Effects of Autologous Stem Cell Transplantation in HIV: Searching for the Origins of Viral Replication in Settings of Profound CD4 + T Cell Depletion

E ditor: The observation of high-level HIV-RNA rebound during a profound phase of CD4⁺ lymphocyte depletion in recipients of myeloablative regimens raises an important question about the origins of viral replication: how can the virus replicate so actively in the virtual absence of a CD4⁺ substrate?

Bortolin et al. ¹ recently published a fascinating article describing the significant predictive value of HIV-DNA levels on overall survival following high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) in HIV-infected lymphoma patients. Data regarding viral replication dynamics [gathered via measurement of plasmatic HIV-RNA levels and HIV-DNA contents in peripheral blood mononuclear cells (PBMCs) before and after ASCT] were reported, and were of additional interest. Patients who discontinued antiretroviral therapy (cART) after HDC experienced a sustained rebound in viral load, primarily during the aplastic period. Moreover, HIV-DNA levels were detectable in a high percentage of patients before and after ASCT, and did not fluctuate significantly until 12 months of follow-up, although a significant drop was observed at the day of CD34⁺ cell harvesting.

In patients not treated with cART, viremia is primarily generated by repeated cycles of infection-replication in activated CD4⁺ T cells. ² Activation of latently infected T cells and replication in other cell types, such as macrophages and dendritic cells, make up a minimal contribution to viral load. Notably, in patients undergoing long-term cART, persistent residual viremia (1–5 copies per ml) is frequently detectable. Reactivation from long-lived reservoir(s) of latently infected T cells has been proposed as the likely culprit for this ongoing viremia.

Analyzing the effects of autologous stem cell transplantation on HIV infection, a previous study ³ found large numbers of HIV-DNA copies in reinfused autologous blood stem cells, meaning that HIV-RNA rebound in patients after discontinuation of cART could be an effect of high-level HIV replication in graft-included PBMCs. However, Bortolin and colleagues ¹ elegantly showed that reinfusion of HIV-infected autologous cells does not amplify the peripheral HIV reservoir.

A second explanation could be that reactivation from a long-lived reservoir of latently infected cells causes HIV replication in the virtual absence of CD4⁺ lymphocytes. Studies on the origins of residual viremia ^4,5 have, in fact, shown that predominant plasma clones are homogeneous populations that remain genetically stable for years, suggesting a fundamental role of long-lasting cells that never enter into the blood circulation (tissue CD4⁺ T cells, tissue macrophage, or monocyte-macrophage-lineage stem cells), which are relatively chemotherapy-resistant cells and thus are not completely depleted by myeloablative conditioning regimens. ⁶ However, a recent study by Simonelli and colleagues ⁷ showed a significant decrease in the magnitude of peripheral HIV reservoir 2 years after transplantation, suggesting that if HDC and ASCT do produce reactivation of a latent reservoir, in doing so they might also be playing a role in the purging of latent virus. Therefore, the presence of high viral replication in conditions of CD4⁺ absence, despite years of suppressive cART, presents a clear picture of the magnitude of the non-CD4⁺ reservoir, the eradication of which must involve monocyte–macrophages, dendritic cells, and central nervous system residents.

In conclusion, our belief is that ASCT might represent a study model in which in vivo CD4⁺ and CD8⁺ lymphocyte depletion can reveal mechanisms of HIV latency and persistent viral replication. Analysis of viral clones, together with the development of technologies such as RNA interference, could provide interesting clues for the development of new strategies aimed at viral eradication.