Molecular mechanisms of HIV-1 proviral latency

Background: Since the beginning of the HIV/AIDS epidemic, 75 million people have been infected with the HIV and about 32 million people have died of AIDS. Investigation of the molecular mechanisms critical to the HIV replication cycle led to the identification of potential drug targets for AIDS therapy. One of the most important discoveries is HIV-1 protease, an enzyme that plays an essential role in the replication cycle of HIV. Objective: The aim of the present study is to synthesize and investigate anti-HIV-1 protease activity of some chalcone derivatives with the hope of discovering new lead structure devoid drug resistance. Methods: 20 structurally similar chalcone derivatives were synthesized and their physico-chemical characterization was performed. Binding of chalcones to HIV-1 protease was investigated by fluorimetric assay. Molecular docking studies were conducted to understand the interactions. Results: The obtained results revealed that all compounds showed anti-HIV-1 protease activity. Compound C1 showed the highest inhibitory activity with an IC50 value of 0.001 μM, which is comparable with commercial product Darunavir. Conclusion: It is difficult to provide general principles of inhibitor design. Structural properties of the compounds are not the only consideration; ease of chemical synthesis, low molecular weight, bioavailability, and stability are also of crucial importance. Compared to commercial products the main advantage of compound C1 is the ease of chemical synthesis and low molecular weight. Furthermore, compound C1 has a structure that is different to peptidomimetics, which could contribute to its stability and bioavailability.

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Molecular mechanisms of HIV-1 infection in neonatal target cells

Future Virology ◽

10.2217/fvl.12.26 ◽

2012 ◽

Vol 7 (5) ◽

pp. 489-503

Author(s):

Nafees Ahmad

Keyword(s):

Molecular Mechanisms ◽

Target Cells ◽

Hiv 1

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High-resolution view of HIV-1 reverse transcriptase initiation complexes and inhibition by NNRTI drugs

Nature Communications ◽

10.1038/s41467-021-22628-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Betty Ha ◽

Kevin P. Larsen ◽

Jingji Zhang ◽

Ziao Fu ◽

Elizabeth Montabana ◽

...

Keyword(s):

Reverse Transcriptase ◽

Viral Entry ◽

Reverse Transcription ◽

Molecular Mechanisms ◽

Dissociation Kinetics ◽

Structural Mechanism ◽

Medium Resolution ◽

Kinetics Of ◽

Hiv 1

AbstractReverse transcription of the HIV-1 viral RNA genome (vRNA) is an integral step in virus replication. Upon viral entry, HIV-1 reverse transcriptase (RT) initiates from a host tRNALys3 primer bound to the vRNA genome and is the target of key antivirals, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Initiation proceeds slowly with discrete pausing events along the vRNA template. Despite prior medium-resolution structural characterization of reverse transcriptase initiation complexes (RTICs), higher-resolution structures of the RTIC are needed to understand the molecular mechanisms that underlie initiation. Here we report cryo-EM structures of the core RTIC, RTIC–nevirapine, and RTIC–efavirenz complexes at 2.8, 3.1, and 2.9 Å, respectively. In combination with biochemical studies, these data suggest a basis for rapid dissociation kinetics of RT from the vRNA–tRNALys3 initiation complex and reveal a specific structural mechanism of nucleic acid conformational stabilization during initiation. Finally, our results show that NNRTIs inhibit the RTIC and exacerbate discrete pausing during early reverse transcription.

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IL-8 responsiveness defines a subset of CD8 T cells poised to kill

Blood ◽

10.1182/blood-2004-03-1067 ◽

2004 ◽

Vol 104 (12) ◽

pp. 3463-3471 ◽

Cited By ~ 56

Author(s):

Christoph Hess ◽

Terry K. Means ◽

Patrick Autissier ◽

Tonia Woodberry ◽

Marcus Altfeld ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Chemokine Receptor ◽

Cd8 T Cells ◽

Molecular Mechanisms ◽

Cell Subset ◽

Cd8 T Cell ◽

Effector Memory ◽

Immune System Activation ◽

Hiv 1

CD8 T cells play a key role in host defense against intracellular pathogens. Efficient migration of these cells into sites of infection is therefore intimately linked to their effector function. The molecular mechanisms that control CD8 T-cell trafficking into sites of infection and inflammation are not well understood, but the chemokine/chemokine receptor system is thought to orchestrate this process. Here we systematically examined the chemokine receptor profile expressed on human CD8 T cells. Surprisingly, we found that CXC chemokine receptor 1 (CXCR1), the predominant neutrophil chemokine receptor, defined a novel interleukin-8/CXC ligand 8 (IL-8/CXCL8)–responsive CD8 T-cell subset that was enriched in perforin, granzyme B, and interferon-γ (IFNγ), and had high cytotoxic potential. CXCR1 expression was down-regulated by antigen stimulation both in vitro and in vivo, suggesting antigen-dependent shaping of the migratory characteristics of CD8 T cells. On virus-specific CD8 T cells from persons with a history of Epstein-Barr virus (EBV) and influenza infection, CXCR1 expression was restricted to terminally differentiated effector memory cells. In HIV-1 infection, CXCR1-expressing HIV-1–specific CD8 T cells were present only in persons who were able to control HIV-1 replication during structured treatment interruptions. Thus, CXCR1 identifies a subset of CD8 T cells poised for immediate cytotoxicity and early recruitment into sites of innate immune system activation.

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Quantitative analysis of the interactions between HIV-1 integrase and retroviral reverse transcriptases

Biochemical Journal ◽

10.1042/bj20071279 ◽

2008 ◽

Vol 412 (1) ◽

pp. 163-170 ◽

Cited By ~ 21

Author(s):

Alon Herschhorn ◽

Iris Oz-Gleenberg ◽

Amnon Hizi

Keyword(s):

Conformational Changes ◽

Protein Interactions ◽

Molecular Mechanisms ◽

Reaction Model ◽

Protein Protein Interactions ◽

Common Site ◽

Leukaemia Virus ◽

Reverse Transcriptases ◽

Interaction Kinetics ◽

Hiv 1

The RT (reverse transcriptase) of HIV-1 interacts with HIV-1 IN (integrase) and inhibits its enzymatic activities. However, the molecular mechanisms underling these interactions are not well understood. In order to study these mechanisms, we have analysed the interactions of HIV-1 IN with HIV-1 RT and with two other related RTs: those of HIV-2 and MLV (murine-leukaemia virus). All three RTs inhibited HIV-1 IN, albeit to a different extent, suggesting a common site of binding that could be slightly modified for each one of the studied RTs. Using surface plasmon resonance technology, which monitors direct protein–protein interactions, we performed kinetic analyses of the binding of HIV-1 IN to these three RTs and observed interesting binding patterns. The interaction of HIV-1 RT with HIV-1 IN was unique and followed a two-state reaction model. According to this model, the initial IN–RT complex formation was followed by a conformational change in the complex that led to an elevation of the total affinity between these two proteins. In contrast, HIV-2 and MLV RTs interacted with IN in a simple bi-molecular manner, without any apparent secondary conformational changes. Interestingly, HIV-1 and HIV-2 RTs were the most efficient inhibitors of HIV-1 IN activity, whereas HIV-1 and MLV RTs showed the highest affinity towards HIV-1 IN. These modes of direct protein interactions, along with the apparent rate constants calculated and the correlations of the interaction kinetics with the capacity of the RTs to inhibit IN activities, are all discussed.

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Early Pro-Inflammatory Signal and T-Cell Activation Associate With Vaccine-Induced Anti-Vaccinia Protective Neutralizing Antibodies

Frontiers in Immunology ◽

10.3389/fimmu.2021.737487 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jue Hou ◽

Shuhui Wang ◽

Dan Li ◽

Lindsay N. Carpp ◽

Tong Zhang ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Neutralizing Antibodies ◽

Cell Activation ◽

Molecular Mechanisms ◽

Neutralizing Antibody ◽

Activator Protein 1 ◽

Successful Vaccine ◽

Hiv 1 ◽

Core Genes

Both vaccine “take” and neutralizing antibody (nAb) titer are historical correlates for vaccine-induced protection from smallpox. We analyzed a subset of samples from a phase 2a trial of three DNA/HIV-1 primes and a recombinant Tiantan vaccinia virus-vectored (rTV)/HIV-1 booster and found that a proportion of participants showed no anti-vaccinia nAb response to the rTV/HIV-1 booster, despite successful vaccine “take.” Using a rich transcriptomic and vaccinia-specific immunological dataset with fine kinetic sampling, we investigated the molecular mechanisms underlying nAb response. Blood transcription module analysis revealed the downregulation of the activator protein 1 (AP-1) pathway in responders, but not in non-responders, and the upregulation of T-cell activation in responders. Furthermore, transcriptional factor network reconstruction revealed the upregulation of AP-1 core genes at hour 4 and day 1 post-rTV/HIV-1 vaccination, followed by a downregulation from day 3 until day 28 in responders. In contrast, AP-1 core and pro-inflammatory genes were upregulated on day 7 in non-responders. We speculate that persistent pro-inflammatory signaling early post-rTV/HIV-1 vaccination inhibits the nAb response.

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