The advent of highly active anti-retroviral therapy (HAART) has dramatically influenced the AIDS epidemic in developed countries. HAART treatment suppresses HIV replication, thereby preventing further immune destruction. However, many patients have a limited immune recovery due to the immune degradation imparted from the direct and indirect effects of the previously untreated chronic viral infection. We hypothesize that an effective immune therapy provided concurrently with HAART will result in a more functionally complete immune recovery and a better prognosis for HIV+ patients. Previous studies supported by this grant investigated immune dysfunction in HIV+ patients and SIV+ macaques. Here we utilize this knowledge to test a potential immune therapeutic in the SIV/macaque model. The immune therapeutic to be assessed is the cytokine interleukin (IL)-7, which normally functions as a homeostatic regulator to maintain steady T-cell levels. Compared to other immune therapeutic candidates IL-7 is unique in that it has the ability to impact T-cell renewal in the periphery as well as thymocyte maturation and T-cell production in the thymus. The general approach used here will be to treat SIV+ macaques with HAART alone or HAART with IL-7, to evaluate the ability of IL-7 to influence immune reconstitution. One of the strengths of this proposal is that IL-7 therapy will be assessed in macaques that are HAART treated both during the acute as well as during the chronic phase of the infection.
Aim 1 will assess the effect of IL-7 on T-cell phenotypes, proliferation and thymic production in HAART treated SIV infected macaques.
Aim 2 will evaluate any potentially negative effects of the IL-7 therapy through an assessment of viral replication and cell types infected.
Aim 3 will determine if IL-7 administration increases the levels of SIV specific T-cells and improves clinical outcome after cessation of HAART. We anticipate that use of the SIV/macaque model will dramatically assist in the approval of IL-7 as an immune therapeutic for HIV infected patients as well as identify the patient populations most likely to benefit from this therapy. Furthermore, these studies may indicate the means by which IL-7 therapy may assist other T-cell depleting conditions such as those following chemotherapy and bone marrow transplantation.
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