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A Case of Mistaken Identity: Commensal Bacteria Direct the Antibody Response to HIV

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Science Translational Medicine  27 Aug 2014:
Vol. 6, Issue 251, pp. 251ec149
DOI: 10.1126/scitranslmed.3010130

Over 30 years after the discovery of HIV as the cause of AIDS, there is still no vaccine or cure. This is in part because HIV cripples the immune system’s strategies for eliminating pathogens, including HIV itself. The development of an effective vaccine depends on eliciting an appropriate and long-lasting antibody response, making identification of mechanisms that influence antibody production to HIV of substantial clinical interest.

The gastrointestinal tract is home to the greatest density and diversity of resident commensal bacteria, which prime immune responses and provide resistance to pathogens. Interestingly, antibodies in the blood of HIV-1–infected patients are targeted against HIV’s viral envelope glycoprotein, gp41, but also cross-react with commensal bacterial antigens. These data suggested that a component of the antibody response against HIV within the blood might originate from gut B cells that produced polyreactive antibodies before actual HIV infection.

To test this hypothesis, Trama et al. isolated single B cells from intestinal biopsies of six HIV-infected individuals, and recombinant antibodies were generated to determine their reactivity. Of the 254 antibodies isolated, ~2% were reactive with HIV gp41. Of these antibodies, 82% also reacted with commensal derived antigens. To definitively test whether gp41 polyreactive antibodies exist before infection with HIV, antibody reactivity was assayed in three healthy, uninfected patients. Two of three uninfected individuals harbored antibodies that cross-reacted with gp41 and commensal bacterial antigens, indicating that the commensal microbiota alone can induce the production of antibodies that react with HIV.

Taken together, these data suggest that our resident microbes can “prime” the immune response to generate protective immunity against HIV. Although more work needs to be done to identify which microbes induce this response, these studies suggest the exciting possibility that doctors could therapeutically manipulate the microbiota to enhance immune responses so as to develop more effective vaccines against HIV. These authors also identified that 12% of gut B cells had a clonal lineage within the systemic circulation, which offers the possibility that protective antibodies can be induced within the intestine and delivered to the rest of the body.

A. M. Trama et. al., HIV-1 envelope gp41 antibodies can originate from terminal ileum B cells that share cross-reactivity with commensal bacteria. Cell Host Microbe 16, 215–226 (2014). [Abstract]

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