HIV-1 vaccine development after STEP

Abstract

Despite more than 25 years of concerted worldwide research, the development of a safe and effective HIV-1 vaccine remains elusive. Prototype antibody-based and T cell-based HIV-1 vaccines have failed to show efficacy in clinical trials to date. Next-generation HIV-1 vaccine candidates are in various stages of preclinical and clinical development, but key scientific obstacles pose major challenges for the field. Critical hurdles include the enormous global diversity of the virus and the challenges associated with generating broadly reactive neutralizing antibody and cellular immune responses. We review the current state of the HIV-1 vaccine field and outline strategies that are being explored to overcome these roadblocks.

Figure 1. Overlapping epitopes

Three well characterized HIV-1 epitopes (B*57 TW10, B*57 IW9, A*02 SL9) are shown in the context of overlapping epitopes that have been described in the literature. The compensatory mutations for the B*57 TW10 escape mutation T242N (92) are also shown embedded in overlapping epitopes to further illustrate the complexity at the population level of these immunologic targets. The epitopes that have been described in the literature are likely only the tip of the iceberg, since reagents used to screen for epitopes are seldom based on autologous sequences, which would enable detection of novel epitopes that are specific for less common variants. The common HLA molecules are in bold.

Figure 2. Global diversity

A phylogenetic tree is shown of HIV-1 Gag from a set of isolates within the last 10 years from diverse locations throughout the world. Branch lengths reflect overall genetic distances between isolates and clades, and the epitope alignment on the right shows the impact of this diversity on three well characterized epitopes. Dashes indicated identity with the form of the epitope most often studied that is depicted at the top of each epitope alignment. The subtype, the two-letter country code indicating where the sample was obtained (www.hiv.lanl.gov/content/sequence/HelpDocs/databasecountrycode.html), and the year of isolation are indicated. The IW9 epitope also includes the preceding amino acid, as an A146P flanking substitution hinders processing and represents a common escape route (97, 98).