Associations of insulin-like growth factor (IGF)-I and IGF-binding protein-3 with HIV disease progression in women.

The insulin-like growth factor (IGF) axis is thought to play a role in host immunity, prompting speculation that it might also affect the host immune response to HIV and influence the rate of HIV disease progression [1–4]. IGF-I, a peptide hormone with strong mitogenic and antiapoptotic activity, mediates many of the effects of growth hormone (GH), and most cells, including human thymocytes, express the IGF-I receptor [1]. IGF-I can inhibit the apoptosis of hematopoietic progenitor cells [5], and, in animal models, IGF-I administration has been shown to stimulate thymic growth, increase lymphocyte numbers, and partially reverse age-related thymic atrophy [1]. Moreover, the administration of recombinant human IGF-I to cats with feline immunodeficiency virus infection was found to induce thymic cortical regeneration [6]. IGF-binding proteins (IGFBPs) may also play a role in HIV-disease progression. Although IGFBPs were originally considered to be passive circulating transport molecules, they are now understood to play a variety of roles in circulation and within cells [7, 8]. IGFBP-3 is the most abundant IGFBP in serum [7] and has IGF-independent effects that are largely opposite those of IGF-I; that is, IGFBP-3 is proapoptotic [7, 9–17] and has direct antiproliferative effects on the cell cycle [16, 18–22]. IGFBP-3 is expressed by immune cells as well as related stromal cells [1], and, in bone marrow models, IGFBP-3 (but no other IGFBP) was found to inhibit hematopoietic stem cell development [8]. It is reasonable, therefore, to hypothesize that high IGFBP-3 levels might limit the capacity of HIV-infected patients to replace depleted immune cells, including CD4+ T cells. No studies, however, have actually addressed the fundamental question of whether circulating endogenous levels of IGF-I and IGFBP-3 are associated with HIV disease progression. Observational studies have to date focused mainly on the associations between IGF-I and metabolic disorders in HIV-infected patients, such as lipodystrophy and AIDS wasting [23]. Although these studies contributed useful information on HIV-related metabolic conditions, they were typically small (n < 100) and cross-sectional and cannot be used to address the pathogenesis of HIV/AIDS. One observational study of 76 HIV-infected patients that focused on stage of HIV disease found that higher CD4+ T cell count was cross-sectionally associated with higher IGF-I level, higher IGFBP-3 protease activity, and lower total IGFBP-2 level [3]. The prospective predictors of HIV disease progression could not be studied, however. Furthermore, coinfection with hepatitis C virus (HCV) was generally not assessed in prior studies, despite evidence that it is an important potential confounder; that is, HCV has been reported to affect HIV disease progression [24] as well as IGF-I and IGFBP-3 production by the liver [25]. Several small clinical trials, principally pilot studies, have been conducted to evaluate the effects of administering IGF-I, GH, and GH-releasing hormone to HIV-infected patients, but, as with the prior observational studies, most of these trials focused on lipodystrophy and AIDS wasting [23, 26]. One study of 5 HIV-infected adults that focused on HIV pathogenesis found that administration of GH for 6–12 months increased thymic mass and circulating naive CD4+ T cell counts [27], whereas another small pilot study with a shorter follow-up found no effect of GH and/or IGF-I level on CD4+ T cell count [28]. Notably, the impact of these interventions on IGFBP-3 levels and how this might have influenced treatment outcomes were not addressed, even though IGF-I and GH administration increase IGFBP-3 levels. The present investigation is the first large prospective investigation of the associations of circulating endogenous levels of IGF-I and IGFBP-3 with the risk of incident clinical AIDS. To best understand these biological relationships, we wished to study HIV disease progression unaffected by the use of highly active antiretroviral therapy (HAART); therefore, only specimens and data obtained before the HAART era were used. If an association of IGF-I and/or IGFBP-3 level with incident AIDS was observed, not only would it provide insight into HIV pathogenesis, it would raise the possibility that the IGF axis could be a target for interventions to slow HIV disease (e.g., to extend the time before use of HAART becomes necessary).