Hide and Seek

This is the fifth post in The Scope blog series “HIV: A Scientific Discovery,” a collection of pieces that explore the major scientific milestones in the discovery of the HIV virus.

The prime suspect had been named: the Human T-Lymphotropic Virus (HTLV). Efforts to find the new strain of HTLV began almost immediately, and on May 20, 1983, a flurry of papers appeared in the journal Science announcing the first glimpses of progress in this hunt. Don Francis from the Centers for Disease Control, Robert Gallo of the National Cancer Institute, and Luc Montagnier of the Pasteur Institute in Paris each published their own initial attempts to isolate HTLV from AIDS patients. What they found was far from comforting.

Francis was able to identify HTLV in only a quarter of his AIDS patients, by a technique known as an antigen-binding assay. In this assay, blood was drawn from patients and mixed with well-identified HTLV proteins, also known as viral antigens. If the antibodies in a blood sample bound to these antigens, scientists would know that the patient had been producing antibodies against the HTLV virus and was thus infected with HTLV. For half of Francis’ AIDS patients, the HTLV antibodies remained unreactive. According to the tests, HTLV was nowhere to be found.

Nearby at the National Cancer Institute, Gallo employed another test to search for HTLV. Instead of using an antigen-binding assay, Gallo tested for the amount of proviral HTLV DNA in his patients’ cells. Proviral DNA is the DNA that is produced from a virus’ own genome and embedded into a host cell’s genome. Gallo took advantage of this revealing marker of viral infection by simply searching for the HTLV genomic sequence in his patients’ own cells.

To his disappointment, Gallo found HTLV proviral DNA in only two of his 33 AIDS patients. Where was the HTLV in the other 31 patients? Despite these discouraging results, both Francis and Gallo were adamant. Given what they knew about viruses and disease, the virus had to be a retrovirus, and the only retrovirus they knew about was HTLV. Francis concluded his paper by noting that the HTLV profile in AIDS patients was already elevated far above that of homosexual individuals without AIDS. Perhaps the old HTLV antibodies developed by Gallo could not bind to this new HTLV strain, and new antibodies had to be developed to detect the virus. Gallo reminded his readers that AIDS’ hallmark was depletion of the very cells that the virus infected. Thus, he argued, HTLV DNA within cells was simply too scarce to be detected in the majority of his patients. He called for the development of more sensitive detection tests and improved methods of isolating the virus. The virus had to be there, he believed. They just couldn’t see it yet.

But what if the AIDS virus was not a strain of HTLV at all? HTLV viruses were simply the only retroviruses that had been discovered by then. If they had found one, why not a second?

For Luc Montagnier, this question was a very real possibility. Montagnier had detected reverse transcriptase – a protein unique to retroviruses – in his AIDS patients, so he was confident that AIDS and retroviruses were linked in some way. He used the antigen-binding assay that Francis used, but instead of failing to find HTLV antibody activity in half of his patients, Montagnier could not find it in any of them. These patients had been infected with some retrovirus, but it was not HTLV. Montagnier had found a new retrovirus.

What, then was HTLV’s role, and why had Gallo and Francis detected it in some but not all of their AIDS patients? The answer was simple. HTLV was no different from cytomegalovirus, pneumocystis carinii, or the dozens of other infectious agents that breached the immunocompromised defenses of AIDS victims: HTLV was just another infection made possible by the one virus that was yet to be found.

Nevertheless, the same could be said of Montagnier’s new retrovirus. Even if Montagnier eventually identified the virus, how would he know that it was truly “the AIDS virus” and not just another virus that had taken advantage of the damage left by the virus he was actually looking for? He could not be certain at this point, but one clue offered promise.

The AIDS patients from which Montagnier had taken blood samples were in fact not formally AIDS patients; they had been diagnosed with lymphadenopathy, an enlargement of the lymph nodes that usually preceded the diagnosis of AIDS. In this early stage of the disease, some viruses like HTLV had not yet had the chance to infect these patients, thus explaining why Francis found HTLV in some of his patients but Montagnier in none of his. The fact that a new retrovirus had been found in AIDS patients at such an early stage made Montagnier optimistic that this virus was indeed the AIDS virus. The Pasteur Institute was on the brink of a historic discovery.

Coming up next week: the French group studies their newly identified virus while Gallo’s research group finds a new retrovirus of their own.

Kevin Wang is a junior in Ezra Stiles College. Contact him at kevin.wang@yale.edu.

(Featured Image courtesy of Wikimedia Commons)