Background:  Broad HIV-1 neutralization sensitivity, including susceptibility to vaccine sera, has generally been limited to lab strain viruses such as NL43 or MN, or R5 viruses with long in vitro passage histories such as SF162 and BAL. Primary viruses with minimal in vitro cell culture history are much more difficult to inhibit. This study describes significant envelope differences between isolates that are neutralization sensitive and resistant, including primary viruses sensitive to inhibition by vaccine sera.

Methods:  Neutralizing antibody responses were measured in a single replication cycle recombinant virus assay using virus pseudotyped with patient-derived HIV envelope proteins. This virus stock was used to infect CD4⁺ U87 cells expressing CCR5 and CXCR4 in the presence of serial dilutions of antibody containing plasma or monoclonal antibodies. Viral envelope fusogenicity was assessed using a cell-cell fusion assay and gp160 sequence was determined using GeneSeq HIV-1 Entry.

Results:  More than 50 viruses were tested for sensitivity to various immunologic reagents, and 3 categories of isolates were defined. The first category of viruses includes those that are difficult or impossible to neutralize with sera from infected or immunized individuals and are inhibited by very few monoclonal antibodies.  The second category includes isolates that are easier to inhibit with monoclonal antibodies and HIV⁺ sera and are occasionally inhibited by potent vaccine sera. The final category is comprised of highly neutralization-sensitive viruses and includes those that are commonly inhibited by vaccine sera and HIV⁺ plasma or sera as well as most or all monoclonal antibodies. The last category includes primary viruses as well as many commonly used lab strain viruses. These neutralization- sensitive viruses are characterized by significantly greater fusogenicity in a cell-cell fusion assay but not necessarily increased infectivity as measured by luciferase expression.  Additionally, the V1V2 regions of neutralization sensitive primary and lab strain viruses are consistently shorter than neutralization resistant viruses.

Conclusions:  HIV-1 isolates that are broadly sensitive to neutralization with many immunologic reagents, including sera from vaccinated individuals, are characterized by pan-sensitivity to monoclonal antibodies directed against diverse regions across gp160. These isolates are also more fusogenic and generally have shorter V1V2 regions than isolates more resistant to neutralization.

Keywords: neutralization; monoclonal antibodies; genotype