Immune Responses but No Protection against SHIV by Gene-Gun Delivery of HIV-1 DNA Followed by Recombinant Subunit Protein Boosts

Abstract

The efficacy of combining immunization with human immunodeficiency vitus type 1 (HIV-1) DNA and HIV-1 recombinant proteins to obtain protection from chimeric simian/human immunodeficiency virus (SHIV) was determined. Four cynomolgus monkeys received four gene-gun immunizations intraepidermally of plasmid DNA encoding HIV-1lai env (gp160), gag, tat, nef, and rev proteins. Ten micrograms of DNA was used per immunization. The animals were boosted twice intramuscularly with 50 microgram of HIV-1lai Env (MicroGeneSys), Gag, Tat, Nef, and Rev recombinant proteins mixed in Ribi adjuvant. The antibody responses were amplified following the administration of the recombinant subunit boosts. One month after the final subunit immunization, the vaccinated animals together with four control animals were challenged intravenously with 10 monkey infectious doses of SHIV that expresses the env, tat and rev genes of HIV-1 and gag and nef from SIV. However, only low titers of neutralizing antibodies were present at the day of challenge. The consecutive HIV-1 DNA and recombinant protein immunizations induced B- and T-cell responses but not protection against SHIV replication nor reduction of the viral load.

Preclinical and clinical progress of particle-mediated DNA vaccines for infectious diseases

“…With few exceptions [45,46], PMED DNA vaccines have consistently induced at least transient viral containment and partial to complete protection against AIDS viruses in nonhuman primates (Table 1). In one study, a PMED DNA vaccine prime followed by boosting with a recombinant fowlpox virus vaccine aVorded complete protection against a nonpathogenic HIV infection [47].…”

Codon Optimization of the Tat Antigen of Human Immunodeficiency Virus Type 1 Generates Strong Immune Responses in Mice following Genetic Immunization

“…Importantly, Tat antigens usually do not induce strong immune responses in a natural infection (53,56,58,78,92,101). Additionally, when delivered through different formats, Tat elicited a limited magnitude of immune responses in humans (15) and experimental animals (8,73). Other factors in favor of selecting Tat for this study are the functional importance of this viral antigen to the infectivity of the virus (35,47,81,82) and the existence of an inverse correlation between immune responses to Tat and disease progression (4,75,76,78,95,106).…”

“…While some studies reported complete (14,30,69) or partial (2, 3, 13, 70) protection, others failed to observe such protection (3,61,73,88). Especially when delivered as a DNA, most of the studies used the Tat gene directly cloned from the virus, which may have limited the efficacy of the vaccines.…”

Expression and Immunogenicity of Human Immunodeficiency Virus Type 1 Gag Expressed by a Replication-Competent Rhabdovirus-Based Vaccine Vector

“…These data suggest that HIV-1 Gag is a promising target for an HIV-1 vaccine. Today, a variety of approaches to generate an immune response against HIV-1 are in different stages of investigation, and recent approaches include recombinant proteins (17,39,48), peptides (5,7,34), naked DNA (3,4,9,26,36,40,50), and viral vectors (6,12,22,30,32,33,45). The induction of efficient CD8 ϩ T-lymphocytemediated cellular immune responses requires the endogenous synthesis of the target protein, which can be achieved easily with recombinant, live viral vectors.…”