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.”
Nature Medicine
Published online: 13 July 2009 | doi:10.1038/nm.2004
Letter
Sex differences in the Toll-like receptor–mediated response
of plasmacytoid dendritic cells to HIV-1
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.
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