TABLE 1.

Models for the study of CNS latent reservoirs

Human clinical samples	Macaque models	Rodent models
Advantages True representation of CNS cell types needed to study HIV reservoirs All cell types of human origin and real reflection of the disease time course Prefect for therapeutic targeting and reliable disease outcome from longitudinal studies	Advantages Macaques are closer to humans in terms of physiologic make up SIV infection of macaques follow a progressive disease pattern similar to that of humans SIV infection in primates respond to cART therapy as like in humans Myeloid reservoir cell types from CNS can be isolated at different time points to study and perform long‐term in vitro mechanistic studies Larger animal size allows more sample collection at a particular time point Both HIV and SIV have similar histone acetylation pattern in the brain Replication‐competent virus carrying macrophages were reported in macaques Cells of myeloid origin have more or less similar distribution in HIV and SIV	Advantages HIV‐infected humanized mice have shown hall mark signs of HIV infection in the brain such as neuronal death, neurocognitive impairments and activation of microglia Microglia and lymphocytes in humanized mice represent brain reservoir Replication‐competent virus was isolated from virally suppressed humanized mice brains and shown to establish fresh infection in new humanized mice Fewer brain cells are required to perform QVOA in humanized mice for validation of HIV cure studies Myeloid cells isolated from MoM mice have been shown to carry and spread viral infection independent of T cells Low cost maintenance and these colonies can be established around the world for any longitudinal studies Shorter duration to get accurate data on any proposed model to look at CNS reservoirs Have a complete functional human immune system, which lasts up to 1 year for any neurologic and CNS reservoir studies
Limitations Difficult to obtain CNS samples The variability of the timing of infection and comorbidities Variability in viral load and immune cell expression because of recent late‐stage patients Variability of therapeutic approaches most studies on microglia are limited to primary cultures or from postmortem brains, which may not reflect latent reservoirs as in living patients	Limitations SIV and HIV virus are not identical genetically and have differential response in disease progression Larger differences in MHC genes between humans and macaques Macaques have different innate immune factors that control SIV replication as compared to humans High cost and maintenance for any proposed CNS studies Primate research facility availability is scarce around the world for CNS and reservoir studies CNS reservoirs get established much earlier (∼3 days) than in other models SIV viral loads are much higher in brains of macaques as compared to humans so studying latency is a challenge Vpx protein in SIV have been shown to reduce a myeloid restriction factor leading to higher level of infection in myeloid cells, as compared with other HIV model studies	Limitations ‐Collection of lesser volume of samples during intermediate time point of analysis ‐Need sterile environment for HIV‐specific CNS studies on severely immunodeficient mice ‐Graft‐versus‐host disease in some humanized mice models based on transplantation of human hematopoietic stem cells