HIV co-receptor-tropism: cellular and molecular events behind the enigmatic co-receptor switching.

Recognition of cell-surface receptors and co-receptors is a crucial molecular event towards the establishment of HIV infection. HIV exists as several variants that differentially recognize the principal co-receptors, CCR5 and CXCR4, in different cell types, known as HIV co-receptor-tropism. The relative levels of these variants dynamically adjust to the changing host selection pressures to infect a vast repertoire of cells in a stage-specific manner. HIV infection sets in through immune cells such as dendritic cells, macrophages, and T-lymphocytes in the acute stage, while a wide range of other cells, including astrocytes, glial cells, B-lymphocytes, and epithelial cells, are infected during chronic stages. A change in tropism occurs during the transition from acute to a chronic phase, termed as co-receptor switching marked by a change in disease severity. The cellular and molecular events leading to co-receptor switching are poorly understood. This review aims to collate our present understanding of the dynamics of HIV co-receptor-tropism vis-à-vis host and viral factors, highlighting the cellular and molecular events involved therein. We present the possible correlations between virus entry, cell tropism, and co-receptor switching, speculating its consequences on disease progression, and proposing new scientific pursuits to help in an in-depth understanding of HIV biology.

Confronting Tuberculosis: A Synthetic Quinoline-Isonicotinic Acid Hydrazide Hybrid Compound as a Potent Lead Molecule Against Mycobacterium tuberculosis.

The current tuberculosis (TB) treatment is challenged by a complex first-line treatment for drug-sensitive (DS) TB. Additionally, the prevalence of multidrug (MDR)- and extensively drug (XDR)-resistant TB necessitates the search for new drug prototypes. We synthesized and screened 30 hybrid compounds containing aminopyridine and 2-chloro-3-formyl quinoline to arrive at a compound with potent antimycobacterial activity, UH-NIP-16. Subsequently, antimycobacterial activity against DS and MDR Mycobacterium tuberculosis (M.tb) strains were performed. It demonstrated an MIC50 value of 1.86 ± 0.21 µM for laboratory pathogenic M.tb strain H37Rv and 3.045 ± 0.813 µM for a clinical M.tb strain CDC1551. UH-NIP-16 also decreased the MIC50 values of streptomycin, isoniazid, ethambutol, and bedaquiline to about 45, 55, 68, and 76%, respectively, when used in combination, potentiating their activities. The molecule was active against a clinical MDR M.tb strain. Cytotoxicity on PBMCs from healthy donors and on human cell lines was found to be negligible. Further, blind docking of UH-NIP-16 using Auto Dock Vina and MGL tools onto diverse M.tb proteins showed high binding affinities with multiple M.tb proteins, the top five targets being metabolically critical proteins CelA1, DevS, MmaA4, lysine acetyltransferase, and immunity factor for tuberculosis necrotizing toxin. These bindings were confirmed by fluorescence spectroscopy using a representative protein, MmaA4. Envisaging that a pathogen will have a lower probability of developing resistance to a hybrid molecule with multiple targets, we propose that UH-NIP-16 can be further developed as a lead molecule with the bacteriostatic potential against M.tb, both alone and in combination with first-line drugs.

Mycobacterial Control of Host Mitochondria: Bioenergetic and Metabolic Changes Shaping Cell Fate and Infection Outcome.

Mitochondria, are undoubtedly critical organelle of a eukaryotic cell, which provide energy and offer a platform for most of the cellular signaling pathways that decide cell fate. The role of mitochondria in immune-metabolism is now emerging as a crucial process governing several pathological states, including infection, cancer, and diabetes. Mitochondria have therefore been a vulnerable target for several bacterial and viral pathogens to control host machinery for their survival, replication, and dissemination. Mycobacterium tuberculosis, a highly successful human pathogen, persists inside alveolar macrophages at the primary infection site, applying several strategies to circumvent macrophage defenses, including control of host mitochondria. The infection perse and specific mycobacterial factors that enter the host mitochondrial milieu perturb mitochondrial dynamics and function by disturbing mitochondrial membrane potential, shifting bioenergetics parameters such as ATP and ROS, orienting the host cell fate and thereby infection outcome. In the present review, we attempt to integrate the available information and emerging dogmas to get a holistic view of Mycobacterium tuberculosis infection vis-a-vis mycobacterial factors that target host mitochondria and changes therein in terms of morphology, dynamics, proteomic, and bioenergetic alterations that lead to a differential cell fate and immune response determining the disease outcome. We also discuss critical host factors and processes that are overturned by Mycobacterium tuberculosis, such as cAMP-mediated signaling, redox homeostasis, and lipid droplet formation. Further, we also present alternate dogmas as well as the gaps and limitations in understanding some of the present research areas, which can be further explored by understanding some critical processes during Mycobacterium tuberculosis infection and the reasons thereof. Toward the end, we propose to have a set of guidelines for pursuing investigations to maintain uniformity in terms of early and late phase, MOI of infection, infection duration and incubation periods, the strain of mycobacteria, passage numbers, and so on, which all work as probable variables toward different readouts. Such a setup would, therefore, help in the smooth integration of information across laboratories toward a better understanding of the disease and possibilities of host-directed therapy.