HIV-1 Tat Promotes Integrin-Mediated HIV Transmission to Dendritic Cells by Binding Env Spikes and Competes Neutralization by Anti-HIV Antibodies

Abstract

Use of Env in HIV vaccine development has been disappointing. Here we show that, in the presence of a biologically active Tat subunit vaccine, a trimeric Env protein prevents in monkeys virus spread from the portal of entry to regional lymph nodes. This appears to be due to specific interactions between Tat and Env spikes that form a novel virus entry complex favoring R5 or X4 virus entry and productive infection of dendritic cells (DCs) via an integrin-mediated pathway. These Tat effects do not require Tat-transactivation activity and are blocked by anti-integrin antibodies (Abs). Productive DC infection promoted by Tat is associated with a highly efficient virus transmission to T cells. In the Tat/Env complex the cysteine-rich region of Tat engages the Env V3 loop, whereas the Tat RGD sequence remains free and directs the virus to integrins present on DCs. V2 loop deletion, which unshields the CCR5 binding region of Env, increases Tat/Env complex stability. Of note, binding of Tat to Env abolishes neutralization of Env entry or infection of DCs by anti-HIV sera lacking anti-Tat Abs, which are seldom present in natural infection. This is reversed, and neutralization further enhanced, by HIV sera containing anti-Tat Abs such as those from asymptomatic or Tat-vaccinated patients, or by sera from the Tat/Env vaccinated monkeys. Thus, both anti-Tat and anti-Env Abs are required for efficient HIV neutralization. These data suggest that the Tat/Env interaction increases HIV acquisition and spreading, as a mechanism evolved by the virus to escape anti-Env neutralizing Abs. This may explain the low effectiveness of Env-based vaccines, which are also unlikely to elicit Abs against new Env epitopes exposed by the Tat/Env interaction. As Tat also binds Envs from different clades, new vaccine strategies should exploit the Tat/Env interaction for both preventative and therapeutic interventions.

Novel Biopanning Strategy To Identify Epitopes Associated with Vaccine Protection

“…Since the virus challenges alone, without preceding immunization, could not induce detectable anti-Tat responses, we suggest that the Tat immunogen had primed Ab responses in RRi-11, undetectable with our phage ELISAs, which were then boosted by Tat present in the virus stock. Recently, Monini et al (69) described potential mechanisms, which parallel our own observations described above. First, Monini et al (69) showed that extracellular HIV-1 Tat can form a molecular complex with trimeric Env, which provides a possible explanation for Tat being present in the virus stock and boosting preexisting anti-Tat Ab responses even in the absence of systemic infection.…”

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

“…Regarding the GP120-Tat interaction domains, molecular docking analyses suggest that the CD4-binding site and the V3 loop of GP120 may interact with the cysteine-rich domain of Tat (87,88). Other studies have also proposed the binding of the V1/V2 loop of GP120 to the second exon of Tat (86,89) (Fig.…”

“…HIV-1 Tat can physically interact with GP120, an interaction detected by isothermal titration calorimetry, pulldown assays, ELISAs, electron cryomicroscopy, and surface plasmon resonance analyses (86)(87)(88)(89). Although Tat is dispensable for viral entry, the binding of Tat to GP120 contributes to efficient viral entry (86), and Tat-mediated viral entry promotes the infection of monocytederived dendritic cells (88).…”

“…Although Tat is dispensable for viral entry, the binding of Tat to GP120 contributes to efficient viral entry (86), and Tat-mediated viral entry promotes the infection of monocytederived dendritic cells (88). After HIV-infected cells release Tat to the extracellular space (86,90), the GP120-Tat interaction undertakes multiple activities.…”

“…After HIV-infected cells release Tat to the extracellular space (86,90), the GP120-Tat interaction undertakes multiple activities. (i) Extracellular Tat binds to Env spikes, a process which blocks the recognition of anti-Env antibodies, allowing HIV to escape from Env neutralization (88). Furthermore, extracellular Tat interacts with chemokine receptors (e.g., CCR2 and CCR3) to recruit chemokine receptor-expressing monocytes and macrophages toward HIV-infected cells (91).…”