Singh, Vir Publications
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Item HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology.(International Journal of Molecular Sciences, 4/25/2024) Thompson, Landon John-Patrick*; Genovese, Jessica*; Hong, Zhenzi*; Singh, Meera Vir; Singh, Vir BahadurDespite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with HIV continue to experience HIV-associated neurocognitive disorder (HAND). HAND is associated with neurocognitive impairment, including motor impairment, and memory loss. HIV has been detected in the brain within 8 days of estimated exposure and the mechanisms for this early entry are being actively studied. Once having entered into the central nervous system (CNS), HIV degrades the blood-brain barrier through the production of its gp120 and Tat proteins. These proteins are directly toxic to endothelial cells and neurons, and propagate inflammatory cytokines by the activation of immune cells and dysregulation of tight junction proteins. The BBB breakdown is associated with the progression of neurocognitive disease. One of the main hurdles for treatment for HAND is the latent pool of cells, which are insensitive to cART and prolong inflammation by harboring the provirus in long-lived cells that can reactivate, causing damage. Multiple strategies are being studied to combat the latent pool and HAND; however, clinically, these approaches have been insufficient and require further revisions. The goal of this paper is to aggregate the known mechanisms and challenges associated with HAND.Item Complete genome sequences of G phages OtterstedtS21 and Patos.(Microbiology Resource Announcements, 9/29/2023) Meng, Bowen; Bleau, Alexander*; Bombaywala, Riddhi R*; DeGraw, Audrey S*; Deol, Manjot S*; Dollard, Kendall E*; Gentile, Nicolas*; Jebaraj, Julianna*; Kayayan, Gregory N*; Miranda, Briana C*; Momoh, Ayobamidele E*; Morales, Elias*; Nunes, Amalia C*; Oropallo, Antonia M*; Otterstedt, Sophia C*; Pridell, Anna T*; Roberts, Jenna I*; Ruiz, Gabriel* A; Sangasani, Dhatri*; Smith, Renee D*; Tarar, Mahad*; Singh, Vir B; Jayachandran, PradeepaWe report the genomes of two viruses with siphovirus morphology, OtterstedtS21 and Patos, from Albany, New York, using . The genomes of OtterstedtS21 and Patos are ~68 kbp long with 58% GC content. Both phages group with cluster DV based on gene content similarity to phages in the Actinobacteriophage database.Item Initiation of combined antiretroviral therapy confers suboptimal beneficial effects on neurovascular function in people with HIV.(Frontiers in Neurology, 2023-08) Singh, Meera V; Uddin, Md Nasir; Singh, Vir B; Peterson, Angelique N; Murray, Kyle D; Zhuang, Yuchuan; Tyrell, Alicia; Wang, Lu; Tivarus, Madalina E; Zhong, Jianhui; Qiu, Xing; Schifitto, GiovanniIntroduction: Due to advances in combined anti-retroviral treatment (cART), there is an increased burden of age-related cerebrovascular disease (CBVD), in people living with HIV (PWH). The underlying CNS injury can be assessed by measuring cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). Methods: 35 treatment-naïve PWH and 53 HIV negative controls (HC) were enrolled in this study. Study participants underwent T1-weighted anatomical, pseudo-continuous arterial spin labeling, and resting-state functional MRI to obtain measures of CBF and CVR prior to starting cART treatment and at two-time points (12 weeks and 2 years) post-cART initiation. Controls were scanned at the baseline and 2-year visits. We also measured plasma levels of microparticles of endothelial and glial origin and well-known endothelial inflammation markers, ICAM-1 and VCAM-1, to assess HIV-associated endothelial inflammation and the interaction of these peripheral markers with brain neurovascular function. Results: HIV infection was found to be associated with reduced CVR and increased levels of endothelial and glial microparticles (MPs) prior to initiation of cART. Further, CVR correlated negatively with peripheral MP levels in PWH. Discussion: Our results suggest that while cART treatment has a beneficial effect on the neurovascular function after initiation, these benefits are suboptimal over time.Item Sulforaphane prevents the reactivation of HIV-1 by suppressing NFκB signaling.(Journal of Virus Eradication, 2023-08) Jamal, Imran; Paudel, Anisha*; Thompson, Landon*; Abdelmalek, Michel*; Khan, Irfan A; Singh, Vir BDespite more than 20 years of combination antiretroviral therapy (cART), complete eradication of HIV remains a daunting task. While cART has been very effective in limiting new cycles of infection and keeping viral load below detectable levels with partial restoration of immune functions, it cannot provide a cure. Evidently, the interruption of cART leads to a quick rebound of the viral load within a few weeks. These consistent observations have revealed HIV ability to persist as an undetectable latent reservoir in a variety of tissues that remain insensitive to antiretroviral therapies. The 'Block-and-Lock' approach to drive latent cells into deep latency has emerged as a viable strategy to achieve a functional cure. It entails the development of latency-promoting agents with anti-HIV functions. Recent reports have suggested sulforaphane (SFN), an inducer of NRF-2 (nuclear erythroid 2-related factor 2)-mediated antioxidative signaling, to possess anti-HIV properties by restricting HIV replication at the early stages. However, the effect of SFN on the expression of integrated provirus remains unexplored. We have hypothesized that SFN may promote latency and prevent reactivation. Our results indicate that SFN can render latently infected monocytes and CD4 T cells resistant to reactivation. SFN treatments antagonized the effects of known latency reactivating agents, tumor necrosis pactor (TNF-α), and phorbol 12-myristate 13-acetate (PMA), and caused a significant reduction in HIV transcription, viral RNA copies, and p24 levels. Furthermore, this block of reactivation was found to be mediated by SFN-induced NRF-2 signaling that specifically decreased the activation of NFκB signaling and thus restricted the HIV-1 promoter (5'LTR) activity. Overall, our study provides compelling evidence to highlight the latency-promoting potential of SFN which could be used in the 'Block-and-Lock' approach to achieve an HIV cure.Item Monocytes complexed to platelets differentiate into functionally deficient dendritic cells.(Journal of Leukocyte Biology, 2021-04) Singh, Meera V; Suwunnakorn, Sumanun; Simpson, Sydney R; Weber, Emily A; Singh, Vir B; Kalinski, Pawel; Maggirwar, Sanjay BIn addition to their role in hemostasis, platelets store numerous immunoregulatory molecules such as CD40L, TGFβ, β2-microglobulin, and IL-1β and release them upon activation. Previous studies indicate that activated platelets form transient complexes with monocytes, especially in HIV infected individuals and induce a proinflammatory monocyte phenotype. Because monocytes can act as precursors of dendritic cells (DCs) during infection/inflammation as well as for generation of DC-based vaccine therapies, we evaluated the impact of activated platelets on monocyte differentiation into DCs. We observed that in vitro cultured DCs derived from platelet-monocyte complexes (PMCs) exhibit reduced levels of molecules critical to DC function (CD206, dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin, CD80, CD86, CCR7) and reduced antigen uptake capacity. DCs derived from PMCs also showed reduced ability to activate naïve CD4 and CD8 T cells, and secrete IL-12p70 in response to CD40L stimulation, resulting in decreased ability to promote type-1 immune responses to HIV antigens. Our results indicate that formation of complexes with activated platelets can suppress the development of functional DCs from such monocytes. Disruption of PMCs in vivo via antiplatelet drugs such as Clopidogrel/Prasugrel or the application of platelet-free monocytes for DCs generation in vitro, may be used to enhance immunization and augment the immune control of HIV.