HIV-1 Entry and Prospects for Protecting against Infection

Bruxelle, J.; Trattnig, Nino; Mureithi, Marianne; Landais, Elise; Pantophlet, Ralph

doi:10.3390/microorganisms9020228

Cited by 9 publications

(3 citation statements)

References 295 publications

(282 reference statements)

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“…There are several CCR5 inhibitors that were halted or are in ongoing, late-stage clinical trials [ 44 ], and there is a CXCR4 inhibitor, Plerixafor (AMD3100), but it is only approved for mobilization of hematopoietic stem cells, due to severe off-target effects associated with CXCR4 inhibition [ 42 , 550 ]. A number of small molecular inhibitors and monoclonal antibodies have also been investigated as potential methods for blocking HIV interactions with CCR5, but most have not progressed past phase II trials, and none to date have been approved by the FDA [ 37 , 547 , 551 , 552 ], although the monoclonal antibody leronlimab (PRO 140) has been granted fast-track status [ 551 ]. And although they do not target the co-receptors directly, the anti-CD4 antibody Trogarzo, the gp120-targeting attachment inhibitor Fostemsavir, and the fusion inhibitor Enfurvitide also inhibit the entry process mediated by CCR5 and CXCR4 [ 553 – 555 ].…”

Section: Co-receptors As Targets In Antiretroviral Therapymentioning

confidence: 99%

Co-receptor signaling in the pathogenesis of neuroHIV

et al. 2021

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The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development.

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Section: Co-receptors As Targets In Antiretroviral Therapymentioning

confidence: 99%

Co-receptor signaling in the pathogenesis of neuroHIV

et al. 2021

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“…Men who have sex with men and injectable drug users are at a higher risk of HIV infection [22][23][24][25]. Body fluids such as semen, vaginal fluids and blood of infected persons contain free-floating viruses and virus-infected CD4 + -positive cells that facilitate the transmission of infection to the next cell or host [26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

HIV–Host Cell Interactions

Masenga,

Mweene,

Luwaya

et al. 2023

Cells

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The development of antiretroviral drugs (ARVs) was a great milestone in the management of HIV infection. ARVs suppress viral activity in the host cell, thus minimizing injury to the cells and prolonging life. However, an effective treatment has remained elusive for four decades due to the successful immune evasion mechanisms of the virus. A thorough understanding of the molecular interaction of HIV with the host cell is essential in the development of both preventive and curative therapies for HIV infection. This review highlights several inherent mechanisms of HIV that promote its survival and propagation, such as the targeting of CD4+ lymphocytes, the downregulation of MHC class I and II, antigenic variation and an envelope complex that minimizes antibody access, and how they collaboratively render the immune system unable to mount an effective response.

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“…2 HIV replication consists of an initial "entry" phase followed by a "postentry" phase. 3 The post-entry phase is the most chronic phase because-different steps such as integration, reverse transcription, protein synthesis, and protein packaging occurred. In the past decades, different HAART (highly active antiretroviral therapy) antiviral drugs have been used to reduce AIDS.…”

mentioning

confidence: 99%