Biology subjects

Turk, G.

Publications and source records attributed to Turk, G..

3 recordsLinked to original sources

bioRxiv2025

The tuberculosis-associated microenvironment promotes HIV-1 persistence by impairing CD8+ T cell-mediated viral control

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the most common coinfection in people living with HIV-1 (PLWH). This coinfection is associated with accelerated HIV-1 disease progression and reduced survival. However, the immunological and virological mechanisms driving this progression are incompletely understood. To address this knowledge gap, using pleural effusion samples from PLWH and TB, we investigated the HIV-1 genetic landscape and the anti-HIV-1 immune response impacted by a TB-associated microenvironment. Our results revealed an enrichment of genetically intact HIV-1 and impaired CD8+ T cell-mediated antiviral response at the site of HIV-1/Mtb coinfection. These findings indicate that the TB-associated microenvironment promotes the persistence of cells infected with replication-competent HIV-1 by creating a niche of reduced antiviral immune pressure, potentially contributing to the worsened clinical outcomes observed in PLWH and TB.

immunology↗

bioRxiv2024

CD4+ T cells facilitate replication of primary HIV-1 strains in macrophages and formation of macrophage internal virus-containing compartments.

HIV-1 infects CD4+ T cells and macrophages. However, replication of HIV-1 in these cell types is highly variable and may depend on the use of CCR5 as a co-receptor. In addition, there is internal accumulation of infectious HIV-1 in so-called virus-containing compartments of macrophages (VCCs). VCCs are thought to represent a persistent viral reservoir that is shielded from the antiviral immune response. To date, VCC formation has only been studied in lab-adapted HIV-1 and it is unknown whether VCCs play a role in the replication of primary HIV-1 strains. Furthermore, although macrophages transmit HIV-1 from VCCs to CD4+ T cells, it is unknown whether T cells have an impact on VCC formation. We analyzed the ability of primary and lab-adapted HIV-1 to replicate in macrophages, the effect of coculture with non-infected CD4+ T cells and the extent of VCC formation. Although differentially, all HIV-1 strains replicated in CD4+ T cells, whereas only lab-adapted HIV-1 replicated in macrophages. Strikingly, replication of patient-derived HIV-1 in macrophages was enhanced by coculture with non-infected CD4+ T cells and correlated with VCC formation. In conclusion, non-infected CD4+ T cells facilitate the replication of primary HIV-1 strains in macrophages and the formation of VCCs appears to be a proxy for this phenotype. Our study suggests an essential role for VCCs in the replication of patient-derived HIV-1 in macrophages, which is fueled by non-infected CD4+ T cells. Furthermore, our findings call for strategies to specifically disrupt VCC formation in order to eliminate the HIV-1 reservoir in macrophages. IMPORTANCEHere we focus on the intimate interplay between HIV-1 infected macrophages and CD4+ T cells. Specifically, we analyzed whether primary HIV-1 strains induce virus-containing compartments (VCCs) within macrophages, which are thought to serve as viral sanctuaries and macrophage reservoirs. Notably, primary HIV-1 strains were unable to replicate in macrophages and induce VCCs unless they were cocultured with non-infected CD4+ T cells, leading to increased VCC formation and viral replication. This suggests an essential role for non-infected CD4+ T cells in facilitating primary HIV-1 replication in macrophages. Our data highlight the importance of not only targeting the latent HIV-1 T-cell reservoir, but also targeting VCC formation in macrophages to achieve the ultimate goal of functional HIV-1 cure.

microbiology↗

bioRxiv2023

The immunosuppressive Tuberculosis-associated microenvironment inhibits viral replication and promotes HIV-1 latency in CD4+ T cells

Author SummaryMycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the most common coinfection among people living with HIV-1. This coinfection alters the efficacy of the immune response against both HIV-1 and Mtb, and is associated with accelerated HIV-1 disease progression and reduced survival. Enhanced HIV-1 replication in macrophages induced by Mtb coinfection may contribute to the worsened clinical outcomes observed in HIV-1/TB coinfected individuals. However, the impact of the HIV-1/TB coinfection on HIV-1 replication and latency in CD4+ T cells remains poorly studied. In this study, we used the acellular fraction of tuberculous pleural effusion (TB-PE) as a proxy for the microenvironment generated by Mtb infection. Using this physiologically relevant fluid, we investigated whether viral replication and HIV-1 latency in CD4+ T cells are affected by a TB-associated microenvironment. Interestingly, our results revealed that TB-PE shaped the transcriptional profile of CD4+ T cells impairing T cell receptor-dependent cell activation and decreased HIV-1 replication. Moreover, this immunosuppressive TB microenvironment promoted viral latency and inhibited HIV-1 reactivation in CD4+ T cells from people living with HIV-1. This study indicates that the immune response induced by TB may contribute to the persistence of the viral reservoir by silencing HIV-1 expression in individuals coinfected with both pathogens, allowing the virus to persist undetected by the immune system and increasing the size of the HIV-1 latent reservoir in cells at the site of the coinfection.

pathology↗