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November 3, 2014
The Structure and Dynamics of HIV Surface Spikes
At a Glance
- Scientists illuminated the movement and complete structure of the spikes that the HIV virus uses to bind to the cells it infects.
- The findings will help guide efforts to develop HIV vaccines and treatments.
More than 35 million people worldwide are infected with HIV, the virus that causes AIDS. Once in the body, HIV attacks and destroys immune cells, which normally protect the body from infection. Current treatments help to prevent the virus from multiplying. However, scientists haven’t yet designed a vaccine that can protect people from HIV.
A major target for potential HIV vaccines is a spike-shaped virus protein known as Env. Env extends from the surface of the HIV virus particle. The protein is “trimeric”—with 3 cap-like subunits called glycoprotein 120 (gp120) and 3 stem-like subunits called glycoprotein 41 (gp41) that anchor Env in the viral membrane. Env adopts different shapes before and after the virus fuses with a cell. In its closed, pre-fusion state, Env can evade immune system attack. Antibodies to this closed state have been found, but designing an effective vaccine that prompts the immune system to generate such antibodies has been a challenge.
The atomic-level structures of pre-fusion gp120 and post-fusion gp120 and gp41 had previously been determined. However, the structural rearrangement of gp41 from pre-fusion to post-fusion is what drives membrane fusion between HIV and its target cell. In 2 papers published online on October 8, 2014, researchers illuminated the movement and complete structure of Env, including the pre-fusion gp41 structure. The work was supported in part by NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of General Medical Sciences (NIGMS).
In Nature, an NIAID-based team described the atomic-level structure of the entire pre-fusion Env trimer. Their study revealed the pre-fusion configuration of gp41 and detailed the rearrangements needed for Env to fuse with target cells. The constant, functional portions of Env remain protected by an exterior with regions that mutate rapidly. The protein surface is also covered by a coat of sugar molecules that help shield Env from the immune system. The structure revealed exactly where neutralizing antibodies succeed in recognizing the HIV spike. This information will be crucial for future vaccine development.
In Science, a team based at Weill Cornell Medical College and the Yale University School of Medicine described the use of a sophisticated technique called single-molecule fluorescence resonance energy transfer (smFRET) to study prefusion Env. They showed that the unbound spike actually shifts among 3 distinct configurations. The findings suggest that, rather than target proteins triggering structural changes in Env upon binding, transient shifts in Env may instead enable it to bind target proteins.
The team found that the predominant form of Env is the closed or ground state. When broadly neutralizing antibodies and entry-inhibiting drugs bind to HIV, they often stabilize Env in this ground state and thereby prevent the virus from infecting a cell. These findings indicate that effective vaccines should thus be based strictly on the ground-state, pre-fusion form of the spike. Knowing the atomic structure of this configuration now gives researchers the tools to design such a vaccine.
“The determination of the structure of this closed configuration of the HIV spike protein and the direct visualization of its fast openings represent a major step forward for drug and vaccine design,” says Dr. Walther Mothes of Yale University, co-senior author of the Science paper.
—by Harrison Wein, Ph.D.
Reference: Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions. Munro JB, Gorman J, Ma X, Zhou Z, Arthos J, Burton DR, Koff WC, Courter JR, Smith AB 3rd, Kwong PD, Blanchard SC, Mothes W. Science. 2014 Oct 8. pii: 1254426. [Epub ahead of print]. PMID: 25298114. Structure and immune recognition of trimeric pre-fusion HIV-1 Env. Pancera M, Zhou T, Druz A, Georgiev IS, Soto C, Gorman J, Huang J, Acharya P, Chuang GY, Ofek G, Stewart-Jones GB, Stuckey J, Bailer RT, Joyce MG, Louder MK, Tumba N, Yang Y, Zhang B, Cohen MS, Haynes BF, Mascola JR, Morris L, Munro JB, Blanchard SC, Mothes W, Connors M, Kwong PD. Nature. 2014 Oct 23;514(7523):455-61. doi: 10.1038/nature13808. Epub 2014 Oct 8.. PMID: 25296255.
Funding: NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of General Medical Sciences (NIGMS); U.S. Agency for International Development; International AIDS Vaccine Initiative: Bill & Melinda Gates Foundation; Irvington Fellows Program of the Cancer Research Program; Ministry of Foreign Affairs of Denmark; Irish Aid; Ministry of Finance of Japan; Ministry of Foreign Affairs of the Netherlands; Norwegian Agency for Development Cooperation; and UK Department for International Development.