What David Rasnick learned at the Gordon Conference:

Chasing Markowitz

[Martin Markowitz-co-author on some of Ho’s most famous papers, including the 1995 Nature article that introduced the virological mayhem model and popularized the viral load test-stayed through the Wednesday presentations, and I was able to question him several times.]

Erickson [Jack Erickson-an HIV protease expert from the National Cancer Institute] left my poster and walked straight over to Markowitz, who was at the other end of the room. I knew Erickson wanted to discuss with Markowitz the points of my poster, and I went over to join them.

Sure enough, my poster was the topic. Markowitz greeted me with a smile. Perhaps he did not yet recognize me from his earlier lecture. I started asking about the infectivity assay used in the March 1996 article he wrote with Ho (Science 271, p. 1582), which I held in my hand. The paper concerned the administration of cocktail therapy to five patients. Prior to this treatment, the patients had HIV "viral loads" between 12,000 and 643,000 (per ml of plasma). After therapy began, the viral loads for each patient went to zero, and stayed at zero for the duration of the study.

I wanted to know about patient 105, the one who started with the largest viral load, 643,000. He was the only patient for which "tissue culture infectious doses" (TCID) were measured. Prior to therapy-when his "viral load" was 643,000-he had 1,000 infectious doses of HIV (per ml of plasma). Two days after initiating therapy, his infectious doses dropped to zero, but his "viral load" had not dropped below 500,000.

I wanted to know the relationship between the "viral load" figure and the infectious dose figure. I started by asking, Did one "infectious dose" correspond to one infectious HIV?

Yes, Markowitz said, one infectious dose equaled one infectious virus.

How did you determine that an HIV (a "dose") was infectious? By looking for the p24 protein?

Yes, Markowtiz replied. Detection of p24 was accepted as evidence of a fully functioning virus.

Well, I said, p24 is not good enough.

With this, I figured our scientific discourse would proceed along predictable lines. He would ask me why p24 "wasn’t good enough." I would explain, as documented in my paper, that p24 has been shown by many researchers, including John Erickson, not to be a reliable indicator of infectious virus. I was prepared with references to defend this statement. But Markowitz didn’t bite.

As following his lecture when I had asked about the health of his patients, Markowitz simply said nothing.

I turned my attention to the disparity between the "viral load" and infectious dose figures. If infectious doses equaled infectious HIV particles, then the difference between patient 105’s infectious doses and his "viral load" must represent non-infectious HIV particles.

I showed Markowitz the graph he and Ho et al. had published for patient 105. In one case a viral load of 643,000 corresponded with 1,000 infectious HIV particles, and in another case a viral load of over 500,000 corresponded to zero infectious HIV partic les. Markowitz agreed with my interpretation of the data.

So I asked him, What was the significance of the hundreds of thousands of non-infectious viral particles per ml that you detected in the blood plasma of patient 105? He frowned, and seemed not to know what to do next. His puzzled look and silence lasted about 30 seconds. Then he simply turned and walked away.

It was the first time a scientist had ever run away from me. Typically scientists are bulldogs. They fight for their position. But the HIV guys don’t. They run.

I noticed at this time that Erickson had vanished. He’d slipped away sometime during this strange exchange with Markowitz, and I never spoke to him again.

Were it not for Erickson’s devotion to HIV, he and I could have been buddies and colleagues. He is otherwise a sharp scientist who knows enzymes and the technical particulars quite well. Regrettably, though, he yields to the virologists and physicians when it comes to HIV pathogenesis, and he takes his cues from the folks who run the HIV show.

As for Markowitz, I was determined to get an answer to my question. I cornered him two more times. On both occasions I had to literally stop him from walking away. In each instance I repeated my question about the significance of all that non-infectious HIV.

Both times he ran off without answering the question. In the midst of his second retreat he turned and called back with a meaningless response, devoid of even a hint of scientific or logistical merit: "Trust me!"

I cried back, "Trust has nothing to do with it!" It was an absurd exchange, and I would have laughed were it not so pathetic.