Immune modulation by estrogens: role in CNS HIV-1 infection

Experimental and epidemiological data suggest that estrogen can be protective in both brain injury and infection. While estrogens can act directly on neurons to promote neuronal survival, estrogen also has antiinflammatory properties that may contribute to overall neuroprotection. Accordingly, estrogens may have particular relevance in chronic neuroimmune disorders such as HIV dementia. As AIDS is now a leading cause of death among women in their reproductive years, understanding the role that female sex hormones might play in the physiology of HIV-1 infection is especially critical. Indeed, there is accumulating evidence that many manifestations of HIV differ in women. For instance, it is now well established that women present with a lower viral titer at the time of seroconversion, have lower HIV viral loads compared to men at similar stages of disease, and may have altered disease progression during pregnancy. Conversely, while epidemiological studies suggest that women may be more vulnerable to certain late-stage AIDS-related illnesses including HIV dementia, there is accumulating data that strongly suggest an estrogen-deficient state is associated with long-term HIV infection in some women. Evaluated as a whole, existing evidence indicates that estrogen can directly protect neurons from damage, can modulate brain inflammation, and could act to maintain low titers of the HIV-1 virus. Accordingly, it can be hypothesized that maintenance of serum estradiol levels could decrease the incidence of HIV dementia and other AIDS-related neurological syndromes in HIV-1 positive women. In this article, we both summarize current understanding and present new data related to the potential mechanisms whereby estrogen could modulate the mechanics and the consequences of HIV-1 infection in the brain and thereby thwart the development of HIV dementia.