Objective:

To evaluate the safety and immunogenicity of a polyvalent (PV) HIV envelope synthetic peptide immunogen, C4-V3. The immunogen comprised four peptides containing T-helper epitopes from the fourth constant region (C4) of gp120 of HIV-1 MN, and T-helper, cytotoxic T-lymphocyte HLA-B7-restricted, and B-cell neutralizing epitopes from the gp120 third variable region (V3) of four clade B HIV-1 isolates, HIV-1 MN, HIV-1 RF, HIV-1 EV91, and HIV-1Can0A.

Design:

A pilot, Phase I controlled trial [Division of AIDS Treatment Research Initiative (DATRI) 010] conducted at a single center.

Methods:

Ten HIV-infected, HLA-B7-positive patients with CD4 cells> 500× 10 6/l were enrolled. Eight patients received the C4-V3 PV immunogen emulsified in incomplete Freund's adjuvant in five intramuscular injections over 24 weeks, and two controls received incomplete Freund's adjuvant alone. All subjects were followed for 52 weeks.

Results:

Four out of eight C4-V3 PV recipients generated at least fourfold rise in serum antibody titers to at least three immunogen peptides in contrast to none of the control subjects. Four out of eight C4-V3 PV recipients and none of the controls had an at least fourfold rise in neutralizing antibodies to either HIV-1 MN, HIV-1 RF, or HIV-14489-5 laboratory-adapted HIV isolates. 3H-Thymidine incorporation assays of peripheral blood mononuclear cells increased at least fivefold over the baseline stimulation index to at least one of the immunogen peptides in two consecutive post-immunization timepoints in five out of eight C4-V3 PV recipients versus none of the controls. CD4 cell counts and plasma HIV RNA levels did not change in patients who received either C4-V3 PV or adjuvant alone. Adverse events consisted primarily of grade 1 injection site reactions in six subjects (four C4-V3 recipients, two controls).

Conclusions:

C4-V3 PV synthetic peptides demonstrated both immunogenicity and safety in HIV-infected patients.

Introduction

Efforts to develop effective HIV vaccines have been hampered by lack of knowledge of the correlates of protective immunity to HIV and lack of a strategy to confront the extraordinary diversity of HIV quasi-species [1, 2]. To explore the issues related to HIV diversity and their implication for HIV immunogen design, HIV gp120 envelope synthetic peptides were used as a prototype polyvalent (PV) immunogen to generate or boost humoral and cellular anti-HIV immune responses in HIV-infected patients. HIV gp120 C4-V3 peptides are linearly synthesized hybrid peptides comprised of T-helper determinants from the fourth constant (C4) and third variable (V3) gp120 regions, neutralizing antibody epitopes from the V3 region, and a V3 HLA-B7-restricted cytotoxic T-lymphocyte (CTL) epitope [3–6]. The primary amino-acid sequences of four different HIV V3-loop motifs from United States and Europe clade B isolates were included in this prototype immunogen (HIV-1 MN, HIV-1 RF, HIV-1 EV91, and HIV-1Can0A)[6], to initially evaluate the possibility of using PV peptide mixtures to induce broadly reactive anti-HIV neutralizing antibodies and anti-HIV CTL activity in human subjects. Given the presence an HLA-B7-restricted CTL epitope within the peptide, the C4-V3 PV immunogen was a prototype HLA-based vaccine that required selection of subjects who were HLA-B7+ for the development of vaccine-induced CD8+ CTL. In future trials, a practical HLA-based vaccine for use in an outbred population will require the inclusion of sufficient CTL epitopes such that most members of a cohort will express HLA molecules capable of reacting with several components of a PV HIV immunogen [1, 2].