FIGHT HIV-1 INFECTION FROM DAY ONE; DON'T WAIT FORSYMPTOMS
By David N. LeffScience Editor
Twenty HIV-1-infected patients in New York and 18 in Alabamahave helped to overturn much conventional wisdom as to the courseand cure of AIDS.
Two back-to-back papers in the current issue of Nature, dated Jan.12, report what the editors of that journal acclaim as "some of themost significant findings on HIV and AIDS to have appeared insome time, which will completely change our understanding ofwhat's going on." These words from the usually staid and reservedNature brought half a hundred journalists to a press briefing thisweek at New York University.
This is the venue where one of the two principal authors, David Ho,directs the Aaron Diamond AIDS Research Center. His paper bearsthe bland title, "Rapid turnover of plasma virions and CD4lymphocytes in HIV-1 infection." Slightly more dynamic is theheading on the article by George Shaw, et al., at the University ofAlabama, Birmingham: "Viral dynamics in humanimmunodeficiency virus type 1 infection."
"The concordance of their data is remarkable," observed SimonWein-Hobson of the Pasteur Institute, Paris, in an editorialaccompanying the two papers, and titled "Virological Mayhem".(Both groups submitted their papers for publication during the sameweek in November 1994.)
"The picture that emerges," says the editorial, "is of a titanic strugglebetween the virus and the immune system." This may sound like dejavu, but both groups reached their innovative conclusions bydeploying experimental antiviral drugs, a new system for assayingviral load, and mathematical algorithms to compute the growthkinetics of these molecular adversaries.
Novel Therapies To `Perturb The Balance'
In New York, Ho administered an investigational anti-HIV drug,ABT-538, to 20 Phase I/II AIDS patients whose pretreatment CD4T-lymphocyte counts (the measure of HIV-1 infection) ranged from36 to 490 per cubic millimeter. These immune-system cellsconfronted a viral load of 15,000 to 554,000 virions per milliliter.The team's goal was to "perturb the balance between virusproduction and clearance."
In fact, viral levels declined drastically within two weeks of initiatingtherapy, and CD4 counts rose, in some cases dramatically.
ABT-538, produced by Abbott Laboratories, of Chicago, inhibitsviral protease of HIV-1, and thus boosts CD4 counts. The Alabamagroup gave its 18 patients either ABT-538, or Novirapine (NVP), anexperimental Boehringer-Ingelheim GmbH (Germany) product,which blocks HIV-1 reverse transcriptase. Both compounds have theeffect of preventing de novo infection of virally targeted T cells.
Shaw pointed out that before these potent new drugs becameavailable to abrogate viral replication, "very little quantitativeinformation [was] available regarding . . . the rapidity of virus andCD4 cell population turnover."
Both groups measured changes in viral load by means of branched-DNA signal amplification, a sensitive, still-experimental quantitativeassay for plasma virus RNA, provided to them by Chiron Corp., ofEmeryville, Calif.
"When new cycles of infection are interrupted by potent anti-retroviral therapy," the Alabama group reported, "viral levels fallabruptly by an average of 99 percent, and in some cases by as muchas 99.99 percent (10,000-fold)." At least 30 percent of them must bereplaced daily.
The down-side of this virion wipe-out is that a single base change inthe HIV-1 genome can generate viral strains resistant to a new drug,whether its target be protease or polymerase. "Almost completereplacement of wild-type virus in plasma by drug-resistant variantsoccurs after 14 days," Shaw pointed out.
Drug Curbed Replication But Boosted Resistance
Recent findings report that the main reservoirs of HIV-1 replicationin the body are the lymphoid tissues -- lymph nodes, spleen, guttissues and macrophages. Here the holed-up virus encounters itsnemesis and prey -- T lymphocytes in the process of maturing.
Thus, in four patients treated with NVP, the drug potently inhibitedHIV-1 replication, but also selected for codon substitutions in theviral reverse transcriptase it was designed to inhibit. "Thesemutations," Shaw wrote, "result in dramatic increases (up to 1,000-fold) in drug susceptibility _ and a corresponding loss of viralsuppression in vivo."
After only 28 days of therapy, the NVP-resistant mutant hadcompletely replaced the original wild-type strain. "This implies,"Shaw concluded, "that HIV-1 must have enormous potential toevolve in response to selection pressures, as exerted by the immunesystem."
He suggested that "the virus does not suppress the immune system asmuch as it exhausts the system by producing more viral material thanthe immune system is able to destroy."
The immune system loses to viral attack _ and replenishes _ on theorder of 1 billion CD4 cells a day. The researchers interpret thiscontinual viral onslaught to reflect continuous rounds of new virusinfection, replication and cell turnover, rather than previouslyinfected cells that keep pumping out new virions.
Ho compared this seesaw stand-off beween the invading HIV-1 andthe defending T cells "to a sink containing a low water level, withthe tap and drain both equally wide open." But he added, "As theregenerative capacity of the immune system is not infinite, it is notdifficult to see why the sink eventually empties."
Ergo, he advocated targeting virally mediated destruction (plug thedrain) rather than lymphocyte reconstitution (put in a second tap).Shifting from analogy to therapy, Ho concluded: "Monitoring theacute antiviral activity of novel compounds must be modified tofocus on the first few days following drug initiation."
Echoing this suggested strategy, Alabama's Shaw pointed out that"Currently, researchers must wait four to 12 months to see if apotential drug has an effect against the AIDS virus. Since the rate ofviral replication is faster than previously thought, they should be ableto tell in four to six weeks whether a drug or vaccine is having aneffect on virus progression."
The ever-proliferating and differentiating HIV-1 population, Wein-Hobson observed, includes drug-resistant mutations even in theabsence of therapy. "Against this background," he asserted,"monotherapy cannot succeed. Only combinations of drugs have thepotential to outgun the virus." n
(c) 1997 American Health Consultants. All rights reserved.