Here we show that several markers of innate immune activation and aging occur prematurely in HIV positive women. Of these, the increased proportion of CD16+ monocytes and plasma sCD163 appear approximately 10–14 years earlier in HIV positive compared to HIV negative women. These novel findings demonstrate an increase in the rate of age-related changes (as shown here with CXCL10) in women during HIV infection.
We have recently shown that levels of innate immune activation markers including sCD163 and CXCL10 in young, HIV positive males are similar to those in elderly seronegative men 
. Whilst many studies demonstrate similarities between HIV and age-related immune changes, few studies address the interaction between these two factors. To do this, we analysed data with age as a continuous variable and compared the trajectory in innate immune changes between HIV positive and negative women. Our finding of an age-related increase in sCD163 levels (a marker of monocyte activation) and inflammatory CD16+
monocytes in both HIV positive and HIV negative women is consistent with previous findings in men/mixed cohorts 
. We and others have previously shown HIV-related increases in both sCD163 levels and CD16+
. In the present study we quantified this difference and found HIV positive women have levels of sCD163 and CD16+
monocytes equivalent to those in seronegative women aged on average 14.47 or 10.55 years older, respectively. Such premature changes in the inflammatory milieu may contribute to the early development of age-related diseases in HIV positive individuals.
In contrast, age-related increases in CXCL10 concentrations were found to occur at an accelerated rate in HIV positive women, suggesting age and HIV may act synergistically to increase CXCL10 levels. CXCL10 is an inflammatory chemokine which has been associated with risk of coronary heart disease 
and myocardial infarct size 
in the general population. Additionally, a direct role for CXCL10 in the development of atherosclerotic plaques in mice has been demonstrated 
. Thus, the finding that HIV acts synergistically with age to increase CXCL10 levels may have implications for the development of cardiovascular disease in HIV positive individuals.
Multivariable modeling indicated that age-related changes to sCD163 and CXCL10 were independent, and furthermore that these innate immune changes were independent of previously demonstrated changes in the proportion of CD28+CD57− CD8+ T cells indicative of adaptive immune senescence. This novel finding demonstrates that in aging and HIV infection, adaptive and innate changes are independent of one another. This finding suggests that parallel but independent mechanism may be driving innate and adaptive immune changes during HIV infection and justifies the inclusion of innate immune parameters, including CXCL10 and sCD163, alongside adaptive immune parameters in studies of immune senescence.
In addition to increases in sCD163 and CXCL10 levels, we also found elevated plasma levels of neopterin (a GTP metabolite produced by macrophages following IFN-γ stimulation 
), in HIV positive women, similar to our previous observation in males 
. Unlike our findings in males, we found significantly elevated levels of sCD14 in HIV positive women which has been linked to HIV-related mortality 
. Increased sCD14 levels have been previously shown in some 
but not all 
studies in HIV positive adults and in a pediatric HIV cohort 
. sCD14 is required for LPS stimulation of TLR4 and is shed from the surface of monocytes following activation 
. In HIV positive individuals, sCD14 has been associated with elevated LPS levels related to microbial translocation across the gut mucosa 
. However, LPS levels within the HIV positive group were not elevated in this study. Plasma levels of LPS and sCD14 have been shown to be discrepant in other studies, suggesting the relationship between LPS and sCD14 may be complex and context-dependent 
or that LPS may be a less robust biomarker. Taken together, these results suggest that whilst HIV may have a similar effect in males and females with respect to augmenting plasma levels of CXCL10, neopterin and sCD163, HIV positive females may not exhibit significant changes in factors such as LPS. This, combined with previously reported significant differences between males and females in CD4 T cell counts at AIDS onset 
, indicate sex-related differences exist in certain aspects of HIV-related immune dysfunction. It remains to be determined whether these sex-related differences translate to differences in morbidity risk.
Drivers of immune aging remain to be fully defined. We have previously shown that although cART is associated with an improvement in innate immune dysfunction, age-related changes to innate immune markers persist despite virological suppression 
, suggesting the involvement of other factors in addition to HIV viremia. Microbial translocation and resultant endotoxemia, which persist despite viral suppression, have been postulated to contribute to persistent immune activation and senescence, however numerous other factors including reactivation of latent viruses may also be involved (see 
There are several limitations to this study. Given the relatively small number of participants, there was insufficient power to perform separate analyses for virologically suppressed and viremic individuals or to control for unmatched demographic variables between the two groups. Levels of the innate immune parameters measured here are known to be elevated in viremic as compared to virologically suppressed HIV positive males and the relationship between viral load, CD4 T cell count and innate immune activation markers in HIV positive women requires investigation in larger cohorts studies. Significant differences existed between the HIV positive and HIV negative groups with regards to BMI and co-infection with hepatitis C virus (HCV; seen in 27.3% of HIV positive participants). CXCL10 levels 
and the level of CD8+
T cell activation 
in HIV/HCV co-infected patients have been shown to be higher than in patients individually infected with either virus. Although menopausal status was not significantly different between our HIV positive and HIV negative cohorts, we cannot exclude the possibility that hormonal and menopausal variations may influence the parameters measured here. Significantly larger cohort studies would be required to investigate these more complex associations.
We have shown an increase in the rate of age-related change in CXCL10 with HIV infection. As the increases in CXCL10 and sCD163 in HIV positive women were independent of well-characterized HIV-associated CD8+ T cell senescence, this study highlights the importance of including innate immune markers in future investigations. The premature development of innate immune changes in the setting of HIV infection may underlie the acceleration and/or heightened risk of diseases associated with aging in this patient population.