Pk antigen KOs HIV infection

Pk, an antigen found on the surface of several types of cells including red blood cells, thwarts HIV infection, researchers in Canada and Sweden reported recently in the journal Blood (Blood 2009; 113:4980–4991). Although Pk is not highly expressed on T cells, the main target of HIV, principal author Don Branch of Canadian Blood Services says it ‘might be a true natural resistance factor.’ The P/P1/Pk antigen group is one of the 30 blood group systems recognized by the International Society of Blood Transfusion. Pk itself is a precursor for P, a glycosphingolipid or carbohydrate-containing fat-soluble molecule. Glycosphingolipids are implicated in HIV host-cell fusion and several bind to HIV-gp120 in vitro. Branch and colleagues in the laboratory of Cliff Lingwood at the Hospital for Sick Children, Ontario, Canada, had reported earlier that cells from individuals with Fabry disease, in which Pk builds up within cells, consistently inhibited R5 HIV-1 infection and had very little Pk or the chemokine (C-C motif) receptor 5 (CCR5) coreceptor on the surface, suggesting that Pk might play a role in HIV infection. In the current study, the investigators first tested whether Pk itself, rather than cell abnormalities caused by Fabry disease, hindered HIV infection. In collaboration with Martin Olsson from Lund University, Sweden, Branch and Lingwood looked at peripheral blood mononuclear cells from healthy but rare individuals who either build up excess amounts of Pk on the surface of their cells (roughly one person in a million) or make no Pk at all (about five people per million). The team found that cells from two people who made excess amounts of Pk were ‘highly resistant’ to R5 and X4 HIV-1 infection compared with controls. In contrast, cells from three people who made no Pk showed a 10-fold to 1000-fold increase in susceptibility to R5 and X4 HIV-1 infection compared with controls. The researchers then tinkered with Pk expression in various kinds of cells to see how that affected HIV infection. They began with a series of ‘knock down’ experiments on CD4+–HeLa cells. These cervical cancer-derived cells naturally produce Pk and have been genetically engineered vulnerable to HIV infection. The team reduced Pk production by either inhibiting synthesis of all glycosphingolipids or by selectively blocking transcription of Pk. Both techniques resulted in significantly increased infection levels compared with controls. The investigators also used gene therapy techniques to make CD4+–HeLa cells express excess amounts of Pk. Compared with controls, HIV-1 infection in the transduced CD4+–HeLa cells was ‘significantly lower’. The scientists then manipulated HIV's natural target, T cells, which normally produce no Pk. By incubating Jurkat T cells with semi-synthetic Pk, approximately 35% of them began expressing Pk on their surface. The CD4+ T cells in that group had an HIV-1 infection level 43% that of control cells. Pk throws a monkey wrench into HIV infection through competitive inhibition, the researchers say. The same short sequence of amino acids on HIV's gp120 can bind with either Pk or the CCR5 or chemokine (C-X-C motif) receptor 4 CXCR4 coreceptors on the cell surface. If enough Pk is present, the researchers theorize that HIV latches onto Pk rather than a chemokine receptor. As a result, no fusion of virus to cell occurs. Currently, the Swedish researchers are looking at the distribution of Pk on cells in the general population and performing HIV infection experiments to see whether there is a correlation. The preliminary results ‘look promising’, Branch says, and may lead to a way to predict who is more susceptible to infection. Meanwhile, the research group led by Branch is testing the efficacy of a totally synthetic Pk molecule, produced in New Zealand, to prevent HIV infection in vitro. They hope to eventually test it in animals. They will also begin experiments soon to determine under what conditions T cells can be coaxed into expressing Pk. ‘I think,’ Branch says, ‘we’re going to be proving that this is an important molecule.'

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