We sought to estimate sex differences in circulating IL-7 levels controlled for CD4 count. We also investigated whether the previously reported relation between circulating IL-7 levels and CD4 counts, established in a predominantly HIV-1–infected male cohort,12
is present as well in HIV-1–infected women. Theoretically, increased CD4 counts in women might be attributable to higher levels of IL-7 or to alterations in T-cell homeostasis attributable to sex-based differences in the relation between IL-7 and CD4 counts. In a cross-sectional analysis of 299 HIV-1–infected persons, we found a similar inverse relation between IL-7 and CD4 counts in women and men. We also found that circulating levels of IL-7 averaged 40% higher in women, and we reason it is likely that increased levels of circulating IL-7 reflect higher local concentrations of IL-7 in peripheral or central immune tissues. Because IL-7 facilitates T-cell development and proliferation,7–13
increased circulating IL-7 levels may contribute to the higher CD4 counts found in women. In addition, and despite some evidence to the contrary,16,17
IL-7 may enhance HIV-1 infection, replication, and cytopathicity in vivo.18–21
Thus, it is possible that higher levels of IL-7 in women might contribute to faster disease progression at a given viral set point.22–24
Certain limitations of this study warrant consideration. We cannot exclude the possibility that a difference in the duration of infection between these cohorts contributed to the observed differences, because reliable data on the duration of infection were not available. We did, however, control for CD4 count, which is commonly used as an indicator of disease progression. Although controlling for viral load reduced the estimated effect of sex on log IL-7 and increased its P
value to 0.10, the evidence for a viral load effect on IL-7 was not strong (P
= 0.12), and plausible mechanisms for such an effect are not apparent, other than via CD4 count, which is already controlled for in the model. A longitudinal analysis of men and women from the point of infection could provide more definitive conclusions than a cross-sectional analysis with regard to the contribution of IL-7 to sex-based differences in HIV disease. In fact, given the well-documented differences in immune function between women and men,25,26
we believe that a prospective longitudinal cohort of HIV-1–infected women and men is warranted to examine sex-based differences in many aspects of HIV immunopathogenesis.
Whereas the data reported here do not confirm a role for IL-7 in sex-based differences in CD4 counts in HIV-1–seronegative individuals, a role is possible, because the estimated effect of sex on IL-7 seemed similar to the overall estimate when restricted to those with a CD4 count >350 cells/µL. Additional sex-based differences, including differences in sex steroids, may contribute to differences in the homeostatic regulation of CD4 counts via mechanisms independent of IL-7 or by influencing the regulation of IL-7. Continued research is indicated to determine the cause of sex-based differences in IL-7 levels and to define factors responsible for sexual dimorphism in lymphocyte populations and immune function.