Vaccines that stimulate T cell immunity to HIV-1: the next step

Abstract

The search for a vaccine against human immunodeficiency virus type 1 (HIV-1) has many hurdles to overcome. Ideally, the stimulation of both broadly neutralizing antibodies and cell-mediated immune responses remains the best option, but no candidate in clinical trials at present has elicited such antibodies, and efficacy trials have not demonstrated any benefit for vaccines designed to stimulate immune responses of CD8(+) T cells. Findings obtained with the simian immunodeficiency virus (SIV) monkey model have provided new evidence that stimulating effective CD8(+) T cell immunity could provide protection, and in this Perspective we explore the path forward for optimizing such responses in humans.

Figure 1

Control of SIV or HIV-1 by vaccines that stimulate CTLs. Effect of various T cell–stimulating vaccines (key) on viral load over time (with infection on day 0) during natural infection with HIV or SIV, showing the decrease in viral load achieved without a vaccine (None), by CTL responses (Partial control; as in ref. , for example), by the RhCMV vaccine (Slow eradication)^, and by a hypothetical vaccine that targets the virus at the site of infection (Rapid eradication).

Figure 2

Vaccines that deal with HIV-1 variability. Construction of vaccines based on viral sequences in four viral isolates (top; simplified representation): horizontal lines indicate viral sequences; circles indicate sites of greatest variability between isolates (and potential escape mutations from CTL pressure; there may be more than two alternative sequences at each spot); and blue lines indicate regions of relative conservation (although in reality no region of HIV-1 is invariant). The mosaic vaccine (middle) is constructed to include the most common variants from the isolates in as few strands as possible while conserving naturally occurring sequence stretches. In the conserved region–containing vaccine (bottom), the relatively conserved regions (blue) are excised and then are ‘stitched’ together (which creates an unnatural junctional region). The regions typically vary from 30 to 120 amino acids in length.