Nineteen-eighty can be called the Annus mirabilis in whichbiotechnology emerged as a scientific and industrial discipline in itsown right _ trail-blazed by Cetus Corp., of Emeryville, Calif., andGenentech Inc., of South San Francisco.

That same 1980 was the Annus terribilis when physicians inCalifornia began suspecting that a new and lethal infection hademerged, striking gay men with weird diseases seldom seen until thenoutside medical textbooks. At first, they called it GRID _ Gay-Related Immunodeficiency Disease.

In the 1980s, AIDS (replacing "GRID") proliferated to otherpopulations, as biotech trials and errors zigzagged toward _ but notyet to _ viable vaccines and therapeutic drugs, Meanwhile, basicresearch forced HIV to begin giving up its guilty secrets.

Now in the 1990s, the balance shows signs of beginning to tip froman unrestrained epidemic of HIV and AIDS to knowledge-basedcontrol. That word "balance," between the viral attack and itsvictim's defenses, is the key concept of a stock-taking article in theNature, dated Dec. 12, 1996.

Titled: "Host factors and the pathogenesis of HIV-induced disease,"its author is Anthony Fauci, who directs the National Institute ofAllergy and Infectious Diseases (NIAID), and heads NIAID'slaboratory of immunoregulation. Wearing these two hats, he is one ofthe best-known American ombudsman of science in the HIV/AIDSarena."

"A clearer picture is now emerging," Fauci stated, "of how factorsintrinsic to the HIV-infected individual influence the rate at whichHIV replicates in the person's body, and how rapidly the patient willdevelop AIDS."

He discerned a triad of these host factors:

specific immune response to the virus;

non-specific factors;

the individual's genetic makeup.

These three intertwined elements define Fauci's analysis of why andhow an HIV-1 infection does _ or does not _ progress to full-blownAIDS, as well as an agenda for future research and development.

"If I were in the biotechnology world, Fauci told BioWorld Today,"what I would see is that it's become very clearly known now thatyou can up- or down-regulate virus, merely by manipulatingsomewhat-well-characterized host factors that go above and beyondthe HIV-specific immune response.

"So to me," he continued, "it opens up the door to a variety of othertargets that one can aim at in order to interfere with the effectivereplication of the virus, by blocking certain host factors that areexpressed heavily during HIV infection, or inducing those factors thatare known to themselves block virus. So that really is the message tobiotechnology people."

Knocking The AIDS Virus Off Balance

As recently as "the past few months" of this year, he observed,"scientists have made important new discoveries about thepathogenesis of HIV disease [which] create unprecedentedopportunities for developing new treatment and vaccine strategies."

These new insights, he added, "have provided renewed optimism forpeople living with HIV disease, as well as for the researchersworking to understand and control this extraordinarily complexproblem."

In HIV's balancing act, one key is cytokine balance Some of theseimmune system signaling molecules, for example, interferon-b (INF-b) and IL-10, suppress the virus. (See BioWorld Today, July 11, June21, May 3, 1996, p. 1.) Other cytokines, notably proinflammatorytumor necrosis factor (TNF-a) and interleukins 1b and 6 (IL1b andIL-6) actually induce the invader to replicate in the body, as docolony-stimulating facts M-CSF and GM-CSF.

But cytokines aren't the only partners in HIV's crime.

The immune system itself, once activated by the virus or byopportunistic infections it engenders, allows HIV to multiply moreefficiently. One striking example: Onset of an active tuberculosisinfection brings with it heightened viremia; as soon as the TB issuccessfully treated, these viral swarms in the blood go down tobaseline.

Even during the early weeks and months after HIV penetrates thebody, when the virus seems to be lying low, it is in fact, Faucipointed out, "turning over very rapidly, [with] 10 billion virionsproduced and cleared from the circulation each day."

Some cytokines actually team up with the virus to manipulate certainco-receptors, without which it cannot gain entry to its target cells.(See BioWorld Today, Nov. 14, Sept. 27, 1996, p. 1.) These fifth-column cell surface molecules, however, have their up-side: Theyoffer targets for peptides, antibodies or other pharmacological meansof blocking access routes.

As those cytokines and co-receptors operate and cooperate, certainstrains of HIV appear that replicate more readily in T lymphocytes,rather than in their initial bulls'-eye cells of entry, the immunesystem's macrophages.

Hereditary Component Of HIV Infection

And then there's the genetic connection: It takes genes to producethose co-receptor proteins. Some of their mutations, notably of theCCCR5 gene, suggest why individuals with a certain genomic patterncan go through a life of repeated exposure to HIV-1 infection withoutever progressing to AIDS, and dying.

Viral target cells that express these mutants, Fauci pointed out, "maypredominate at the mucosal surfaces through which the virus issexually transmitted." Such inflammation at the site of viral exposure,he added, "may tip the balance between expression of the co-receptorand the corresponding ligand in favor of viral entry . . . in individualswith a concomitant sexually transmitted disease producing genitalinflammation."

Blocking or down-regulating the CCR5 co-receptor, as by peptide orother ligands, preventing its expression, by gene therapy, orvaccinating against co-receptor epitopes, Fauci cautioned, "may notbe simple [and] may even enhance viral entry." Likewise, interferingwith CD4, the primary HIV-1 receptor, for an extended period oftime, "would be problematic, as CD4 is essential for immunefunction."

Fauci concluded: "Despite these concerns, however, there can be nodoubt that the new strategies suggested by recent advances in ourunderstanding of host-HIV interactions have remarkable potentialand should be vigorously pursued." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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