Xu Wang

The persistence of human immunodeficiency virus type 1 (HIV-1) in the central nervous system (CNS) remains a major barrier to a cure and a key driver of HIV-associated neurocognitive disorders (HAND). For decades, progress in understanding HIV-1 neuropathogenesis has been limited by the lack of experimental models capable of recapitulating the complexity of the human brain. The development of three-dimensional (3D) brain organoids derived from human induced pluripotent stem cells (iPSCs) has significantly advanced the field by providing a physiologically relevant and clinically translatable platform for studying HIV-1 infection in the CNS. This review summarizes the evolution of brain organoid technologies, from self-organizing cultures to immune-competent organoids and multi-region assembloids. We highlight their contributions to understanding HIV-1 neuroinflammation, neuronal injury, and CNS reservoir establishment. We also discuss emerging advances integrating organoids with bioengineering and single-cell omics approaches to overcome current limitations and accelerate the development of therapeutic and curative strategies targeting HIV-1 persistence in the CNS.

The persistence of human immunodeficiency virus type 1 (HIV-1) in the central nervous system (CNS) remains a major barrier to a cure and a key driver of HIV-associated neurocognitive disorders (HAND). For decades, progress in understanding HIV-1 neuropathogenesis has been limited by the lack of experimental models capable of recapitulating the complexity of the human brain. The development of three-dimensional (3D) brain organoids derived from human induced pluripotent stem cells (iPSCs) has significantly advanced the field by providing a physiologically relevant and clinically translatable platform for studying HIV-1 infection in the CNS. This review summarizes the evolution of brain organoid technologies, from self-organizing cultures to immune-competent organoids and multi-region assembloids. We highlight their contributions to understanding HIV-1 neuroinflammation, neuronal injury, and CNS reservoir establishment. We also discuss emerging advances integrating organoids with bioengineering and single-cell omics approaches to overcome current limitations and accelerate the development of therapeutic and curative strategies targeting HIV-1 persistence in the CNS.

Microglia are the primary target and reservoir of HIV infection in the central nervous system (CNS), which contributes to HIV-associated neurocognitive disorder (HAND). However, studying HIV infection of microglia has been challenged by the limited availability of primary human microglial cells. To overcome this issue, investigators have developed various microglial models for HIV studies, including immortalized human microglial cell lines, HIV latently infected microglial clones, peripheral blood monocyte-derived microglia (MMG), induced pluripotent stem cell (iPSC)-derived microglia (iMg), and microglia-containing cerebral organoids (MCOs) from iPSCs. Though these models have been used in many laboratories, the published data about their expression of the specific human microglia markers and the HIV entry receptors are conflicting. In addition, there is limited information about their feasibility and applicability as a suitable model for acute and/or latent HIV infection. This review provides a concise summary of the currently used human microglial models, with a focus on their suitability for NeuroHIV research.

Microglia are the primary target and reservoir of HIV infection in the central nervous system (CNS) which contribute to HIV-associated neurocognitive disorder (HAND). However, studying HIV infection of microglia has been challenged by limited availability of primary human microglial cells. To overcome this issue, investigators have developed various microglial models for HIV studies, including immortalized human microglial cell lines, HIV latently infected microglial clone, peripheral blood monocyte-derived microglia (MMG), induced pluripotent stem cell (iPSC)-derived microglia (iMg) and microglia containing cerebral organoids (MCOs) from iPSC. Though these models have been used in many laboratories, the published data about their expression of the specific human microglia markers and the HIV entry receptors is conflicting. In addition, there is limited information about their feasibility and applicability as a suitable model for acute and/or latent HIV infection. This review provides a concise summary of the currently used human microglial models with a focus on their suitability for NeuroHIV research.

Because the vaccine-elicited antibody and neutralizing activity against spike protein of SARS-CoV-2 are associated with protection from COVID-19, it is important to determine the levels of specific IgG and neutralization titers against SARS-CoV-2 elicited by the vaccines. While three widely used vaccine brands (Pfizer-BNT162b2, Moderna-mRNA-1273 and Johnson-Ad26.COV2.S) are effective in preventing SARS-CoV-2 infection and alleviating COVID-19 illness, they have different efficacy against COVID-19. It is unclear whether the differences are due to varying ability of the vaccines to elicit a specific IgG antibody response and neutralization activity against spike protein of the virus. In this study, we compared the plasma IgG and neutralization titers against spike proteins of wild-type SARS-CoV-2 and eight variants in healthy subjects who received the mRNA-1273, BNT162b2 or Ad26.COV2.S vaccine. We demonstrated that subjects vaccinated with Ad26.COV2.S vaccine had significantly lower levels of IgG and neutralizing titers as compared to those who received the mRNA vaccines. While the linear regression analysis showed a positive correlation between IgG levels and neutralizing activities against SARS-CoV-2 WT and the variants, there was an overall reduction in neutralizing titers against the variants in subjects across the three groups. These findings suggest that people who received one dose of Ad26.COV2.S vaccine have a more limited IgG response and lower neutralization activity against SARS-CoV-2 WT and its variants than recipients of the mRNA vaccines. Thus, monitoring the plasma or serum levels of anti-SARS-CoV-2 spike IgG titer and neutralization activity is necessary for the selection of suitable vaccines, vaccine dosage and regimens.

The Bowman‒Birk inhibitor (BBI), a protease inhibitor derived from soybeans, has been extensively studied in anti-tumor and anti-inflammation research. We recently reported that BBI has an anti-HIV-1 property in primary human macrophages. Because HSV-2 infection plays a role in facilitating HIV-1 sexual transmission, we thus examined whether BBI has the ability to inhibit HSV-2 infection. We demonstrated that BBI could potently inhibit HSV-2 replication in human cervical epithelial cells (End1/E6E7). This BBI-mediated HSV-2 inhibition was partially through blocking HSV-2-mediated activation of NF-κB and p38 MAPK pathways. In addition, BBI could activate the JAK/STAT pathway and enhance the expression of several antiviral interferon-stimulated genes (ISGs). Furthermore, BBI treatment of End1/E6E7 cells upregulated the expression of tight junction proteins and reduced HSV-2-mediated cellular ubiquitinated proteins’ degradation through suppressing the ubiquitin‒proteasome system. These observations indicate that BBI may have therapeutic potential for the prevention and treatment of HSV-2 infections.

Although opioids have been extensively studied for their impact on the immune system, limited information is available about the specific actions of opioids on intracellular antiviral innate immunity against HIV infection. Thus, we investigated whether heroin, one of the most abused drugs, inhibits the expression of intracellular HIV restriction microRNA (miRNA) and facilitates HIV replication in macrophages. Heroin treatment of macrophages enhanced HIV replication, which was associated with the downregulation of several HIV restriction miRNAs. These heroin-mediated actions on the miRNAs and HIV could be antagonized by naltrexone, an opioid receptor antagonist. Furthermore, the in vitro negative impact of heroin on HIV-associated miRNAs was confirmed by the in vivo observation that heroin addicts had significantly lower levels of macrophage-derived HIV restriction miRNAs than those in the control subjects. These in vitro and in vivo findings indicate that heroin use compromises intracellular anti-HIV innate immunity, providing a favorable microenvironment for HIV survival in the target cells.

(−)-Epigallocatechin gallate (EGCG) is a major polyphenol component of green tea that has antioxidant activities. Lipopolysaccharide (LPS) induces inflammatory cytokine production and impairs blood–brain barrier (BBB) integrity. We examined the effect of EGCG on LPS-induced expression of the inflammatory cytokines in human cerebral microvascular endothelial cells (hCMECs) and BBB permeability.

Lipopolysaccharide (LPS), the major component of the outer membrane of gram-negative bacteria, can activate immune cells including macrophages. Activation of macrophages in the central nervous system (CNS) contributes to neuronal injury. Bowman-Birk inhibitor (BBI), a soybean-derived protease inhibitor, has anti-inflammatory properties. In this study, we examined whether BBI has the ability to inhibit LPS-mediated macrophage activation, reducing the release of pro-inflammatory cytokines and subsequent neurotoxicity in primary cortical neural cultures.