Considerations in the development of nonhuman primate models of combination antiretroviral therapy for studies of aids virus suppression, residual virus, and curative strategies

Abstract

Purpose of review Animal models will be critical for preclinical evaluations of novel HIV eradication and/or functional cure strategies in the setting of suppressive combination antiretroviral therapy (cART). Here, the strengths, limitations, and challenges of recent efforts to develop nonhuman primate (NHP) models of cART-mediated suppression for use in studies of persistent virus and curative approaches are discussed. Recent findings A number of combinations of NHP species and viruses that recapitulate key aspects of human HIV infection have been adapted for cART-mediated suppression studies. Different cART regimens implementing drugs targeting multiple different steps of the viral life cycle have provided varying levels virologic suppression, dependent in part upon the host species, virus, drug regimen and timing, and virologic monitoring assay sensitivity. New, increasingly sensitive virologic monitoring approaches for measurements of plasma viral RNA, cell- and tissue-associated viral RNA and DNA, and the replication-competent residual viral pool in the setting of cART in NHP models are being developed to allow for the assessment of persistent virus on cART and to evaluate the impact of viral induction/eradication strategies in vivo. Summary Given the vagaries of each specific virus and host species, and cART regimen, each model will require further development and analysis to determine their appropriate application for addressing specific experimental questions.

Effects of Treatment with Suppressive Combination Antiretroviral Drug Therapy and the Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid; (SAHA) on SIV-Infected Chinese Rhesus Macaques

“…Viral replication was suppressed to very low levels in the blood, lymph nodes and the GALT, and this response parallels HIV-1 patients on effective cART [9]. However, we still observed at least intermittently detectable residual virus and associated immune activation, findings also consistent with clinical results.…”

Effect of Suberoylanilide Hydroxamic Acid (SAHA) Administration on the Residual Virus Pool in a Model of Combination Antiretroviral Therapy-Mediated Suppression in SIVmac239-Infected Indian Rhesus Macaques

“…Despite the utility of NHP models for investigating the complex in vivo biology of AIDS virus infection, their utilization for studies of suppressive cART, residual virus, and viral eradication/functional cure strategies has been limited, due at least in part to challenges with achieving sustained viral suppression to clinically relevant levels with available cART regimens in SIV-infected macaques (reviewed in reference 35). Previous studies suggested that typical three-drug ART regimens, like those used for HIV-1-infected humans, are often insufficient for durable suppression of SIVmac239 replication to clin- ically relevant levels (i.e., Ͻ50 vRNA copies/ml), particularly for animals with high viral loads typical of SIVmac infection in Indian-origin rhesus macaques (35,(68)(69)(70)(71)(72). For the present study, we implemented a three-class (reverse transcriptase inhibitors, integrase strand transfer inhibitors, and protease inhibitors), six-drug regimen, which we identified through a number of pilot studies that evaluated various antiretroviral drugs in SIV-infected macaques (35; G. Q. Del Prete and J. D. Lifson, unpublished observations) and tested its efficacy in 6 de novo SIVmac239-infected animals.…”

Long-term multilineage engraftment of autologous genome-edited hematopoietic stem cells in nonhuman primates

“…43 The data presented here are particularly applicable to models of combination antiretroviral therapy (cART)-suppressed HIV infection, for which the NHP setting is uniquely suited. 44 An important aspect of macaque models that distinguishes them from mouse xenografts is the ability to demonstrate infection resistance in multiple cell types, such as T cells, monocytes, dendritic cells, etc, and in relevant tissues that constitute viral reservoirs (sites that harbor replication competent provirus during suppressive cART). In the context of HIV eradication strategies, it will be essential to target infection-resistant cells to long-lived viral reservoirs in blood and secondary sites such as gut-associated lymphoid tissue, a well characterized reservoir for infected cells in patients on cART.…”