To determine the protective potential of the humoral immune response against HIV-1 in vivo we evaluated the potency of three neutralizing antibodies (2G12, 2F5 and 4E10) in suppressing viral rebound in six acutely and eight chronically HIV-1-infected individuals undergoing interruption of antiretroviral treatment (ART). Only two of eight chronically infected individuals showed evidence of a delay in viral rebound during the passive immunization. Rebound in antibody-treated acutely infected individuals upon cessation of ART was substantially later than in a control group of 12 individuals with acute infection. Escape mutant analysis showed that the activity of 2G12 was crucial for the in vivo effect of the neutralizing antibody cocktail. By providing further direct evidence of the potency, breadth and titers of neutralizing antibodies that are required for in vivo activity, these data underline both the potential and the limits of humoral immunity in controlling HIV-1 infection.

BackgroundTo explore the possibility that antibody-mediated complement lysis contributes to viremia control in HIV-1 infection, we measured the activity of patient plasma in mediating complement lysis of autologous primary virus.Methods and FindingsSera from two groups of patients—25 with acute HIV-1 infection and 31 with chronic infection—were used in this study. We developed a novel real-time PCR-based assay strategy that allows reliable and sensitive quantification of virus lysis by complement. Plasma derived at the time of virus isolation induced complement lysis of the autologous virus isolate in the majority of patients. Overall lysis activity against the autologous virus and the heterologous primary virus strain JR-FL was higher at chronic disease stages than during the acute phase. Most strikingly, we found that plasma virus load levels during the acute but not the chronic infection phase correlated inversely with the autologous complement lysis activity. Antibody reactivity to the envelope (Env) proteins gp120 and gp41 were positively correlated with the lysis activity against JR-FL, indicating that anti-Env responses mediated complement lysis. Neutralization and complement lysis activity against autologous viruses were not associated, suggesting that complement lysis is predominantly caused by non-neutralizing antibodies.ConclusionsCollectively our data provide evidence that antibody-mediated complement virion lysis develops rapidly and is effective early in the course of infection; thus it should be considered a parameter that, in concert with other immune functions, steers viremia control in vivo.

The CC-chemokine RANTES (regulated on activation normal T-cell expressed and secreted; CCL5) transduces multiple intracellular signals. Like all chemokines, it stimulates G protein-coupled receptor (GPCR) activity through interaction with its cognate chemokine receptor(s), but in addition also activates a GPCR-independent signaling pathway. Here, we show that the latter pathway is mediated by an interaction between RANTES and glycosaminoglycan chains of CD44. We provide evidence that this association, at both low, physiologically relevant, and higher, probably supraphysiologic concentrations of RANTES, induces the formation of a signaling complex composed of CD44, src kinases, and adapter molecules. This triggers the activation of the p44/42 mitogen-activated protein kinase (MAPK) pathway. By specifically reducing CD44 expression using RNA interference we were able to demonstrate that the p44/p42 MAPK activation by RANTES requires a high level of CD44 expression. As well as potently inhibiting the entry of CCR5 using HIV-1 strains, RANTES can enhance HIV-1 infectivity under certain experimental conditions. This enhancement process depends in part on the activation of p44/p42 MAPK. Here we show that silencing of CD44 in HeLa-CD4 cells prevents the activation of p44/p42 MAPK and leads to a substantial reduction in HIV IntroductionThe chemokine RANTES (regulated on activation normal T-cell expressed and secreted; CCL5) is a member of the CC-chemokine family, a group of small proteins with a highly conserved tertiary. 1,2 Chemokines recruit and activate specific leukocyte populations. Multiple chemokine receptors with partially overlapping specificities for ligand binding have been described, suggesting a possible redundancy of the system. However, an increased selectivity of the action of chemokines is thought to be gained through their ability to discern and preferentially bind to certain glycosaminoglycan (GAG) subpopulations, a process considered important in mediating tissue-specific leukocyte recruitment. [3][4][5][6] The chemokine RANTES has a complex influence on the biology of a variety of cell types including T lymphocytes, monocytes, natural killer cells, dendritic cells, basophils, and eosinophils. 7,8 At nanomolar concentrations, RANTES binds to and activates several 7-transmembrane G protein-coupled receptors (GPCRs), namely the chemokine receptors CCR1, CCR3, and CCR5. Ligation of these receptors activates a heterotrimeric G␣i protein-coupled signaling pathway, characterized by a transient Ca 2ϩ influx, 7,9 and triggers activation of cell polarization and chemotaxis. 10 In addition to these classic chemokine-activated responses, RANTES also induces several biochemical and biologic effects that are to date unique to this chemokine and that are triggered through a GPCR-independent pathway. Induction of this pathway is mediated by protein tyrosine kinases (PTKs), occurs at high micromolar concentrations of the chemokine, and leads to a sustained influx of Ca 2ϩ . 9 We and others have previously demonstr...

Recently, passive immunization of human immunodeficiency virus (HIV)-