HIV-1 Env Glycoproteins from Two Series of Primary Isolates: Replication Phenotype and Immunogenicity

Abstract

Seven envelope regions from two series of patient isolates have been molecularly cloned and analyzed for replication phenotypes and immunogenicity. Growth potential was analyzed for env sequences substituted into an HIV-1-NL4-3 backbone (NL4-3/env recombinants). Immunogenicity studies were conducted on secreted monomeric (gp120) and oligomeric (gp140) forms of the Envs using Env-expressing plasmid DNAs for immunizations. The env regions of the patient isolates conferred a spectrum of replication kinetics and cytotropisms on the NL4-3/env recombinants. Both patient series included non-syncytium-inducing viruses with no ability to grow on T-cell lines, and highly syncytium inducing viruses which grew well on T-cell lines. These differences in growth potential did not correlate with the ability of the DNA-expressed Envs to raise antibody in rabbits. Rather, the relative immunogenicity of the Envs was patient and form specific. The Envs from patient 5 raised higher titers of antibody than the Envs from patient 6. For each primary Env, the gp120 form of the Env raised higher titers of antibody than the gp140 form. Thus, structural features of Env that affect replication do not necessarily affect the ability to raise antibody.

DNA Vaccines: Immunology, Application, and Optimization

“…Whereas a single vaccination with DNA can induce both an antibody and CTL response in several model systems, both cellular and humoral immune responses are increased by successive boosting (one or two additional immunizations). This requirement for multiple immunizations is well documented for the induction of humoral responses to HIV envelope proteins (118)(119)(120)(121)(122)(123)(124). It should be noted, however, that, in one study, antibody responses to HIV-1 gp120 were actually enhanced in rhesus macaques when the number of DNA vaccinations (as delivered by gene gun) was reduced but the interval between immunizations increased, suggesting the importance of a rest period between immunizations (128).…”

“…The most common of these booster regimens have used either recombinant protein or poxviruses. Thus, for HIV, because multiple DNA vaccinations elicit only modest and transient titers of neutralizing antibody (118)(119)(120)(121)(122)(123)(124), there have been many studies evaluating the effects of peptide (125) or protein boosting after DNA vaccination (119,(126)(127)(128). In two separate studies that used rhesus macaques, it was shown that antibody production could be substantially increased in monkeys vaccinated with DNA encoding an HIV-1 envelope protein followed by a protein boost (127,128).…”

C3d Enhances Immune Responses Using Low Doses of DNA Expressing the HIV-1 Envelope from Codon-Optimized Gene Sequences

“…The development of an effective DNA vaccine against HIV-1 has been challenging due to the poorly immunogenic nature of the envelope glycoprotein (Env) when expressed from wild-type DNA sequences. DNA vaccines expressing the gp120 subunit of HIV-1 Env elicit transient antibody titers, which are relatively poor at neutralizing viral infection [15,25,27,28]. The inability of DNA expressing gp120 to elicit high titer, crossreactive antibodies may be due to a variety of factors, including the long period required for Env-specific antibody maturation [7].…”

Elicitation of Neutralizing Antibodies with DNA Vaccines Expressing Soluble Stabilized Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Trimers Conjugated to C3d

“…DNA vaccinations effectively induce both humoral and cellular immune responses to immunogens from diverse infectious agents. DNA vaccines targeting the gp120 subunit of HIV-1 Env have elicited transient antibody titers and have been less successful at generating neutralizing antibodies against HIV-1 (29,41,44,47). This inability to elicit high-titer, cross-clade antibodies may be due to a variety of factors, including the long period of maturation that is required for Env-specific antibodies (11).…”