More than the Infinite Monkey Theorem: NHP Models in the Development of a Pediatric HIV Cure

Abstract

Purpose of review: An HIV cure that eliminates the viral reservoir or provides viral control without antiretroviral therapy (ART) is an urgent need in children as they face unique challenges, including lifelong ART adherence and the deleterious effects of chronic immune activation. This review highlights the importance of nonhuman primate (NHP) models in developing an HIV cure for children as these models recapitulate the viral pathogenesis and persistence.

Recent findings: Several cure approaches have been explored in infant NHPs, although knowledge gaps remain. Broadly neutralizing antibodies (bNAbs) show promise for controlling viremia and delaying viral rebound after ART interruption but face administration challenges. Adeno-associated virus (AAV) vectors hold the potential for sustained bNAb expression. Therapeutic vaccination induces immune responses against simian retroviruses but has yet to impact the viral reservoir. Combining immunotherapies with latency reversal agents (LRAs) that enhance viral antigen expression should be explored. Current and future cure approaches will require adaptation for the pediatric immune system and unique features of virus persistence, for which NHP models are fundamental to assess their efficacy.

Keywords: HIV cure; Nonhuman primate; Pediatric; Reservoir.

Fig. 1

SIV/SHIV infection and rebound. A SIV/SHIV infection and dissemination after oral (p.o.) challenge in infant rhesus macaques. In the first 48 h, SIV/SHIV crosses the epithelial layer of the oral and upper gastrointestinal (GI) mucosa, infecting the gut and associated lymphoid tissues. After 96 h, SIV/SHIV traverses the lower intestinal mucosa and systemic infection takes place through hematogenous and lymphatic dissemination with establishment of active and latent infection in multiple tissues. B The timing of virus reactivation following analytical treatment interruption (ATI) in selected tissues is shown. Over the first 2 weeks of ART interruption, increases in viral expression are seen first in the GI tract, followed by nasal-associated lymphoid tissue (NALT), spleen and lymph nodes. Bone marrow also represents a potential source of virus reactivation. The increase in viral replication in tissues is then detectable in the plasma as viremia ~ 14–28 days after ART interruption. Created with BioRender.com