There is a large body of evidence showing that innate and adaptive immune responses can differ in women and men, but the reasons for these differences are only partly understood (as reviewed recently in Nature Reviews Immunology). In HIV infection, it has been reported that average viral loads in early infection are lower in women than men, but women face a 1.6-fold higher risk of developing AIDS compared to men with the same viral load. Marc Hellerstein’s group has also presented data demonstrating that women have significantly higher T cell turnover compared to men with similar CD4 T cell counts. The mechanistic basis for these differences has been unclear.
A paper in Nature Medicine now offers a possible explanation for the observed sex differences in HIV pathogenesis. Angela Meier and colleagues from Marcus Altfeld’s group at the Ragon Institute of Massachusetts General Hospital have previously shown that HIV stimulates an innate immune receptor called toll-like receptor-7 (TLR7). In the new study, they report that a key immune cell called a plasmacytoid dendritic cell (pDC) responds differently to TLR7 stimulation depending on the sex of the donor. Specifically, significantly more pDC from women produced interferon-alpha compared to pDC from men. The study authors note that this finding has also been reported with a different TLR7 stimulus, a drug called imiquimod.
The researchers went on to evaluate the role of sex hormones, finding that the percentage of pDC producing interferon-alpha after TLR7 stimulation was significantly correlated with plasma progesterone concentrations. There was also a trend toward lower percentages of pDC producing interferon-alpha in postmenopausal women compared to premenopausual women.
Because interferon-alpha induces the expression of the immune activation marker CD38 on CD8 T cells in vitro, the researchers decided to explore whether women might show higher levels of immune activation than men despite comparable viral loads. In a comparison of 109 women and 514 men participating in the ACTG 384 trial (all treatment naive), women were found to have significantly higher levels of CD8 T cell activation than men after adjustment for viral load. On average, women had 4.6% more activated CD8 T cells. As immune activation levels are the strongest predictor of disease progression in HIV infection, the study results offer a compelling explanation for why women have a higher risk of developing AIDS compared to men with the same viral load.
The authors conclude: “Modulation of the TLR7 pathways in pDCs could…represent a unique approach to reduce HIV-1–associated pathogenesis and might have implications that go beyond HIV-1 infection, as differential susceptibility to several RNA viruses have been described for men and women, and autoimmune diseases that show sex differences in their incidence, such as systemic lupus erythematosus, have also been shown to involve the TLR7 and TLR8 pathway.”
Published online: 13 July 2009 | doi:10.1038/nm.2004
Angela Meier1,8, J Judy Chang1,8, Ellen S Chan2, Richard B Pollard3, Harlyn K Sidhu1, Smita Kulkarni4, Tom Fang Wen1, Robert J Lindsay1, Liliana Orellana2, Donna Mildvan5, Suzane Bazner1,6, Hendrik Streeck1, Galit Alter1, Jeffrey D Lifson7, Mary Carrington4, Ronald J Bosch2, Gregory K Robbins6 & Marcus Altfeld1,6
Manifestations of viral infections can differ between women and men1, and marked sex differences have been described in the course of HIV-1 disease. HIV-1–infected women tend to have lower viral loads early in HIV-1 infection but progress faster to AIDS for a given viral load than men2, 3, 4, 5, 6, 7. Here we show substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce markedly more interferon- (IFN-) in response to HIV-1–encoded Toll-like receptor 7 (TLR7) ligands than pDCs derived from men, resulting in stronger secondary activation of CD8+ T cells. In line with these in vitro studies, treatment-naive women chronically infected with HIV-1 had considerably higher levels of CD8+ T cell activation than men after adjusting for viral load. These data show that sex differences in TLR-mediated activation of pDCs may account for higher immune activation in women compared to men at a given HIV-1 viral load and provide a mechanism by which the same level of viral replication might result in faster HIV-1 disease progression in women compared to men. Modulation of the TLR7 pathway in pDCs may therefore represent a new approach to reduce HIV-1–associated pathology.
1. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.
2. Harvard School of Public Health, Boston, Massachusetts, USA.
3. University of California–Davis Medical Center, Sacramento, California, USA.
4. Cancer and Inflammation Program, Laboratory of Experimental Immunology and Science Applications International Corporation–Frederick, National Cancer Institute, Frederick, Maryland, USA.
5. Beth Israel Medical Center, New York, New York, USA.
6. Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
7. AIDS and Cancer Virus Program, Science Applications International Corporation–Frederick, National Cancer Institute, Frederick, Maryland, USA.
8. These authors contributed equally to this work.