Monkeying around with HIV vaccines: using rhesus macaques to define 'gatekeepers' for clinical trials

Abstract

Rhesus macaques are an important animal model for the study of human disease and the development of vaccines against HIV and AIDS. HIV vaccines have been benchmarked in rhesus macaque preclinical challenge studies using chimeric viruses made up of parts of HIV and simian immunodeficiency viruses. However, the lack of efficacy in a recent clinical trial calls for a re-evaluation of the scientific assumptions regarding the predictive value of using data generated from rhesus macaques as a 'gatekeeper' for the advancement of candidate vaccines into the clinic. In this context, there is significant consensus among HIV vaccinologists that next-generation HIV vaccines must generate 'better' immunity in rhesus macaques than clinically unsuccessful vaccines generated using validated assays. Defining better immunity is the core challenge of HIV vaccine development in this system and is the focus of this Review.

Figure 1. Viral kinetics of SIV in rhesus macaques and HIV in humans

Typical viral kinetics of simian immunodeficiency virus (SIV) in rhesus macaques^, and HIV in humans^,,. Whether SIVmac239, SIVmac251 or SIVsmE660 (SIV from sooty mangabeys) is administered in a high dose intravenously or repeated low doses at a mucosal site, peak viral loads occur approximately 1 week earlier in rhesus macaques than for HIV in humans, and the viral loads are on average 2.5-fold greater in magnitude but may be lower following a low-dose inoculation. The establishment of the HIV viral set point in humans that do not receive therapy occurs approximately 14 weeks or more after infection, whereas the SIV viral set point in rhesus macaques is established by week 6. The SIV viral set point is typically in the order of 1 log higher than that of HIV in humans, and simian AIDS-like illness occurs after 0.5–3 years, compared with after 8–10 years in humans.

Figure 2. genome homology of select Retroviridae

Genome sequence homology among select Retroviridae based on published data deposited in GenBank (HIV-1: NC_001802; SIVcpz: AF115393; SHIV89.6p: SIU89134; SIVsmm, clone PBj6.6: L09212; SIVmne027: SIU79412; SIVmac239: AY588945; SIVmac251, isolate Mm251: M19499 SIVagm, circular replicative intermediate DNA: X07805; HIV-2: NC_001722; SIVsmE660, isolate, TB1L partial: FJ579055; Moloney murine leukaemia virus (MMLV): NC_001,501). *Pathogenic in rhesus macaques; ^‡pathogenic in humans. SHIV, HIV Env-expressing SIV; SIV, simian immunodeficiency virus.