Effects of total lymphoid irradiation on SIV-infected macaques

The identification of antiretroviral drugs that prevent, or delay for extended periods, progression of HIV-related disease has been of limited success. Because the number of HIV-infected people continues to increase, other therapeutic approaches must be tested. Using simian immunodeficiency virus (SIV)-infected macaques in a feasibility study, total lymphoid irradiation (TLI) was administered in fractionated doses to the supradiaphragmatic and then the infradiaphragmatic lymph nodes until a cumulative dose of 34.2 Gy was achieved in each field. During treatment and for more than 1 year of follow-up, the effects of TLI on various virological, hematological, and immunological parameters were evaluated and compared to those of similarly treated, uninfected macaques. Despite sustained low numbers of CD4+ lymphocytes (< 100/microliters blood) during treatment, TLI was well tolerated, did not result in intercurrent infections, and more importantly, induced a transient decrease in viral burden and did not exacerbate disease. Remarkably, this lack of disease progression and apparent containment of SIV replication were maintained despite persistent failure of PBMCs to respond to mitogen stimulation. Because SIV (and HIV) requires activated lymphocytes to replicate, failure of PBMCs to respond fully to stimuli may have contributed to restricting virus replication. This idea was supported by in vitro experiments in which infection of PBMCs before TLI produced higher levels of cell-free SIV than those obtained during or after TLI. Last, repopulation of peripheral blood and lymph nodes with lymphocytes paralleled that observed in uninfected control animals. The results indicate that (1) immunosuppression alone is not sufficient to induce progression to AIDS, (2) SIV infection does not undermine the ability of the immune system to regenerate new cells during the clinically latent phase, and (3) further evaluation of TLI or other immunosuppressive regimens as potential therapies for HIV disease is warranted.