Why some people with HIV develop AIDS and others don”t

May 6, 2010 By Leave a Comment

London, May 6 (ANI): Scientists are a step closer to understanding why some people with HIV develop full-blown AIDS, and others don”t.

Researchers in Massachusetts and California say that the answer lies in how the immune cells that recognize invaders are educated – a finding that may pave the way for new strategies for designing an HIV vaccine.

The human immune system detects foreign cells with the help of cell-surface proteins called human leukocyte antigens (HLAs). Each person”s cells carry a particular set of HLA molecules – the person”s HLA type – which bind fragments of virus or bacterial protein and ”present” them to T cells, the immune cells that recognize and attack infected cells.

But before T cells are ready to perform their killer function, they are in effect trained on fragments of the body”s own proteins – self-peptides – in an organ called the thymus.

To ”graduate” from the thymus, a T cell must be able to recognize at least one combination of HLA molecule and self-peptide, which provides the template for its subsequent immune response against a foreign peptide bound to that HLA molecule. T cells that bind to self-peptides very strongly, however, are rejected, as they would attack the body”s own cells.

Researchers began with two observations. First, HIV-infected people who manage to keep the virus in check – so-called ”elite controllers” – often carry a particular HLA gene variant, HLA B571. Second, people with this gene also have a higher risk of developing autoimmune diseases, in which the immune system does produce a harmful response against the body”s own proteins.

Arup Chakraborty, an immunologist at the Massachusetts Institute of Technology in Cambridge, and one of the lead authors of the study, thought the two observations might be related.

He had not previously studied HIV, but he had studied how T cells are selected in the thymus by their ability to recognize specific HLA molecules and the peptides bound to them. He surmised that the HLA molecules of elite controllers might be binding a relatively small number of self-peptides.

Indeed, a look through a database of the binding properties of HLA molecules revealed that HLA B57, along with HLA B27 – which also protects against HIV – binds a much smaller proportion of self-peptides than HLAs that are not protective. The researchers then used a computer algorithm to predict how this would affect T-cell maturation.

T cells that develop in people with the HLA B57 gene would be presented with a smaller variety of peptides in the thymus. Their model showed these cells have broader activity and would be likely to recognize HIV even if the virus mutates, allowing the immune system of elite controllers to keep the infection under control.

But that same property would also make them more likely to turn on the body”s own cells, explaining why HLA B57 leads to a higher risk of developing autoimmune diseases. “If you have a smaller diversity of self-peptides in the thymus,” says Chakraborty, “there”s a higher probability that T cells with a stronger reactivity and cross-reactivity” might be released.

Testing their model on data from 1,900 HIV-infected individuals with known HLA types, 1,100 of which were elite controllers, the researchers found that the progression of the disease was strongly correlated with the number of self-peptides an HLA molecule was able to bind.

The study has been published online in Nature. (ANI)

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Acne drug may help prevent HIV breakout

March 20, 2010 By Leave a Comment

Washington, Mar 20 (ANI): A cheap acne drug that”s been used for decades effectively targets infected immune cells in which HIV, the virus that causes AIDS, lies dormant and prevents them from reactivating and replicating, claim Johns Hopkins researchers.

The drug, minocycline, likely will improve on the current treatment regimens of HIV-infected patients if used in combination with a standard drug cocktail known as HAART (Highly Active Antiretroviral Therapy), according to research published now online and appearing in print April 15 in The Journal of Infectious Diseases.

“The powerful advantage to using minocycline is that the virus appears less able to develop drug resistance because minocycline targets cellular pathways not viral proteins,” says Janice Clements, Ph.D., Mary Wallace Stanton Professor of Faculty Affairs, vice dean for faculty, and professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine.

“The big challenge clinicians deal with now in this country when treating HIV patients is keeping the virus locked in a dormant state,” Clements adds. “While HAART is really effective in keeping down active replication, minocycline is another arm of defense against the virus.”

Unlike the drugs used in HAART which target the virus, minocycline homes in on, and adjusts T cells, major immune system agents and targets of HIV infection. According to Clements, minocycline reduces the ability of T cells to activate and proliferate, both steps crucial to HIV production and progression toward full blown AIDS.

If taken daily for life, HAART usually can protect people from becoming ill, but it’s not a cure. The HIV virus is kept at a low level but isn’t ever entirely purged; it stays quietly hidden in some immune cells. If a person stops HAART or misses a dose, the virus can reactivate out of those immune cells and begin to spread.

The idea for using minocycline as an adjunct to HAART resulted when the Hopkins team learned of research by others on rheumatoid arthritis patients showing the anti-inflammatory effects of minocycline on T cells. The Hopkins group connected the dots between that study with previous research of their own showing that minocycline treatment had multiple beneficial effects in monkeys infected with SIV, the primate version of HIV. In monkeys treated with minocycline, the virus load in the cerebrospinal fluid, the viral RNA in the brain and the severity of central nervous system disease were significantly decreased. The drug was also shown to affect T cell activation and proliferation.

“Since minocycline reduced T cell activation, you might think it would have impaired the immune systems in the macaques, which are very similar to humans, but we didn’t see any deleterious effect,” says Gregory Szeto, a graduate student in the Department of Cellular and Molecular Medicine working in the Retrovirus Laboratory at Hopkins. “This drug strikes a good balance and is ideal for HIV because it targets very specific aspects of immune activation.” (ANI)

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Patients infected with particular HIV subtype more likely to develop dementia

August 29, 2009 By Leave a Comment

Washington, August 29 (ANI): Johns Hopkins researchers have found that infections with a particular subtype of HIV increase people’s likelihood of developing dementia, compared to infections with other subtypes.

Writing about their findings in the journal Clinical Infectious Diseases, the researchers claimed that theirs is the first study to have shown that the specific type of HIV has any effect on cognitive impairment, one of the most common complications of uncontrolled HIV infection.

In their study report, the researchers highlight the fact that HIV occurs in multiple forms, distinguished by small differences in the virus’ genetic sequence and designated by letters A through K.

They point out that certain subtypes appear to cluster in particular areas of the world, which others have been associated with different rates of progression to full blown AIDS.

They also revealed that the majority of the 35 million HIV-infected people worldwide live in sub-Saharan Africa, where subtypes A, C and D dominate.

According to them, nearly half of patients with advanced HIV infections have at least mild cognitive impairments, and about 5 percent have the severe form of cognitive impairment, known as dementia.

Dr. Ned Sacktor, professor of neurology at the Johns Hopkins University School of Medicine and a clinician at the Johns Hopkins Bayview Medical Center, previously found that about 31 percent of patients visiting an infectious disease clinic in the Ugandan capital, Kampala, where subtypes A and D dominate, had dementia.

The finding led him to wonder whether patients with different subtypes had different rates of dementia.

He and his colleagues then studied 60 HIV-infected patients from a Kampala clinic, all of whom had been part of a different study testing the effect of anti-retroviral drugs on cognitive impairment, but had not begun taking the drugs.

After determining each patient’s HIV subtype, the researchers performed a battery of neurological and cognitive tests to assess each patient’s brain function.

They observed that the majority of the patients had HIV subtypes A or D.

Further analysis by the researchers revealed that, of the 33 subtype A patients, seven had dementia, or about 24 percent.

However, out of the nine patients with subtype D, 8 had dementia, about 89 percent.

“We were amazed to see such a dramatic difference in dementia frequencies between these two subtypes. If this is the case in all of sub-Saharan Africa, HIV-associated dementia may be one of the most common, but thus far unrecognised, dementias worldwide,” Sacktor says.

He says that the study indicates that some biological property of each subtype seems to influence the likelihood that infected patients will develop dementia.

Based on their findings, his team hypothesize that subtype D may cause more inflammation and injury in the brain, a possibility they are currently investigating. (ANI)

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