CD4+ memory T cells infected with latent HIV-1 are susceptible to drugs targeting telomeres

Abstract

The population of HIV reservoir in infected person is very small, but extremely long-lived and is a major obstacle for an HIV cure. We previously showed that cells with established HIV latency have deficiencies in DNA damage response (DDR). Here, we investigated ability of HIV-1 to interfere with telomere maintenance, and the effects of targeting telomeres on latently infected cells. Our results show that telomeres are elongated in cultured primary memory CD4 + T cells (T) after HIV-1 infection and when virus latency is established. Similarly, much longer telomeres were found in several Jurkat-derived latently infected cell lines, indicating that virus stimulates telomere elongation. Exposing primary CD4+ T cells to BRACO19, an agent targeting telomeres, resulted in a higher rate of apoptosis for infected cultures at day 3 post-infection, during HIV-1 latency and for PMA-stimulated cultures with low level of HIV-1 reactivation. Importantly, BRACO19 induced apoptosis in infected cells with potency similar to etoposide and camptothecin, whereas uninfected cells were less affected by BRACO19. We also determined that apoptosis induced by BRACO19 is not caused by telomeres shortening, but is related to formation of gamma-H2AX, implicating DNA damage or uncapping of telomeres, which triggers genome instability. In conclusion, our results indicate that HIV-1 stimulates telomere elongation during latency, suggesting that HIV reservoir has greater capacity for clonal expansion and extended lifespan. Higher rates of apoptosis in response to BRACO19 treatment suggest that HIV reservoirs are more susceptible to targeting telomere maintenance and to inhibitors targeting DDR, which is also involved in stabilizing telomeres.

Developing Novel G-Quadruplex Ligands: From Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction

“…B BRACO-19 shows good anti-tumor activities alone or in combination in several human cancers, including anti-tumor activity on human epidermoid carcinoma A431 cells [151], flavopiridol-resistant colorectal cancer HCT-116 cells [154], human uterus carcinoma UXF1138L cells [155], human prostate cancer DU145 cells [156]. Recently, BRACO-19 has been further developed as anti-HIV agents [173,174]. However, the very poor permeability of BRACO19 limits its further development, and further application requires a suitable formulation to ensure adequate delivery across cellular barriers [175].…”

“…In addition, similar acridine derivatives, including bis(quinacridine) macrocycle [174], dibenzophenan-throlines [180,181], mono- and bis-pyrimidinoacridines [182], 4,5-bis(dialkylaminoalkyl)-substituted acridines [183], and 5,6-dihydrobenzo[ c ]acridine [184,185], also showed stabilizing effects on G-quadruplexes and high telomerase inhibitory activity, due to the structural similarity with the G-quartet.…”

HIV-1 infection renders brain vascular pericytes susceptible to the extracellular glutamate

“…1a). Since single-cycle virus cannot produce new viral particles, the reduction in pericytes population could be due to their sensitivity to the expression of viral proteins, and resulted from cell cycle arrest and apoptosis (Badley et al , 2000; Cummins and Badley, 2010; de Silva et al , 2012; Herbein et al , 1998; Piekna-Przybylska and Maggirwar, 2018; Planelles et al , 1995; Tachiwana et al , 2006).…”

“…Infected primary CD4+ T cells undergo increased rate of apoptosis after HIV infection (Piekna-Przybylska and Maggirwar, 2018). The apoptosis is also induced by HIV reactivation in primary memory T cells and in T cell lines even for latent cells established with defective viruses which cannot produce viral particles (Piekna-Przybylska and Maggirwar, 2018). …”

Biomarkers of Activation and Inflammation to Track Disparity in Chronological and Physiological Age of People Living With HIV on Combination Antiretroviral Therapy

“…HIV-infection leads to establishment of viral reservoirs in various anatomical sites of the body, primarily in long-lived CD4+ T cells which persist even in the presence of ART. HIV appears to stimulate telomere elongation in latently infected memory CD4+ T cells which are vulnerable to BRAC019, a telomere-targeting drug that causes uncapping and apoptosis ( 99 ).…”