New mechanism of blocking HIV-1 from entering cells identified

W
ASHINGTON - Scientists have discovered a new mechanism by which drugs block HIV-1 from entering host cells.

Cellular invasion by HIV-1 requires the concerted action of two proteins on the viral surface: gp120 and gp41. The function of gp41 is to get the viral contents into the interior of the host cells.

This requires the association of two distinct regions of gp41 called N-HR and C-HR. Anti-HIV-1 agents known as fusion inhibitors target the N-HR or C-HR and disrupt their association, which prevents the virus from entering into the host cell. One drug that works like this is Fuzeon (Roche), and there are other agents in the pipeline.

However, blocking the N-HR/C-HR association is not only mechanism by which fusion inhibitors prevent HIV-1 entry, say scientists from the Kimmel Cancer Center at Jefferson. The inhibitors also induce irreversible deactivation of gp41.

“After these drugs bind, they seem to shuttle gp41 into a dead conformation from which the protein cannot recover. Importantly, the speed of this drug-induced deactivation greatly influences how potent a drug is at preventing HIV-1 infection,” said Michael Root, assistant professor of Biochemistry and Molecular Biology at Jefferson Medical College of Thomas Jefferson University.

When the inhibitors bind to the gp41 C-HR, the protein rapidly deactivates before inhibitors have time to dissociate. But when the inhibitors bind to the gp41 N-HR, deactivation takes a very long time, and many inhibitors can readily unbind.

To potently inhibit HIV-1 entry, a C-HR targeting fusion inhibitor can have a relatively low affinity, but an N-HR targeting fusion inhibitor must bind extremely tightly.

A major disadvantage of using Fuzeon and related drugs that target N-HR is the rapid emergence of HIV-1 strains resistant to the drugs.

The new study suggests that the resistance phenomenon is related to the slow speed of gp41 deactivation induced by these fusion inhibitors.

HIV-1 appears to have more difficulty developing resistance to drugs that can remain bound to gp41 for much longer than gp41 takes to deactivate, even if the drugs are no more potent than Fuzeon against the original HIV-1 strain.

Armed with this knowledge, the researchers have developed a new strategy to improve the antiviral activities of N-HR-targeting fusion inhibitors.

The study has been published in PLoS Pathogens. (ANI)

Share

Blogger Widgets

Seawater temperatures in Kuwait Bay rising alarmingly since 1985

W
ASHINGTON - In a new research, scientists have determined that since 1985, seawater temperature in Kuwait Bay, northern Arabian Gulf, has increased on average 0.6 degree Celsius per decade, which is about three times faster than the global average rate reported by the Intergovernmental Panel on Climate Change (IPCC).

Dr Thamer Al-Rashidi and his colleagues from the National Oceanography Centre, Southampton, UK, used data on sea surface temperature (1985-2007) remotely sensed by a number of polar orbiting satellites to assess warming in Kuwait Bay and the Gulf region.

They found that the sea surface temperature of Kuwait Bay increased over the period at an average rate of around 0.62 degree C per decade, with an uncertainty of plus or minus 0.01 degree C.

This is about three times the rate of average global increase estimated by the IPCC.

The increase was greatest in the early summer and least during winter months. The length of summertime increased almost twice as fast as peak summertime temperature.

In 1998 and 2003, the monthly measurements of sea surface temperature showed unusually high peaks in summer temperature coincident with El Nino events - periodic warming of the atmosphere and ocean affecting weather in many parts of the world.

Temperature dipped in 1991, in the aftermath of the Iraqi invasion of Kuwait.

“Dense smoke from the burning of oil fields hung over the region blocking out the sun, and we believe that this atmospheric dimming caused the relatively low summertime temperature peak recorded that year,” said Dr Al-Rashidi, an officer in the Kuwaiti Navy.

However, temperature then increased fairly steadily between 1992 and 2004.

“What all of this tells us is that the global trends reported by the IPCC may not be representative locally,” said Dr Al-Rashidi.

The researchers estimate that about a third (0.2 degree C) of the observed decadal increase in seawater temperature in Kuwait Bay can be attributed to global climate change, while around 13 per cent of the increase (0.08 degree C) is due to human activity along the coast of the bay, especially the direct impacts of power and desalination plants.

The remaining 0.3 degree C (50 per cent) of decadal warming appears to be due to changes in regional drivers, including circulation and mixing of seawater in the Arabian Gulf, the influence of the dominant north-westerly wind, freshwater discharge from the Euphrates and Tigris rivers, and sand storms. (ANI)

Share

Blogger Widgets