These days, one more purported vaccine against AIDS may seem tobe such stuff as dreams are made on. The latest entry, disclosedtoday in Science, proposes to ward off HIV infection in the here-and-now, rather than wait to prevent it in future populations.
The paper reports "Efficient neutralization of primary isolates ofHIV-1 by a recombinant human monoclonal antibody." Its principalauthor is molecular immunologist Dennis Burton, a Member of theScripps Research Institute in La Jolla, Calif.
Like other HIV-1 candidate antibodies, the Scripps model targets thevirus's envelope protein, gp 120 _ specifically the site that binds toHIV's target, the CD4 receptor on the victim's T lymphocytes.
What sets this newest HIV-1 monoclonal antibody apart from andabove its forerunners? Co-author Paul Parren told BioWorld Today:"It is superior because for the first time we show that onemonoclonal antibody can neutralize such a broad range of differentclinical isolates, at concentrations _ typically below 25 microgramsper milliliter _ that are actually achievable in vivo. Otherantibodies," Parren explained, "have been shown to neutralizeprimary isolates, but often the concentrations they need are veryhigh."
Because Scripps' new antibody is broadly reactive, Parrenemphasized, "The first application we are working on is to to give itto people as a passive immunogen." Topping his list of such people,"are HIV-1-infected pregnant women, who will often transmit theirvirus to their child. By giving such a mother our antibody, we wouldbe able to reduce her viral load, as a way to prevent this maternal-fetal transmission."
The Science article points out, "transmission [reportedly] correlateswith an absence of maternal neutralizing antibody to the transmittedvirus." To test the recombinant, enhanced IgG1 b12" antibody in thisapplication, the Scripps study isolated virus from 12 neonatal infantsborn to HIV-1 seropositive mothers, all in California.
Eight of the 12 achieved 90 percent viral neutralization at antibodyconcentrations below 20 micrograms per milliliter. All 12 were 50percent neutralized in the range of 0.3 to 20 mg/ml, and most ofthese at less than 5 mg/ml.
In contrast, a pooled sample of plasma from highly-infectedindividuals neutralized only three of the dozen infant isolates, and todo so required antibody concentrations up to 100 mg/ml.
Given this performance, Parren also nominates the IgG1 b12antibody "as a tool to help people in needle-stick accidents, orexposed to virus in some other way." But he added, "Of course wesee that one antibody by itself won't do it. We will need a cocktailagainst different sites on the HIV." He also cautions that beforegoing into people, the recombinant antibodies must pass safety andanimal testing.
Fabrication of the IgG1 b12 antibody, Perran explained, began withbone-marrow donated by a U.S. male, long infected with HIV-1. Thegp120 antigen for affinity selection came from a laboratory strain ofthe virus.
Fab fragments (i.e., containing only a single variable region) of anti-gp120 antibodies were cloned in E. coli hosts. The plasmidexpressed these on the tips of phages. From this array of Fabs theScripps team selected those that bound antigen most strongly.
Then, to convert the single-variable-region Fabs into whole, double-variable antibodies, DNA from the best Fab went into a vector,where it was combined with genes encoding the constant regions ofthe immunoglobulin G1 molecule. That entire construct wasexpressed in Chinese hamster ovary cells, and perfected post-translationally in tissue culture as IgGi b12, a fully functionalantibody.
Its initial testing, Science reported, "suggests that the antibody isapproximately two orders of magnitude more potent than other CD4-site antibodies used in the NIAID/WHO [National Institute ofAllergies and Infections Diseases/World Health Organization]Antibody Serological Project, and comparable to the best antibodiesdirected to the [gp120] V3 loop."
Burton and his co-authors then tested their IgG1 b12's power toneutralize virus from 10 adult donor isolates, collected in four U.S.cities, New York, New Orleans, San Diego and Los Angeles. TheIgG1 b12 antibody "completely neutralized seven of the ten isolatesat 5 mg/ml."
Results of this and subsequent in vitro trials "clearly demonstratethat, although primary isolates may be more difficult to neutralize byantibody than laboratory strains, they are not intrinsically resistant."
How IgG1 b12 will fare against the constant drift of HIV-1 from onemutant strain to another "is one of the things we are planning to lookat," Parren said. "We know that it does not neutralize all viruses, andof those it does, not all at the same efficiency."
He concluded, "Viral escape has been shown on other antibodies,and probably will be on this one. We have no definite answer yet."n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.