HIV elite controllers are able to control HIV-1 infection spontaneously to undetectable levels in the absence of antiretroviral therapy, but the mechanisms leading to this phenotype are poorly understood. Although, low frequencies of HIV infected peripheral CD4+ T-cells have been reported in this group, it remains unclear to what extent this is due to viral attenuation, active immune containment, or intracellular host factors that restrict virus replication. Here we assessed proviral DNA levels, autologous viral growth from and infectability of in-vitro activated, CD8+ T-cell depleted CD4+ T cells from HIV elite controllers (mean VL<50cp/ml), viremic controllers (mean VL<2000cp/ml), chronic progressors and HAART treated individuals. Although we successfully detected autologous virus production in ex-vivo activated CD4+ T-cells from all chronic progressors and most of the viremic controllers we were only able to measure robust autologous viral replication in only 2 of 14 elite controllers subjected to the same protocol. In vitro activated autologous CD4+ T-cells from elite controllers, however, supported infection with both X4 and R5 tropic HIV strains at comparable levels to CD4+ T-cells from HIV negative subjects. Proviral DNA levels were the lowest in elite controllers, suggesting that extremely low frequencies of infected cells contributes to difficulty in isolation of virus. These data indicate that elite control is not due to inability of activated CD4+ T-cells to support HIV infection, but the relative contribution of host and viral factors that account for maintenance of low level infection remain to be determined.
Viral envelope proteins are required for productive viral entry and initiation of infection. Although the humoral immune system provides ample evidence for targeting envelope proteins as an antiviral strategy, there are few pharmacological interventions that have this mode of action. In contrast to classical antiviral targets such as viral proteases and polymerases, viral envelope proteins as a class do not have a well-conserved active site that can be rationally targeted with small molecules. We previously identified compounds that inhibit dengue virus by binding to its envelope protein, E. Here, we show that these small molecules inhibit dengue virus fusion and map the binding site of these compounds to a specific pocket on E. We further demonstrate inhibition of Zika, West Nile, and Japanese encephalitis viruses by these compounds, providing pharmacological evidence for the pocket as a target for developing broad-spectrum antivirals against multiple, mosquito-borne flavivirus pathogens.
Summary
Dengue virus infects over 300 million people annually, yet there is no widely protective vaccine or drugs against the virus. Efforts to develop antivirals against classical targets such as the viral protease and polymerase have not yielded drugs that have advanced to the clinic. Here we show that the allosteric Abl kinase inhibitor GNF-2 interferes with dengue virus replication via activity mediated by cellular Abl kinases but additionally blocks viral entry via an Abl-independent mechanism. To characterize this newly discovered antiviral activity, we developed disubstituted pyrimidines that block dengue virus entry with structure-activity relationships distinct from those driving kinase inhibition. We demonstrate that biotin- and fluorophore-conjugated derivatives of GNF-2 interact with the dengue glycoprotein, E, in the prefusion conformation that exists on the virion surface and that this interaction inhibits viral entry. This study establishes GNF-2 as an antiviral compound with polypharmacological activity and provides ‘lead’ compounds for further optimization efforts.
The immune correlates of protection in human immunodeficiency virus type 1 (HIV-1) infection remain poorly defined, particularly the contribution of CD4 ؉ T cells. Here we explore the effector functions of HIV-1-specific CD4 ؉ T cells. We demonstrate HIV-1 p24-specific CD4 ؉ -T-cell cytolytic activity in peripheral blood mononuclear cells directly ex vivo and after enrichment by antigen-specific stimulation. We further show that in a rare long-term nonprogressor, both an HIV-1-specific CD4؉ -T-cell clone and CD4 ؉ T cells directly ex vivo exert potent suppression of HIV-1 replication. Suppression of viral replication was dependent on cell-cell contact between the effector CD4 ؉ T cells and the target cells. While the antiviral effector activity of CD8 ؉ T cells has been well documented, these results strongly suggest that HIV-1-specific CD4 ؉ T cells are capable of directly contributing to antiviral immunity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.