AIDSWEEKLY Plus, Monday, 8 September 1997
Daniel J. DeNoon, Senior Editor
Combinations of different anti-HIV monoclonal antibodies may both protect against the virus and prevent the emergence of viable escape mutants.
The findings by a research team from Aaron Diamond AIDS Research Center (ADARC) and Scripps Research Institute are based on intensive studies of a single human MAb, IgG1b12.
"The results suggest that escape from IgG1b12 neutralization is due to a local rather than a global modification of the gp120 [HIV envelope protein] structure," ADARC researcher Hongmei Mo et al. observed. "Our findings have implications for the therapeutic and prophylactic applications of antibodies for HIV-1 infection."
Mo et al. reported their findings in the Journal of Virology ("Human Immunodeficiency Virus Type 1 Mutants That Escape Neutralization by Human Monoclonal Antibody IgG1b12," J Virol, 1997;71(9):6869-74).
IgG1b12 recognizes discontinuous epitopes overlapping the CD4 binding site on gp120. Previous studies showed that IgG1b12 could neutralize 32 of 40 HIV-1 clade B patient isolates, with neutralization defined as a 90 percent reduction in in vitro infectivity at a physiologically relevant antibody dose of <50 (micro)g (Parren, P.W.H.I. et al., XI Int Conf AIDS, 1996;11(1):9, Abstract Mo.A.274; see AIDS Weekly Plus, September 9, 1996).
Remarkably, IgG1b12 was also able to neutralize about 55 percent of HIV-1 isolates from other clades.
Mo et al. set out to characterize escape mutants to IgG1b12 by culturing a primary HIV-1 isolate (strain JRCSF) in the presence of the MAb. They eventually obtained an escape mutant with a 100-fold increase in resistance to IgG1b12.
Solubilized and virion-associated gp120 from the escape mutant had reduced affinity for IgG1b12. Sequencing of the mutant env gene showed three amino acid substitutions in gp120: D164N and D182N in the V2 region, and P365L in the C3 region.
Resistance was traced to the D182N and P365L mutations, both individually and in combination.
"Introduction of the D164N substitution into the P365L variant results in a nonviable virus (D164N/P365L)," Mo et al. noted. "In contrast, addition of D164N to the D182N or D182N/P365L mutant partially restored replicative function to near wild-type levels."
Fortunately, the mutants resistant to IgG1b12 remained sensitive to other potent anti-HIV MAbs, including 2G12 and 2F5. The immunoadhesin CD4-IgG, a genetically engineered hybrid linking recombinant CD4 to an antibody, also was effective against the mutants except for a small increase in resistance seen in mutants containing P365L.
These findings suggest that a suitable combination of anti-HIV MAbs - or a vaccine eliciting comparable antibodies - could prevent the development of viable escape mutants while exerting significant anti-HIV activity.
The corresponding author for this study is Hongmei Mo, Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10016.
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