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4 results on '"Zhong, Daniel"'

1. Brain microglia serve as a persistent HIV reservoir despite durable antiretroviral therapy

Author

Tang, Yuyang, Chaillon, Antoine, Gianella, Sara, Wong, Lilly M, Li, Dajiang, Simermeyer, Theresa L, Porrachia, Magali, Ignacio, Caroline, Woodworth, Brendon, Zhong, Daniel, Du, Jiayi, de la Parra Polina, Eduardo, Kirchherr, Jennifer, Allard, Brigitte, Clohosey, Matthew L, Moeser, Matt, Sondgeroth, Amy L, Whitehill, Gregory D, Singh, Vidisha, Dashti, Amir, Smith, Davey M, Eron, Joseph J, Bar, Katherine J, Chahroudi, Ann, Joseph, Sarah B, Archin, Nancie M, Margolis, David M, and Jiang, Guochun

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, HIV/AIDS, Genetics, Sexually Transmitted Infections, Infectious Diseases, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Infection, Good Health and Well Being, Animals, Humans, Microglia, HIV-1, Brain, Macrophages, Proviruses, HIV Infections, AIDS/HIV, Drug therapy, Medical and Health Sciences, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Here, we isolated brain myeloid cells (BrMCs) from nonhuman primates and rapid autopsy of people with HIV (PWH) on ART and sought evidence of persistent viral infection. BrMCs predominantly displayed microglial markers, in which up to 99.9% of the BrMCs were TMEM119+ MG. Total and integrated SIV or HIV DNA was detectable in the MG, with low levels of cell-associated viral RNA. Provirus in MG was highly sensitive to epigenetic inhibition. Outgrowth virus from parietal cortex MG in an individual with HIV productively infected both MG and PBMCs. This inducible, replication-competent virus and virus from basal ganglia proviral DNA were closely related but highly divergent from variants in peripheral compartments. Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions. These data demonstrate that MG harbor replication-competent HIV and serve as a persistent reservoir in the brain.

Published
2023

2. 'Block and Lock' HIV Persistence in Human Brain Myeloid Cells

Author

Zhong, Daniel

Abstract

This study explores the potential of a BRD4-selective small molecule modulator (ZL0580) to “block and lock” HIV transcription in brain myeloid cells (BrMCs), a potential HIV reservoir, within the central nervous system (CNS). Primary microglia isolated from fresh autopsy brain tissue was used to test the effects of ZL0580 to block and lock HIV expression. HIV transcription was measured through digital droplet PCR. After a week of treatment, we observed that variable doses of ZL0580 resulted in increased levels of HIV RNA in the supernatants of BrMCs. After prolonged post-treatment of BrMCs with ZL0580 for 16 days, we discovered that HIV latency reversal induced by a combination of LRAs (JQ-1, SAHA, and CM272) was reduced, compared with the untreated control. The data suggest that BrMCs isolated from human brain tissues can be successfully infected with HIV in vitro. Additionally, ZL0580 exhibited a potential to reactivate HIV infection. Thus, our data do not entirely suggest the observations that ZL0580 may enforce HIV into deep latency in the CNS reservoir cells. Further studies are needed to optimize the treatment conditions and test the impact of ZL0580 on HIV transcription and latency. We may also study some new approaches to reduce HIV reservoirs by different killing compounds, including Dexamethasone (DEXA), Polycytidylic acid (Poly I:C), and Nurr1/Nor1 agonist 6-MP. These studies may help us better understand the molecular mechanisms of HIV latency in long-lived BrMCs in people living with HIV on antiretroviral therapy.

Published
2023
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3. Human Immunodeficiency Virus-1 Reservoir in Human Brain Myeloid Cells

Author

Zhong, Daniel

Abstract

While it is known that the reservoir of human immunodeficiency virus type-1 (HIV) resides in the memory CD4+ T cell compartment, there is an incomplete understanding of the persistence of HIV in brain myeloid cells (BMC) in the central nervous system (CNS), which may be essential to the creation of a cure of HIV in people living with HIV (PLWH). I am interested in whether BMCs harbor replication-competent HIV and its underlined molecular mechanism. I will test my hypothesis that BMCs isolated from the brains of PLWH are latently infected and harbor replication-competent HIV in the CNS with the following aim: AIM: Understand the components and molecular machinery that cause underlying HIV latency in long-lived BMCs. Through this study, I will help my lab to understand the role of HIV myeloid reservoirs in the brain in PLWH and start to understand how HIV achieves its latency in BMCs, especially long-lived brain microglia.

Published
2022
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4. Brain microglia serve as a persistent HIV reservoir despite durable antiretroviral therapy.

Author

Yuyang Tang, Chaillon, Antoine, Gianella, Sara, Wong, Lilly M., Dajiang Li, Simermeyer, Theresa L., Porrachia, Magali, Ignacio, Caroline, Woodworth, Brendon, Zhong, Daniel, Jiayi Du, de la Parra Polina, Eduardo, Kirchherr, Jennifer, Allard, Brigitte, Clohosey, Matthew L., Moeser, Matt, Sondgeroth, Amy L., Whitehill, Gregory D., Singh, Vidisha, and Dashti, Amir

Subjects
*ANTIRETROVIRAL agents, *HIV, *MICROGLIA, *VIRUS diseases, *PARIETAL lobe
Abstract

Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Here, we isolated brain myeloid cells (BrMCs) from nonhuman primates and rapid autopsy of people with HIV (PWH) on ART and sought evidence of persistent viral infection. BrMCs predominantly displayed microglial markers, in which up to 99.9% of the BrMCs were TMEM119+ MG. Total and integrated SIV or HIV DNA was detectable in the MG, with low levels of cell- associated viral RNA. Provirus in MG was highly sensitive to epigenetic inhibition. Outgrowth virus from parietal cortex MG in an individual with HIV productively infected both MG and PBMCs. This inducible, replication-competent virus and virus from basal ganglia proviral DNA were closely related but highly divergent from variants in peripheral compartments. Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions. These data demonstrate that MG harbor replication-competent HIV and serve as a persistent reservoir in the brain. [ABSTRACT FROM AUTHOR]

Published
2023
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