Human Immunodeficiency Virus Type 1 Subtype C Molecular Phylogeny: Consensus Sequence for an AIDS Vaccine Design?

Epitope-based vaccines designed to induce CTL responses specific for HIV-1 are being developed as a means for addressing vaccine potency and viral heterogeneity. We identified a set of 21 HLA-A2, HLA-A3, and HLA-B7 restricted supertype epitopes from conserved regions of HIV-1 to develop such a vaccine. Based on peptide-binding studies and phenotypic frequencies of HLA-A2, HLA-A3, and HLA-B7 allelic variants, these epitopes are predicted to be immunogenic in greater than 85% of individuals. Immunological recognition of all but one of the vaccine candidate epitopes was demonstrated by IFN-γ ELISPOT assays in PBMC from HIV-1-infected subjects. The HLA supertypes of the subjects was a very strong predictor of epitope-specific responses, but some subjects responded to epitopes outside of the predicted HLA type. A DNA plasmid vaccine, EP HIV-1090, was designed to express the 21 CTL epitopes as a single Ag and tested for immunogenicity using HLA transgenic mice. Immunization of HLA transgenic mice with this vaccine was sufficient to induce CTL responses to multiple HIV-1 epitopes, comparable in magnitude to those induced by immunization with peptides. The CTL induced by the vaccine recognized target cells pulsed with peptide or cells transfected with HIV-1 env or gag genes. There was no indication of immunodominance, as the vaccine induced CTL responses specific for multiple epitopes in individual mice. These data indicate that the EP HIV-1090 DNA vaccine may be suitable for inducing relevant HIV-1-specific CTL responses in humans.

Section: Discussionmentioning

confidence: 99%

Development of a DNA Vaccine Designed to Induce Cytotoxic T Lymphocyte Responses to Multiple Conserved Epitopes in HIV-1

Wilson

McKinney²,

Anders

et al. 2003

“…These viral sequences included isolates from the following HIV-1 subtypes, groups, and circulating recombinant forms: 12 A, 22 B, 62 C, 4 D, 5 F, 3 G, 3 H, 2 J, 2 K, 1 U, 46 circulating recombinant forms, 1 N-group, and 4 O-group. Fifty-one of 62 HIV-1C sequences used represented viral isolates collected from HIV-1 ϩ patients throughout the South African country of Botswana (15,42,43). Viral sequences were analyzed using motif-based search software to identify putative CTL epitopes analogous to those encoded in the EP HIV-1090 DNA vaccine (17).…”

Section: Identification Of Variant Ctl Epitopes From Hiv-1 Sequencesmentioning

confidence: 99%

“…Vaccine strategies developed to address HIV-1 variation include the use of subtype-based ancestral or consensus sequences (13,15,16) and the use of highly conserved regions or epitopes (17). The logic behind this latter approach is that these regions of the HIV-1 genome are conserved because mutations would negatively impact gene function and general viral fitness.…”

mentioning

confidence: 99%

Recognition of Variant HIV-1 Epitopes from Diverse Viral Subtypes by Vaccine-Induced CTL

McKinney¹,

Skvoretz²,

Livingston³

et al. 2004

Recognition by CD8+ T lymphocytes (CTL) of epitopes that are derived from conserved gene products, such as Gag and Pol, is well documented and conceptually supports the development of epitope-based vaccines for use against diverse HIV-1 subtypes. However, many CTL epitopes from highly conserved regions within the HIV-1 genome are highly variable, when assessed by comparison of amino acid sequences. The TCR is somewhat promiscuous with respect to peptide binding, and, as such, CTL can often recognize related epitopes. In these studies, we evaluated CTL recognition of five sets of variant HIV-1 epitopes restricted to HLA-A*0201 and HLA-A*1101 using HLA transgenic mice. We found that numerous different amino acid substitutions can be introduced into epitopes without abrogating their recognition by CTL. Based on our findings, we constructed an algorithm to predict those CTL epitopes capable of inducing responses in the HLA transgenic mice to the greatest numbers of variant epitopes. Similarity of CTL specificity for variant epitopes was demonstrated for humans using PBMC from HIV-1-infected individuals and CTL lines produced in vitro using PBMC from HIV-1-uninfected donors. We believe the ability to predict CTL epitope immunogenicity and recognition patterns of variant epitopes can be useful for designing vaccines against multiple subtypes and circulating recombinant forms of HIV-1.

“…To contend with this issue, some attempts have been made to match candidate vaccines with strains prevalent in sites in which phase III efficacy trials are to be conducted (2)(3)(4). Other strategies include the use of mixture vaccines containing Ags representative of several genetic subtypes (5,6), the design of candidate vaccines targeting conserved HIV-1 epitopes (7,8), and the use of candidate vaccines based on the consensus or ancestor sequences selected to minimize genetic differences between vaccine strains and current isolates (2,9).…”

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confidence: 99%

Effects of Immunization with CCR5-Based Cycloimmunogen on Simian/HIVSF162P3 Challenge

Misumi

Nakayama

Kusaba

et al. 2006

A synthetic cycloimmunogen targeting the HIV-1 coreceptor CCR5 was evaluated for its capacity to induce CCR5-specific Abs with anti-HIV-1 activity in cynomolgus macaques. The cyclic closed-chain dodecapeptide (cDDR5) mimicking the conformation-specific domain of human CCR5 was chemically prepared, in which the Gly-Glu dipeptide links the amino and carboxy termini of the decapeptidyl linear chain (Arg168 to Thr177) derived from the undecapeptidyl arch (Arg168 to Cys178) of extracellular loop-2 in CCR5. The immunization of cynomolgus macaques with the cDDR5-conjugated multiple-Ag peptide (cDDR5-MAP) induced anti-cDDR5 serum production for ∼15 wk after the third immunization. The antisera raised against cDDR5-MAP reacted with both human and macaque CCR5s, and potently suppressed infection by the R5 HIV-1 laboratory isolate (HIVJRFL), R5 HIV-1 primary isolates (clade A:HIV93RW004 and clade C:HIVMJ4), and a pathogenic simian/HIV (SHIVSF162P3) bulk isolate in vitro. To examine the prophylactic efficacy of anti-CCR5 serum Ab for acute HIV-1 infection, cynomolgus macaques were challenged with SHIVSF162P3. The cDDR5-MAP immunization attenuated the acute phase of SHIVSF162P3 replication. The geometric mean plasma viral load in the vaccinated macaques was 217.10 times lower than that of the control macaques at 1 wk postchallenge. Taken together, these results suggest that cDDR5-MAP immunization is an effective prophylactic vaccine strategy that suppresses and delays viral propagation during the initial HIV-1 transmission for the containment of HIV-1 replication subsequent to infection.