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Recipe for a Cure

tagline 1998

One Part Aged Innovation, Two Parts Hubris: Is Remune Merely Reheated '93 Berlin Fare?


Memories of mock apple pie

Just six months ago, when the whole eradication thing came crashing down on us like some rickety Times Square scaffolding, the field of HIV therapeutics (or, at least, a sizeable minority of those who had heretofore fetishized the antiviral quick fix) began to refocus its gaze away from the critical but arguably oversold antiretroviral combination therapies and toward immune-based therapies. A prescient editorial by editor Adrian Ivinson in the increasingly relevant Nature Medicine (May 1997) dared to ask whether the current obliterate-the-virus macho fixation was "likely to meet the long-term needs of the community" and called instead for a combined antiviral and immune-based approach. Well, the first hints of just such an approach have begun to trickle in -- and we can expect much more before the year is out.

Take a group of people whose plasma virus appears to have been well controlled by some sort of HAART regimen. Then tinker with their immune responses to see if you can coax back the ones that were missing (or destroyed) in the first place and enabled this insidious infection to begin taking over. While there are various proposed methods for accomplishing this, Bruce Walker's now high-profile work with long-term nonprogressors suggests that certain cellular immune responses to core HIV proteins are the ones most deserving of coaxing back.

According to Walker, this so-called "HIV-specific T help," critical to the maturation of certain specialized CD8+ cytotoxic T "killer" lymphocytes (a.k.a. CTLs), is the front line of immune attack against HIV. Its intrepid ambition, it seems, ill-serves it; and these crucial immune cells are nearly wiped out within perhaps a few days of HIV infection. Walker thinks that if we can somehow get the HIV-specific T-help back, CTLs capable of attacking and destroying HIV-infected cells will be effectively remobilized and HIV infection will be officially turned into a chronic, manageable viral infection -- like herpes or, say, genital warts. In fact, Walker as well as other research teams in Switzerland, France, Italy, Australia and the U.S. claim that they are well on their way to proving (or disproving, in the case of France's Brigitte Autran) this in newly infected individuals who are treated aggressively with antiretroviral therapy within the first 2-10 weeks of infection. (See summary of Australian Don Smith's experiment and Madame Autran's work in Lago Maggiore summary, here.)

Enter Fred Valentine and Immune Response Corp. At Geneva's poorly attended Friday late-breaker session, the 9th paper to be fired off in dizzying succession was this one which examined the use of Remune (previously known as the Salk Immunogen in its first -- or second? -- ill-fated incarnation and discarded years ago as ineffective). Valentine presented preliminary findings from a 32-week clinical trial conducted at eight research centers. Although the entire 32-weeks of treatment have been completed, only the first 20 weeks of data were said to be available for the Geneva debut.

As way of background, Valentine noted that lymphoproliferative responses ("LPRs," we'll call them) to HIV proteins are "either missing or of quite small magnitude at all stages of HIV infection." From a cohort of 101 HIV-infected individuals, Valentine showed that all but the much heralded long-term nonprogressors (LTNPs) had stimulation indexes (or "indices") to HIV env and gag proteins of <5. By contrast, LTNPs showed stimulation indices to HIV-env of 76-200 and to HIV-gag of 10 or more, "with some," Valentine cheered, "quite a lot larger." In HIV-negative individuals, Valentine explained, a stimulation index of 30-50 is "considered normal for immunogens against which a delayed-type hypersensitivity (DTH) reaction would register positive."

In the experiment, forty-three HIV-infected individuals were initially treated with the triple combination of indinavir+AZT+3TC. Four weeks after starting this regimen they were then randomized to receive either the Salk envelope-depleted vaccine or a vaccine composed of only the mineral oil adjuvant (incomplete Freund's) by intramuscular injection every three months.

After Valentine's study volunteers had ostensibly received the first two (weeks 4 and 16) of their three real or dummy immunizations, their lymphocytes were harvested and analyzed in vitro for proliferative ("LPR") responses to a panel of four antigens. The four antigens used included: 1) The Salk immunogen itself (now known as Remune or "HZ321," a Zairean clade A/clade E natural recombinant virus that accidentally lost its envelope during the Remune production process) grown in the T-cell line HuT78; 2) A core protein (p24) from the Salk immunogen itself; 3) A whole inactivated clade B virus (BaL) grown in monocyte derived macrophage cultures; and 4) A recombinant HIV-p24 protein produced in an insect cell baculovirus expression system.

In the frustratingly abbreviated slide show, we were first treated to lymphoproliferative responses to Valentine's "best responder": Subject #3. His or her stimulation index to the p24 core protein of the immunogen at Week 8 was in the 100-200 range; at Week 16, the 200-500 range; and by Week 20 around 600. "Absolutely huge responses," spracht Dr. Valentine. Responses to the whole immunogen and a different laboratory HIV strain (the clade B BaL) were also in the 200-600 range throughout the period of follow-up. What about the lymphoproliferative responses for the treatment group at large? Stimulation indices to the immunogen and its core (p24) were about 0.7 log above controls (p=0.008 and 0.03, respectively); and to the BaL strain, some 0.6 log above controls (p=0.03). "Well within the magnitude for individuals who fall into the long-term nonprogressor category," explained an exuberant Valentine. In his closing slide, Valentine concluded that "the HIV Immunogen [sic] can induce HIV-specific immune responses comparable to, in fact, and exceeding often, those seen in long-term nonprogressors."

Taken at face value, one would have thought Valentine and the Immune Response folks had stumbled onto a quick and easy recipe for a clinical cure: To four months' HAART gradually add quarterly immunizations with envelope-depleted HZ321 until of desired consistency. Let sit uncovered until trebled in volume. When knife inserted in middle comes out clean, remove HAART and allow to cool. Serve alongside a generous dollop of Dream Whip.

But cries of "Eureka!" were few and far between. With the exception of a one-day 60% up-tick in IRC's fastidiously manipulated share price and a hypo-analytical rim job in John James' AIDS Treatment News, the earth remained unshaken. Remune may have generated "astronomical" stimulation indices but precious little enthusiasm among Geneva conference goers. While some of this is a direct result of the company's penchant for sleaze and shameless self-promotion (abundantly available, it is reported, at their Thursday morning "satellite symposium"), the majority of the unethused simply observe that all Valentine really showed was that an HIV-infected individual could produce measurable immune responses to a recombinant immunogen -- something we've known (and seen over and over again with a variety of failed vaccine candidates) for years now.

What, exactly, was missing in the Remune media blitz? For starters, a broad, proliferative response to viral proteins from a panel of different primary isolates would be nice. And, of course, CTL data. Better still, what if the Immune Response bozos could show Remune capable of inducing -- or augmenting -- proliferative responses to autologous HIV; that is, the strain that an individual is infected with? Now then you might just have something! But stimulation indices to the immunogen itself? Come on, Fred, you can do better than that. "But we included a clade B heterologous strain in the antigen panel," you counter? We all know that experimental results obtained from laboratory strains painstakingly propagated in culture are notoriously misleading.

Then there's the question of the assay itself -- its sensitivity, its validation, its reproducibility, its clinical significance. As Martin Delaney and Brenda Lein, two of Project Inform's most seasoned trials analysts, observe, "We have no idea whether [the in vitro responses measured] correlate to any kind of clinical outcome. There are no data yet on whether they add, in any way, to further significant reduction in viral load. (They certainly should if Remune does what they say it does.) No information on what size changes in the assay are meaningful. No real information on the repeatability of the assay itself. No meaningful information on the durability of response. No information on how this response compares, in its clinical significance, to the original HIV specific response -- which itself almost always fails over time."

And it's curious that a product that has been shown to have a marginal (or no) effect on plasma HIV viral load (see JAIDS 1996; 11:351-64) would end up inducing a clinically significant improvement in HIV-specific cellular immunity. In a recent issue of the journal AIDS, for example, another almost as aggressively promoted prophylactic vaccine-failure-né-immunotherapeutic-vaccine, VaxSyn recombinant gp160, was reported to show clear evidence of restoration of HIV-specific T-cell immunity with no associated clinical benefit. This, again, begs the question of the clinical significance of these immune responses (see AIDS 1998; 12(2): 157-66).

Aaron Diamond's John Moore is quick to remind us that in HAART-treated individuals immune responses naturally wane because there is no longer enough antigen to maintain effector functions. This applies not only to CD4+ T cells, Moore adds, but also to B cells and CD8s. Adding some inactivated core antigens (which is all Remune is) will no doubt re-activate some immune responses that are antigen-limited in the context of HAART, Moore explains. But the re-activation of an immune response is not necessarily beneficial. "It could simply be irrelevant."

Whither Eradication?

Nineteen ninety-six's naïve assumptions:

  • Drugs are shutting off virus replication 100%. Nope. More sensitive tests now regularly produce evidence of low level on-going viral replication.
     
  • Infected cells turnover and die. Guess again. Most researchers show no decay of latently infected CD4+ memory T cells (the best characterized source of chronic infection to date), while Ho's new estimate of the half life of these cells figures in at 6 months. This translates into an "eradication" time table of some 15-20 years.
     
  • No "privileged sites" or "third" (fourth or fifth) compartment exists. Oops! There now appear to be reservoirs of virus -- whether anatomical or pharmacologic -- that the current class of agents simply cannot reach.