Some long-term survivors of HIV infection produce rare and extremely potent antibodies that keep the disease from progressing to AIDS, and might point to a way to protect uninfected people from the virus, researchers reported yesterday in the closing hours of the 17th International AIDS Conference in Mexico City. The antibodies, against a particular part of a much-studied HIV protein called gp120, might prove useful as a microbicide for blocking infection during sexual intercourse. If researchers could find a way to prompt the immune system to make its own supply of the antibodies before encountering the virus, they would have a vaccine.

The CCR5 co-receptor binds to the HIV-1 gp120 envelope glycoprotein and facilitates HIV-1 entry into cells. Its N terminus is tyrosine-sulfated, as are many antibodies that react with the co-receptor binding site on gp120. We applied nuclear magnetic resonance and crystallographic techniques to analyze the structure of the CCR5 N terminus and that of the tyrosine-sulfated antibody 412d in complex with gp120 and CD4. The conformations of tyrosine-sulfated regions of CCR5 ({alpha}-helix) and 412d (extended loop) are surprisingly different. Nonetheless, a critical sulfotyrosine on CCR5 and on 412d induces similar structural rearrangements in gp120. These results now provide a framework for understanding HIV-1 interactions with the CCR5 N terminus during viral entry and define a conserved site on gp120, whose recognition of sulfotyrosine engenders posttranslational mimicry by the immune system.

Human immunodeficiency virus (HIV)-1 infection requires envelope (Env) glycoprotein gp120-induced clustering of CD4 and coreceptors (CCR5 or CXCR4) on the cell surface; this enables Env gp41 activation and formation of a complex that mediates fusion between Env-containing and target-cell membranes1. Kinetic studies show that viral receptors are actively transported to the Env-receptor interface in a process that depends on plasma membrane composition and the actin cytoskeleton2, 3, 4, 5, 6, 7. The mechanisms by which HIV-1 induces F-actin rearrangement in the target cell remain largely unknown. Here, we show that CD4 and the coreceptors interact with the actin-binding protein filamin-A, whose binding to HIV-1 receptors regulates their clustering on the cell surface. We found that gp120 binding to cell receptors induces transient cofilin-phosphorylation inactivation through a RhoA–ROCK-dependent mechanism. Blockade of filamin-A interaction with CD4 and/or coreceptors inhibits gp120-induced RhoA activation and cofilin inactivation. Our results thus identify filamin-A as an adaptor protein that links HIV-1 receptors to the actin cytoskeleton remodelling machinery, which may facilitate virus infection.

A weak spot in HIV that leaves it vulnerable to antibody attack has been identified and mapped, paving the way for a potential vaccine. Researchers at the US National Institute of Allergy and Infectious Diseases (NIAID) found that, despite HIV's known ability to mutate, some surfaces of the virus must remain unchanged for it to bind to the host cell. Their findings are published in Nature today (15 February).

In a finding that could have profound implications for AIDS vaccine design, researchers led by a team at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), have generated an atomic-level picture of a key portion of an HIV surface protein as it looks when bound to an infection-fighting antibody. Unlike much of the constantly mutating virus, this protein component is stable and — more importantly, say the researchers — appears vulnerable to attack from this specific antibody, known as b12, that can broadly neutralize HIV.

Scientists have shown what happens when an infection-fighting antibody attacks a gap in HIV's formidable defences. The National Institute of Allergy and Infectious Diseases-led team say the work could aid HIV vaccine development. They have published an atomic-level image in Nature showing the antibody, b12, attacking part of a protein on surface of the virus.

The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 Å resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.