Identification of highly conserved and broadly cross-reactive HIV type 1 cytotoxic T lymphocyte epitopes as candidate immunogens for inclusion in Mycobacterium bovis BCG-vectored HIV vaccines

One of the fundamental goals of current strategies to develop an efficaciou s vaccine for AIDS is the elicitation of cytotoxic T lymphocyte (CTL) react ivities capable of recognizing cells infected with different subtypes of th e human immunodeficiency virus type 1 (HIV-1). In efforts to explore new va ccine candidates by the UNAIDS/WHO Vaccine Committee, we review the most re cent data concerning CTL epitopes that are conserved among the different HI V-1 subtypes. Moreover, we examine HLA allelic frequencies in several diffe rent populations, to determine those that could contribute to the goal of a cumulative phenotype frequency (CP) of at least 80%. By analyzing conserve d epitopes in the context of HLA restricting alleles, we define a set of HI V-1 gene regions that may have the greatest potential to induce cross-clade reactive CTLs. The absence of well-defined correlates of immune protection that link CTL epitopes to delayed disease progression and/or prevention of infection does not permit an assignment of rank order of the most relevant component of a candidate vaccine. Thus far, most of the studies conducted in clade B-infected patients to define conserved and immunodominant epitope s indicate gag and pol gene products to be the most conserved among the HIV -1 subtypes. Moreover, anti-Pol and -Gag CTL responses appear to correlate inversely with disease progression, suggesting that they should be among th e first choice of antigens to be included in a candidate vaccine construct aimed at induction of broad CTL responses. The impact of a clade B-based va ccine as a worldwide candidate capable of inducing protective immune respon ses can be determined only after "in vivo" studies. Meanwhile, extensive pa rallel studies in populations infected with non-clade B HIV-1 subtypes shou ld define the patterns of immunodominant epitopes and HLA for comparison wi th the data already collected in clade B-infected subjects.