologists from the Claude Bernard Hospital a blood test for lAY antibodies was formulated. Several examples of lAY or lAV-like viruses were isolated from homosexual men, hemophiliacs and central Africans. Early results of applying the blood test were suggestive but not fully conclusive. lAV antibodies were found in a large fraction of lymphadenopathy patients but in only a minority of AIDS patients. Yet the proportion increased as the sensitivity of the test improved. By October, 1983, it had reached 40 percent. At that point one of us (Montagnier) was convinced lAV was the best candidate for the cause of AIDS.
To the other one of us the evidence did not seem so clear. For one thing, results had been obtained (by Gallo and Essex) indicating that some AIDS patients are infected with HTLV-I or a variant of that virus. It is now known that those results stemmed partly from the fact that among people infected with HIV are some who are also infected with the HTLV's. Moreover, only a minority albeit a substantial one-of AIDS patients had shown serological evidence of lAY infection. In addition, when it was first isolated, lAY could not be grown in large amounts in continuous cell lines. Without large quantities of virus it was difficult to prepare specific lAY reagents that could be used to show that all people with AIDS or pre-AIDS were infected by the same type of virus.
Therefore on the American side much effort was concentrated on growing the pathogen from the blood of AIDS patients in mass, continuous culture. By the end of 1983 that task had been accomplished by the Gallo team: several cell lines had been identified that could support the growth of the new agent. The first reagents for specifically typing this virus were rapidly made. Employing those reagents, it was shown that 48 isolates obtained beginning in early 1983 from AIDS patients and people in risk groups were all the same type of virus, which was called HTLV-III on the American side. A blood test was formulated and used to show that HTLV-III was present in almost all people with AIDS, in a variable proportion of people at risk of the disease (including people who had received blood contaminated by the virus but had no other risk factors) and in no healthy heterosexuals. The cause of AIDS had been conclusively established.
These results confirmed and extended the ones from France. lAV and HTLV-III were soon shown to be the same virus. Before long an international commission had changed its name to HIV, to eliminate confusion caused by two names for the same entity and to acknowledge that the virus does indeed cause AIDS. Thus contributions from our laboratories in roughly equal proportions-had demonstrated that the cause of AIDS is a new human retrovirus.
That HIV is the cause of AIDS is by now firmly established. The evidence for causation includes the fact that HIV is a new pathogen, fulfilling the original postulate of "new disease, new agent." In addition, although the original tests found evidence of HIV infection in only a fraction of people with AIDS, newer and more sensitive methods make it possible to find such evidence in almost every individual with AIDS or pre-AIDS. Studies of blood-transfusion recipients indicate that people exposed to HIV who have no other risk factors develop AIDS. The epidemiological evidence shows that in every country studied so far AIDS has appeared only after HIV. What is more, HIV infects and kills the very T4 cells that are depleted in AIDS. Although the causative role of HIV in AIDS has been questioned, to us it seems clear that the cause of AIDS is as well established as that of any other human disease.
Soon after the causation was established, a series of findings began to fill in the scientific picture of HIV. In a remarkably short time the genetic material of the virus was cloned and sequenced (in our laboratories and several others). The genetic complexity of HIV began to emerge when a gene called TAT was discovered by William A Haseltine of the Dana-Farber Cancer Institute, Flossie Wong-Staal of the National Cancer Institute and their collaborators. Such complexity is significant because it underlies the capacity of HIV to remain latent for a long period, . then undergo a burst of replication, a pattern that may hold the key to the pathology of AIDS.
There were other significant early findings. One of us (Gallo), with his colleagues Mikulas Popovic and Suzanne Gartner, showed that HIV could infect not only the T4 cell but also another type of white blood cell, the macrophage. The same one of us, working with his colleagues Beatrice H. Hahn, George M. Shaw and Wong-Staal, found HIV in brain tissues. It seems possible that the macrophage, which can cross the blood-brain barrier, may bring virus into the brain, explaining the central-nervous-system pathology seen in many AIDS patients.
How the virus infects both T4 cells and macro phages became clear when Robin A Weiss of the Chester Beatty Laboratories and, independently, Klatzmann and the Pasteur group showed that HN enters its target cells by interacting with the molecule called CD4. CD4 has a significant role in the immune function of T4 lymphocytes and also serves as a marker for that group of cells. The early work by the British and French teams showed that HN infects cells by binding to CD4. Hence only cells bearing that marker can be infected. (Although CD4 is the marker for the T4 cells, it is also found in smaller numbers on some macrophages, allowing them to be infected.)
Several additional findings rounded out the early discoveries. The potential of the epidemic to spread beyond the original risk groups was shown when Robert R. Redfield and one of us (Gallo) demonstrated that HIV can be transmitted during heterosexual intercourse. Members of the Gallo team also showed that the genetic makeup of the virus is highly variable from strain to strain, a fact that may complicate the attempt to formulate an AIDS vaccine.
After the rapid initial advance the pace slowed somewhat and began to approximate that of a more mature area of research. Yet the continuing work was not without surprises. In October, 1985, one of us (Montagnier) was engaged in analyzing blood samples brought to his laboratory by a visiting investigator from Portugal. Many of the samples were from people who had lived in Guinea-Bissau, a former Portuguese colony in West Africa. Among them were some people who had been diagnosed by Portuguese clinicians and investigators as having AIDS in spite of the fact that their blood showed no sign of HN infection.