Article

Attachment and Fusion Inhibitors Potently Prevent Dendritic Cell-Driven HIV Infection

Center for Biomedical Research, Population Council, New York, NY 10065, USA.
JAIDS Journal of Acquired Immune Deficiency Syndromes (Impact Factor: 4.39). 11/2010; 56(3):204-12. DOI: 10.1097/QAI.0b013e3181ff2aa5
Source: PubMed

ABSTRACT Dendritic cells (DCs) efficiently transfer captured (trans) or de novo-produced (cis) virus to CD4 T cells. Using monocyte-derived DCs, we evaluated entry inhibitors targeting HIV envelope (BMS-C, T-1249) or CCR5 (CMPD167) for their potency to prevent DC infection, DC-driven infection in T cells in trans and cis, and direct infection of DC-T-cell mixtures. Immature DC-T-cell cultures with distinct mechanisms of viral transfer yielded similar levels of infection and produced more proviral DNA compared with matched mature DC-T-cell cultures or infected immature DCs. Although all compounds completely blocked HIV replication, 16 times more of each inhibitor (250 vs 15.6 nM) was required to prevent low-level infection of DCs compared with the productive DC-T-cell cocultures. Across all cell systems tested, BMS-C blocked infection most potently. BMS-C was significantly more effective than CMPD167 at preventing DC infection. In fact, low doses of CMPD167 significantly enhanced DC infection. Elevated levels of CCL4 were observed when immature DCs were cultured with CMPD167. Viral entry inhibitors did not interfere with Candida albicans-specific DC cytokine/chemokine responses. These findings indicate that an envelope-binding small molecule is a promising tool for topical microbicide design to prevent the infection of early targets needed to establish and disseminate HIV infection.

0 Followers
 · 
94 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cells and their subsets are among the very first immune cells to tackle incoming pathogens and initiate innate and adaptive immune responses. During the past year, some studies investigating the early events occurring at mucosal sites, upon HIV infection, reinforced our view that the virus has evolved subtle strategies to hijack key cellular components in dendritic cells, thus leading to viral acquisition and dissemination while dampening or delaying antiviral responses. In this review, we will detail recent research aimed at investigating the involvement of different dendritic cell subtypes on HIV transmission at mucosal sites, the events and cellular factors in dendritic cell guiding HIV trafficking, and polarization at the virological synapse. Furthermore, we will link some of these basic findings with current and novel therapeutic and prophylactic strategies targeting the early events of mucosal HIV transmission. It is becoming evident that a better characterization of the early events of HIV transmission and the involvement of dendritic cell subtypes in this process would contribute to strengthen our efforts to improve the current therapeutic and prophylactic strategies.
    Current opinion in HIV and AIDS 09/2011; 6(5):391-7. DOI:10.1097/COH.0b013e328349b0a0 · 4.39 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Topical blockade of the gp41 fusogenic protein of HIV-1 is one possible strategy by which microbicides could prevent HIV transmission, working early against infection, by inhibiting viral entry into host cells. In this study, we examined the potential of gp41 fusion inhibitors (FIs) as candidate anti-HIV microbicides. Preclinical evaluation of four FIs, C34, T20, T1249, and L'644, was performed using cellular and ex vivo genital and colorectal tissue explant models. Increased and sustained activity was detected for L'644, a cholesterol-derivatized version of C34, relative to the other FIs. The higher potency of L'644 was further increased with sustained exposure of cells or tissue to the compound. The activity of L'644 was not affected by biological fluids, and the compound was still active when tissue explants were treated after viral exposure. L'644 was also more active than other FIs against a viral escape mutant resistant to reverse transcriptase inhibitors (RTIs), demonstrating the potential of L'644 to be included as part of a multiactive antiretroviral (ARV) combination-based microbicide. These data support the further development of L'644 for microbicide application.
    Antimicrobial Agents and Chemotherapy 02/2012; 56(5):2347-56. DOI:10.1128/AAC.06108-11 · 4.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a novel small-molecule attachment inhibitor that targets HIV-1 gp120 and prevents its binding to CD4(+) T cells. The activity of BMS-626529 is virus dependent, due to heterogeneity within gp120. In order to better understand the anti-HIV-1 spectrum of BMS-626529 against HIV-1, in vitro activities against a wide variety of laboratory strains and clinical isolates were determined. BMS-626529 had half-maximal effective concentration (EC(50)) values of <10 nM against the vast majority of viral isolates; however, susceptibility varied by >6 log(10), with half-maximal effective concentration values in the low pM range against the most susceptible viruses. The in vitro antiviral activity of BMS-626529 was generally not associated with either tropism or subtype, with few exceptions. Measurement of the binding affinity of BMS-626529 for purified gp120 suggests that a contributory factor to its inhibitory potency may be a relatively long dissociative half-life. Finally, in two-drug combination studies, BMS-626529 demonstrated additive or synergistic interactions with antiretroviral drugs of different mechanistic classes. These results suggest that BMS-626529 should be active against the majority of HIV-1 viruses and support the continued clinical development of the compound.
    Antimicrobial Agents and Chemotherapy 04/2012; 56(7):3498-507. DOI:10.1128/AAC.00426-12 · 4.45 Impact Factor
Show more

Preview

Download
2 Downloads
Available from