Featured Research

from universities, journals, and other organizations

New View Of HIV Entry May Lead To Next-generation Of Inhibitors

Date:
May 5, 2009
Source:
Cell Press
Summary:
Scientists may need to rethink the design of drugs meant to block HIV from infecting human cells, according to a new study. That's because the new report shows that HIV doesn't enter cells in the way that experts had generally assumed it did.

Scientists may need to rethink the design of drugs meant to block HIV from infecting human cells, according to a study that appears in the May 1st issue of the journal Cell, a Cell Press publication. That's because the new report shows that HIV doesn't enter cells in the way that experts had generally assumed it did.

Rather than fusing directly with the plasma membrane at cells' outer surfaces to release its contents, HIV fusion primarily occurs via smaller, membrane-bound compartments inside of cells known as endosomes, the new research shows. The discovery implies that anti-HIV drugs known as fusion inhibitors might be more effective in blocking HIV if they too can do their work inside of cells, where fusion takes place.

"We show that HIV fusion occurs virtually exclusively from endosomes," said Gregory Melikian of the University of Maryland School of Medicine. "It appears that it is this path to entry that leads to infection."

"In order to efficiently block intracellular fusion events, the next generation of HIV entry inhibitors must be able to permeate the cell membrane," he continued. Drugs that act on the endocytic machinery itself might also prove useful in limiting HIV infection.

Endosomes form in a process known as endocytosis by which cells take in material by engulfing and pinching off a portion of the cell membrane to form a smaller vesicle. Enveloped viruses that depend on low pH for entry are known to initiate infection by fusion with acidic endosomes. However, entry sites for pH-independent viruses, including HIV, had not yet been clearly defined.

In the new study, Melikian and his colleagues relied on a series of imaging studies to literally watch as HIV-1, the virus that normally infects humans, enters cells. Those experiments showed that complete viral fusion occurs not on the cell surface, but in endosomes. While HIV's envelope sometimes did mix with the cell's plasma membrane, in those cases delivery of the viral contents did not occur.

"Time-resolved imaging of single viruses and differential blocking of fusion by site-specific and universal inhibitors revealed that HIV-1 co-opts the endocytic machinery to enter into and fuse with target cells," the researchers wrote. "By contrast, fusion with the plasma membrane did not progress beyond the lipid mixing step, suggesting that endosomal entry is the pathway that leads to productive infection."

HIV-1 interacted with receptors on the cell surface leading to its internalization long before endosomal fusion, they show. That process minimized the surface exposure of conserved viral epitopes – portions of macromolecules that are recognized by the immune system -- during fusion and reducing the efficacy of inhibitors targeting these epitopes.

The researchers also found that HIV-1's release from endosomes depend on dynamins, enzymes that are important to the formation of new endosomes and their fusion with other membranes. Melikian said that dynamins may provide an additional driving force to expand pores and permit the release of the HIV-1 core out into the cell.

While Melikian said he hopes the findings will have practical implications, it does deliver some bad news for those on a mission to fight HIV. That's because the endosomal path to entry would offer the virus several advantages, including sheltering HIV from antibodies and inhibitors that target key portions of the virus during the unusually slow fusion reaction.

The new result may also have relevance for other so-called pH-independent viruses, all of which were assumed to enter via fusion with the plasma membrane, Melikian said. After all, he noted, HIV has been a "poster child" for that group. "This may be a universal trend. Endosomes may be universally more conducive to viral entry."

The researchers include Kosuke Miyauchi, Yuri Kim, Olga Latinovic, Vladimir Morozov, and Gregory B. Melikian, of the University of Maryland School of Medicine, Baltimore, MD.


Story Source:

The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.


Journal Reference:

  1. Kosuke Miyauchi, Yuri Kim, Olga Latinovic, Vladimir Morozov, Gregory B. Melikian. HIV Enters Cells via Endocytosis and Dynamin-Dependent Fusion with Endosomes. Cell, 2009; 137 (3): 433-444 DOI: 10.1016/j.cell.2009.02.046

Cite This Page:

Cell Press. "New View Of HIV Entry May Lead To Next-generation Of Inhibitors." ScienceDaily. ScienceDaily, 5 May 2009. <www.sciencedaily.com/releases/2009/04/090430121927.htm>.
Cell Press. (2009, May 5). New View Of HIV Entry May Lead To Next-generation Of Inhibitors. ScienceDaily. Retrieved September 21, 2014 from www.sciencedaily.com/releases/2009/04/090430121927.htm
Cell Press. "New View Of HIV Entry May Lead To Next-generation Of Inhibitors." ScienceDaily. www.sciencedaily.com/releases/2009/04/090430121927.htm (accessed September 21, 2014).

Share This



More Health & Medicine News

Sunday, September 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Sierra Leone in Lockdown to Control Ebola

Sierra Leone in Lockdown to Control Ebola

AP (Sep. 21, 2014) Sierra Leone residents remained in lockdown on Saturday as part of a massive effort to confine millions of people to their homes in a bid to stem the biggest Ebola outbreak in history. (Sept. 20) Video provided by AP
Powered by NewsLook.com
Sierra Leone's Nationwide Ebola Curfew Underway

Sierra Leone's Nationwide Ebola Curfew Underway

Newsy (Sep. 20, 2014) Sierra Leone is locked down as aid workers and volunteers look for new cases of Ebola. Video provided by Newsy
Powered by NewsLook.com
Changes Found In Brain After One Dose Of Antidepressants

Changes Found In Brain After One Dose Of Antidepressants

Newsy (Sep. 19, 2014) A study suggest antidepressants can kick in much sooner than previously thought. Video provided by Newsy
Powered by NewsLook.com
Could Grief Affect The Immune Systems Of Senior Citizens?

Could Grief Affect The Immune Systems Of Senior Citizens?

Newsy (Sep. 19, 2014) The study found elderly people are much more likely to become susceptible to infection than younger adults going though a similar situation. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins