HIV patients hold clues to Salmonella vaccine development

Apr 22, 2010

A study published today in the journal Science offers a long-awaited explanation for the link between HIV infection and susceptibility to life-threatening nontyphoidal strains of Salmonella.

The research, funded by the Wellcome Trust and , goes on to identify targets that could be pursued for Salmonella .

Nontyphoidal strains of Salmonella (NTS) usually cause vomiting and diarrhoea in developed countries and are mainly contracted by consuming infected foods, such as uncooked meat and eggs. NTS can also cause fatal bloodstream infections in people with compromised immunity, such as HIV-infected individuals, and children under two years of age or with malaria, or .

This is a particular problem in Africa where Salmonellae are the most common bacteria to infect the blood. Such bloodstream infections can be treated with antibiotics, but is on the increase and there is currently no vaccine available.

"The association between and fatal cases of nontyphoidal Salmonella disease has been known since the onset of the AIDS pandemic 26 years ago, but this is the first time we've been able to offer a scientific explanation why", said Dr Cal MacLennan from the University of Birmingham, who led the research.

In a previous study of African children, the team of researchers working at the Malawi-Liverpool-Wellcome Trust Clinical Research Programme, at the College of Medicine, University of Malawi, and the University of Birmingham had shown that protective Salmonella-specific antibodies generated in the first two years of life are critical for controlling the infection.

In the new study, the researchers turned their attention to immunity in African adults. While blood samples from HIV-uninfected adults killed Salmonella without difficulty, those from many HIV-infected Africans could not kill Salmonella. Since causes significant defects in the immune system, the team examined whether a lack of these antibodies might account for the absence of killing and explain why HIV infected adults are particularly susceptible to Salmonella infections.

Contrary to expectations, the team found that blood from HIV-infected adults harboured high levels of antibodies to Salmonella, molecules that normally help the immune system to fight infections. However, unlike the antibodies in healthy adults, these antibodies were unable to kill Salmonella. In fact, antibodies from these patients actually stopped the antibodies from healthy adults from killing Salmonella.

The team went on to show that this difference in ability to kill Salmonella is due to the part of the Salmonella that the antibodies bind to. The protective 'killing' antibodies bind to structures on the surface of the bacteria known as outer membrane proteins. When the 'killing' antibodies bind to outer membrane proteins, this then allows the immune system to destroy the Salmonella bacteria.

On the other hand, large numbers of antibodies in HIV-infected Africans bind to a structure that sticks out from the surface of the Salmonella known as LPS (lipopolysaccharide). These 'blocking' antibodies appear to divert the immune system away from the surface of the bacteria and stop the 'killing' antibodies from doing their job.

When the researchers specifically removed the 'blocking' antibodies from HIV-infected blood samples, they found 'killing' antibodies present in the blood that could once again kill the bacteria. This shows that patients infected with HIV still have the protective 'killing' antibodies generated in the first two years of life that can control Salmonella infection, but the excess of 'blocking' antibodies stops the 'killing' antibodies from working.

"We normally think of HIV patients as being more susceptible to bacterial infections because of deficiencies in their immune systems, and often they have problems making antibodies when given vaccinations. In the present study, we found that it's actually an excess of antibodies that causes the problem" explained Dr MacLennan.

"The findings are important because LPS is currently being investigated as a potential target for a vaccine. Our observations that targeting LPS can actually impede the protective immune response to Salmonella would caution against this, suggesting that such a vaccine could do more harm than good."

A vaccine that protects both young children and HIV-infected adults from fatal cases of NTS is urgently needed in Africa. The findings from this study suggest that the outer membrane proteins could potentially serve as alternative vaccine targets and this is an area that the team is currently investigating.

Explore further: Scientists discover how a killer fungus attacks HIV patients

More information: C.A. MacLennan et al. Dysregulated humoral immunity to nontyphoidal Salmonella in HIV-infected African adults. Science 2010, 328 (5977)

Related Stories

Exhausted B cells fail to fight HIV

Jul 14, 2008

HIV tires out the cells that produce virus-fighting proteins known as antibodies, according to a human study that will be published online July 14 in the Journal of Experimental Medicine.

Targeted irradiation: A new weapon against HIV?

Nov 07, 2006

Antiretroviral therapy can keep HIV infection in check and delay and ameliorate the symptoms of HIV/AIDS. However, the drugs do not manage to eradicate the virus completely; individuals have to stay on the drugs permanently. ...

HIV isolate from Kenya provides clues for vaccine design

Jan 02, 2008

Two simple changes in its outer envelope protein could render the AIDS virus vulnerable to attack by the immune system, according to research from Kenya and the Fred Hutchinson Cancer Research Center published in PLoS Medicine.

How HIV vaccine might have increased odds of infection

Nov 03, 2008

In September 2007, a phase II HIV-1 vaccine trial was abruptly halted when researchers found that the vaccine may have promoted, rather than prevented, HIV infection. A new study by a team of researchers at the Montpellier ...

Recommended for you

Researchers trace HIV adaptation to its human host

5 hours ago

"Much research has focused on how HIV adapts to antiviral drugs – we wanted to investigate how HIV adapts to us, its human host, over time," says lead author Zabrina Brumme from Simon Fraser University.

Harm-reduction program optimizes HIV/AIDS prevention

Apr 21, 2014

(Medical Xpress)—New research from UC San Francisco and the San Francisco AIDS Foundation has found that clients participating in a harm-reduction substance use treatment program, the Stonewall Project, decrease their use ...

User comments : 0

More news stories

Genetic code of the deadly tsetse fly unraveled

Mining the genome of the disease-transmitting tsetse fly, researchers have revealed the genetic adaptions that allow it to have such unique biology and transmit disease to both humans and animals.