As part of our on-going anniversary year series of interviews and commissions by the organization's founding members, TAGline caught up with founding director, long-time administrator and high-risk brainstormer Peter Staley one bright summery April afternoon in Chelsea. Over the course of a couple of hours, Peter traced through his final embattled days with ACT UP/New York, the extraordinary early successes of the new breakaway group he would call TAG and what many now see as a watershed year for AIDS treatment activism.

TAGline: I thought it might be interesting to begin with the last days of ACT UP and the first days of TAG.

Staley: Yeah, sure. Not that many people know the "pre-history" of TAG, as I call it. During my final years in ACT UP, I was already suffering under the burden of the in-fighting and the personal attacks. There were a lot of us who were. I started looking for a way out.

I had been thinking about it for a long time and then in the summer of 1991… ACT UP had gotten very big on its affinity group structure so I thought maybe I could use that in a different way to set up a transitional process whereby we create an affinity group of ACT UP but also surreptitiously have an organizational structure—and our own checking account—which made it very different from other affinity groups which used the ACT UP bank account.

So I think it was July of '91 I filed a D.B.A. for Treatment Action Guerrillas. And then with that opened a checking account … created a board of directions with a simple organizational, what's it called? That says what your purpose is?

TAGline: Mission statement. You and who else?

Staley: I remember we were required to have at least three people on the board. So it may have just been Derek [Link] and Garance [Franke-Ruta] and myself. There might have been a third, whom I can't remember now. Derek Link at the time was living across the street from me on East 7th street.

TAGline: Oh yeah, that's right.

Staley: I remember at his apartment one night we came up with the idea, came up with the name, and the logo. The logo was actually designed pretty early on, that summer, because we used it for the Helms action.

TAGline: How much of this was a chicken and egg thing? How much of this was a spin off of you guys' already being together to do the Helms thing and how much of it was explicitly your getting together to plot your departure from ACT UP?

Staley: I was pretty explicit. From the get go I was telling people that I was setting this up to be independent of ACT UP and as a place for us to split off if we wanted. I started basically campaigning to put the idea out there, saying, "This is getting nuts with ACT UP. Let's split, and we can do this."

TAGline: And the Helms action was to be your first big signature action?

Staley: Yeah, it was a way to put the Guerrillas on the map and, yeah, starting to do things within a fairly new structure that I'd never really envisioned before. This was all planned in August of '91. At the time I was working with this guy from Greenpeace who was an expert on high end sophisticated civil disobedience techniques—which we used at the Astra action. Hooking up underneath trucks with pipes, things like that.

TAGline: Like what you used at the Burroughs Wellcome action where you drilled through walls barricading yourselves into their offices and granting interviews with the media via cellular phones?

Staley: No, that was way before.

TAGline: But that was kind of sophisticated.

Staley: Yeah, but that we dreamed up on our own.

We started talking to the Greenpeace guy about other techniques. He actually came with me down to D.C. to scope out Helms' house after we got the address from public records. He had a place in Arlington [VA], a simple little colonial—with a very steep roof! We took pictures of it. Based on an average door size, we were able to out-measure the entire house. And then we designed on our own how a condom would cover the house. We took those designs and faxed them out to about five companies that made custom made inflatables for used car lots and things like that. We got quotes ranging from $3,500 to $15,000. I took the $3,500 one, and they were able to do a very quick turnaround too. It was a company outside of Sacramento, California, I think. We told them it was for a backyard benefit at a house in Long Island—so they wouldn't know that we were planning to break the law in an action against a U.S. senator.

TAGline: But where did the money come from? Your own contributions?

Staley: I've never told this to anyone before, but I guess it's okay to tell it now. David Geffen had heard about what we were planning, and that we didn't really have the money to pull it off. He came up to me one day on the beach at Fire Island with a big stack of bills. He stuffed the wad in my hand and said simply, "Go do it."

About a week later it was delivered and we went up to Marvin Shulman's house in New Paltz to practice suspending it. We painted a message on it, "Jesse Helms: Deadlier Than the Virus." We put together a group of seven of us: myself, Derek and Garance, Sean Strub, and three others. We rented a truck, portable generators, fans to blow the thing up. And a humongous ladder to get to the top of the roof.

Sean and I were the roof guys, which was a really dangerous job 'cause Helms' roof was very skinny and steep along the very top. From there we would unroll the thing and throw down all the lines to anchor it.

TAGline: And how long did it take before the TV crews arrived?

Staley: About five minutes. The press had been called beforehand and they were arriving during the blow-up. There was great coverage. It ended up getting that end-of-the news news slot. You know, the major networks always send out some funny little story to all the affiliates that they play for those ten seconds at the end of the local newscast? "This amazing story from suburban Virginia..." It aired on local channels all over the country!

The impact was such that Helms actually felt the need to comment on it on the Senate floor. Our whole goal was this vague notion that he had terrorized us for years and was our number one enemy—but nobody had ever counter-attacked. He had gotten off Scot free from the AIDS community—and he raved about it!

We hoped that he'd have a slight change of heart. And also maybe the Senators he worked with would have a laugh at his expense, which might marginally diminish his effectiveness on the Hill. It's not something you can measure in any rigorous way, but there were very few "Helms amendments" on AIDS after that—and certainly far fewer that were passed. And now, of course, he's talking about wanting to do something about AIDS in Africa.

TAGline: Yeah, I read about that in the Salt Lake City paper in February.

Staley: Yeah, and it was a big story in the Charlotte Observer. They even mentioned the condom action. So, that was actually TAG's first great moment. It put us on the map.

TAGline: And after that was the Astra zap in Massachusetts?

Staley: Yeah, that action got a lot of press. It made Sixty Minutes. The local police department up there threatened to sue Sixty Minutes for having prior knowledge of our plans. So it got alot of great press. But as we got pulled out from underneath those trucks alot of us said that that was it for civil disobedience. It was kind of a psychological turning point. It was ... you realized … for the media and, more importantly, for the public, we were becoming a broken record. That even if we broke through and got press—which the Hoffmann-La Roche action did [later that same winter in Nutley, NJ] big time. They showed it live on the national morning news programs! — the public would see the images and just say, "Oh, it's another AIDS demonstration." They wouldn't know the issue. They wouldn't stop to learn about the issue. They wouldn't stop and say, "Oh, my god…" We had really lost a lot our uniqueness and the ability to get our message out—and therefore we lost the ability to effect change.

At the same time, the "inside" work that T+D had gotten so good at—and that TAG began to really pursue in earnest—was becoming a well oiled machine. There was no door that was closed to us anymore. So we didn't have to demonstrate for that. We could get through any door, including Congress—which was something ACT UP had largely ignored during its history. In ACT UP we never did anything on a Congressional level. All of a sudden we were hot on the Hill—as TAG—once we had shed the bad boy image.

TAGline: Was that because of the coincidence with a new administration?

Staley: Several things. Clinton coming into office, certainly. We also had some friends both on the Senate and House side: Kennedy's office and Waxman's office, who wanted to do something—who had been doing something. TAG had the foresight to distribute its analysis of AIDS research at the NIH. The legislators read it and were very impressed. They thought, "We can use this in legislation that is coming up." The NIH was being reauthorized at that time, and so they basically copied verbatim our recommendations and set them into legislation to create a more powerful Office of AIDS Research. And so the battle was joined. NIH fought it. Fauci fought it hard.

TAGline: Against it.

Staley: Against it. Getting Republicans on his side—who were in the minority at that time. And it passed: out of committees and onto the floors—and Clinton signed it. It was incredible. The first year of a not-for-profit's life ... to have a major legislative victory like that. Which was, by the way, done very much in conjunction with amfAR, PAF and AIDS Action Council. And that was another thing that showed TAG's [maturity] over ACT UP's: where ACT UP tended to act alone and do very little coalition building, we realized we didn't have much name recognition on the Hill, so we started meeting weekly and then every other week with GMHC, AIDS Action Council and amfAR. Meeting in amfAR's board room.

TAGline: "We" being?

Staley: Me, Mark Harrington, Gregg Gonsalves. Mathilde Krim. David Barr. Derek Hodel, who was head of AIDS Action at the time. So those were great times. Since then, we have had a lot of little victories, but nothing on the scale of those early days. Since then it's been more what I like to call "greasing the wheels of AIDS research," both public and private. We've done good greasing year after year. It is an important role—and a unique one. No one else was doing it. And it is our forte. ¤

It's been five years since Bruce Walker and his Harvard colleagues first proposed the key role of CD4 T cells primed specifically to target HIV. These cells, Walker (and later other groups) hypothesized, may typically be wiped out within the first few weeks of HIV infection, but if preserved could potentially control the infection and prevent disease. Subsequent research attempts to maintain this special CD4 cell subgroup (mostly through immediate treatment upon infection) have met with some—but not uniform—success. And as studies progress, it turns out that the task may be more complicated than it appeared initially, with new data suggesting that these CD4 responses may not be wiped out but rendered dysfunctional.

Long-term non-progressors (LNTP) remain a valuable resource for teasing out the precise components of the immune system responsible for keeping HIV infection at bay. In all of Europe, the laboratory group that is, arguably, in hottest pursuit of the missing pieces to this immunological puzzle is Paris-based doctor Brigitte Autran. Richard Jefferys reports on the status of her group's work—and hints at what new discoveries we might expect later in the year.

Renowned Parisian immunologist Brigitte Autran helped kick off the first full day of this year's retrovirus conference with a half-hour plenary on immune reconstitution and correlates of long-term non-progression. Autran began by reviewing seminal work from her group at the Hôpital Pitié-Salpêtrière, originally published in the journal Science in 1997. These studies described the rapid redistribution of mainly memory CD4 T cells from the lymph nodes after HAART initiation, accompanied by a precipitous decline in markers of immune activation and followed by a slow but steady increase of naïve T cells over subsequent years. Concomitant improvements in T cell responses to common opportunistic pathogens were also reported. All of Autran's initial observations regarding HAART-induced immune reconstitution have since been confirmed and extended by other research groups.

The one type of immune response that is typically absent or weak in HAART-treated individuals is HIV-specific; CD4 T cell responses to the virus can be hard to detect and, if detectable, may be functionally compromised. CD8 T-cell responses are typically detectable but also show evidence of functional defects and appear unable to keep pace with viral evolution. The new research priority for Autran's group is to ascertain whether this apparent deficit in HIV-specific immunity can be addressed with therapy. As a first step, a cohort of long-term non-progressors (LTNP) was analyzed in order to try and define clear correlates of immunologic control of HIV infection. No factors related to the infecting virus were identified, but a number of associations relating to the immune response emerged.

As reported by others, certain class I and II HLA genotypes are more common in LTNP, suggesting that the ability of both CD8 and CD4 T cells to recognize and respond to HIV is a key variable influencing the outcome of infection. Using an ELISpot assay to identify HIV-specific CD8 T cells based on their ability to produce interferon-gamma, Autran reported that stronger and more broadly targeted responses were detected in LTNP compared to progressors, although this finding has not been duplicated by some groups. Autran also looked at the expression of the cell-killing enzyme perforin in HIV-specific CD8 T cells and found that fewer cells were perforin-positive in LTNP than people with progressing disease, indicating that this is not a useful correlate (as previous study results had suggested).

Turning to HIV-specific CD4 T cells, the correlation between the proliferative response to p24 and control of viral load in Autran's study was highly significant. A similar link was seen when, instead of proliferation, the frequency of CD4 T cells making interferon-gamma in response to p24 was measured by ELISpot. Since other studies have found that the frequency of HIV-specific CD4 T cells (as measured by ELISpot) is not always correlated with control of viral load, Autran's group identified another marker that may address the functionality of the CD4 T cell response.

Interferon-gamma production is typically associated with a type of CD4 T cell response known as T-helper type 1 or Th1, considered to be important in the defense against many viral infections, including HIV. It is known from basic immunology research that Th1 responses drive B-cells to make a particular class of antibody called IgG2. Although many studies have measured HIV-specific antibodies in infected individuals, Autran's colleague Nicole Ngo-Giang-Houng looked specifically for those belonging to the IgG2 subclass, reasoning that they might be a marker for robust, Th1-type HIV-specific CD4 T cell activity. As reported last year, she found that IgG2 antibodies targeting HIV's gp41 protein were strongly associated with persistent LTNP status. Perhaps surprisingly, the presence of these antibodies was not linked to an ability to neutralize two primary isolates or the lab strain HIV-LAI.

Autran updated these findings at the Seattle retrovirus conference by assessing whether maintenance of LTNP status (over five years of follow-up subsequent to study entry) could be predicted by combining the IgG2 and ELISpot CD4 T cell results. The analysis revealed that a strong HIV-specific CD4 T cell response (over 170 spot-forming units or SFC in the ELISpot test) and the presence of IgG2 antibodies directed against gp41 correlated strictly with LTNP status. One hundred percent of individuals with these responses maintained their non-progressor status over five years of follow-up. In contrast, more than half the individuals with the same HIV-specific CD4 T cell response but no gp41-specific IgG2 antibodies experienced disease progression during this period. Over 80% of the individuals in the remaining two categories (those with gp41-specific IgG2 antibodies but lacking a strong HIV-specific CD4 T cell response and those with neither IgG2 nor a strong CD4 T cell response) developed progressive disease.

Having outlined the immune responses that may protect against progression, Autran described the strategies her research team is employing to try and create (or boost) the same type of HIV-specific immunity in people with acute and chronic HIV infection. The current goals are straightforward: to use candidate vaccines in conjunction with HAART in order to induce strong, broad and durable HIV-specific CD4 and CD8 T cell responses, in the hope of reducing the viral load "set point" when HAART is stopped and thus extending the time that drug therapy can safely be withheld.

A number of studies are under way (see table) using just about every vaccine that's been shown to be safe and to induce at least a meager level of HIV-specific T cell activity: ALVAC, lipopeptides and Remune. Autran coyly referred to "encouraging intermediate results" from these studies, which indicate that new HIV-specific CD4 T cell responses can be induced in both primary and chronic infection. She reported that the frequencies of these responses are comparable to LTNP in vaccinated individuals with primary infection, but are slightly lower in study participants with chronic infection. CD8 T cell data are still pending. Additional trials are now being planned with newer and potentially more immunogenic vaccines such as Merck's DNA/adenovirus combination product. ¤

Emini outlined the studies that are in progress in both HIV negative and HIV positive volunteers (Merck is also pursuing these vaccines as potential therapeutics).

DNA HIV gag vaccine. The ongoing program involves two doses (1mg or 5mg) of gag-expressing DNA in saline or with one of two adjuvants: aluminum phosphate or the experimental nonionic block co-polymer CRL-1005.

Adenovirus 5 (Ad5) HIV gag vaccine. Separate trials are evaluating four escalating doses (108, 109, 1010 and 1011 virus particles or vp) of the gag-expressing Ad5 vector and the final phase of the program (which began in January) is offering recipients of the DNA vaccine an Ad5 booster immunization.

Emini presented data from the separate phase one studies of the DNA and Ad5 candidate vaccines, both conducted in HIV-negative volunteers.

An interesting facet of Merck's vaccine development program involves analyzing the potential of HIV-specific T cells to recognize viruses from multiple clades. Emini reported that the Merck team has looked at T cell responses in HIV-infected individuals from the US, Brazil, Thailand and Malawi (infected with viruses from clades, A, B & C) and assessed their ability to react against a panel of clade B-derived consensus peptides (comprising the viral proteins gag, pol, nef, rev and tat) in an ELISpot assay. Both the frequency and magnitude of the response to gag, pol and nef was indistinguishable by region, indicating substantial cross-clade reactivity. The proteins rev and tat induced a lower level of T cell response from all study participants, and individuals from Malawi did not appear to respond to clade B rev and tat at all.

Emini closed his presentation by outlining the results yet to come, which include immunogenicity data from the highest (1011 vp) Ad5 dose and the DNA/Ad5 prime-boost approach in HIV negative volunteers, as well as the safety and immunogenicity information from ongoing trials of these vaccines in HIV-infected individuals. Merck anticipates that these results will become available sometime in the summer of 2002. ¤