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1277 Results
Background Despite the efficient suppression of HIV-1 replication with combined antiretroviral therapy, viral latency is a barrier to HIV cure. Bispecific antibodies against Env and CD3 have resulted in the ex vivo killing of HIV-containing cells from PLWH. However, the low level of Env expression on the cell surface and the sequence variation in the…
Background Natural killer (NK) cells respond rapidly in early HIV-1 infection. HIV-1 suppression and functional cure strategies can be developed by exploiting the intrinsic function of NK cells in recognizing HIV-infected cells. In our previous work, we profiled the phenotype of human primary NK cells responsive to autologous HIV-1-infected CD4+ T cells in vitro. We…
Background Latency-reversing agents (LRAs) have shown promise in reactivating HIV reservoir within “shock and kill”approaches. However, molecular mechanisms underlying HIV reactivation within CD4+ T cells as well as predictors of LRA efficacy remain partially unknown. Here, we investigated the transcriptomic and whole genome DNA methylation profile of CD4+ T cells cultured in vitro with or…
Background HIV-1 persists despite effective ART due to a reservoir of latently infected CD4+ T cells. Previous studies suggest that intact proviruses integrated in heterochromatic regions are progressively enriched during long-term ART. These proviruses may evade immune recognition due to lower viral gene expression, but their clinical significance upon ART interruption is unclear. Given the…
Background CRISPR-Cas9 excision of the HIV genome is a promising strategy for an HIV cure. However, epigenetic features, including DNA methylation at the HIV integration site, may impede anti-HIV gene editing. In this study, we investigated the impact of an FDA-approved DNA methyltransferase inhibitor, 5-Aza-2′-deoxycytidine, on genome demethylation and provirus reactivation in latently infected CD4+…
Background Following recent successes using chimeric antigen receptor (CAR) T cells for various cancer and autoimmune indications, there has been renewed interest in using CAR T cells to target the reservoir of HIV-infected cells. We have previously shown that CRISPR/Cas9 targeting of CAR constructs to the TCRa constant (TRAC) locus enables physiologic expression of the…
Background Despite effective HIV suppression by ART, the virus persists in latent reservoirs. Our single-cell data from human and primate studies show that individuals with better HIV control and smaller reservoirs have higher interferon stimulated gene (ISG) expression in CD4+ T cells, linked to greater chromatin accessibility and transcriptional activation. ISG expression could be induced…
Background Cyclic adenosine 3′,5′-monophosphate (cAMP) is a secondary messenger involved in the regulation of diverse cellular, metabolic, and immunologic processes. Ex vivo and in vitro studies have shown that cAMP levels are elevated in the setting of HIV infection, with T cells from PLWH harboring twice the cAMP level as uninfected individuals. In our previous…
Background Antiretroviral therapy (ART) is not a cure for HIV-1 infection due to the formation of latent reservoirs. Most long-lived viral reservoir cells are infected by the virus near the time of therapy initiation. A better understanding of the early events in viral reservoir seeding may help prevent latent reservoir formation. Unlike quiescent reservoir cells, CD4+CCR5+ T…
Background Insights gained from successfully treated individuals demonstrate that a definite HIV cure must purge the replication-competent HIV reservoir, whilst making CD4+ cells resistant to HIV reinfection. Due to its versatility, the CRISPR-Cas9 genome editing tool holds great potential to eliminate latent proviral DNA and mutate the viral co-receptor CCR5. Still, its safety and effectiveness…