Toward Cellular-based Therapies for HIV Infection

Abstract

Infection with HIV-1 progressively erodes immune function, leading ultimately to multiple hematopoietic cytopenias. In advanced HIV disease, anemia, neutropenia, and thrombocytopenia occur in a large fraction of patients and are reflective of a striking inability of the bone marrow to accomplish a compensatory increase in production. No failure of compensatory production is greater than that of the T lymphoid system, where despite apparently effective control of HIV replication, restoration of anti-HIV immunity does not occur. Recent technical developments have provided considerable insight into hematopoietic dysfunction in HIV disease and, in particular, in vivo T cell generation. This article will review some of the mechanisms participating in immune regeneration, the stakes involved in effectively accomplishing full reconstitution, and potential approaches to enhance the limited endogenous regenerative process.

A Pre-HAART Follow-up Study of the Hematologic Manifestations in Children With Perinatal HIV-1 Infection: Suggestions for Reclassification of Clinical Staging

“…41,42 A clear pathophysiologic picture of hematologic disorders and of their molecular mechanism is an essential prerequisite for the development of therapeutic strategies, particularly gene therapy and stem cell transplant. 1,[43][44][45] We conclude that combining the 3 hematologic abnormalities in the same cluster of clinical classification produces a confounding effect on the prognostic value for this population.…”

Bringing back the help: autologous bone marrow infusion restores CD4+ T cells in AIDS patients with chronic liver disease

“…These could come from endogenous HSCs or from cellular therapies, such as HSC transplantation. 11 In fact, the only documented ‘cure' of HIV infection remains in the German AIDS patient who underwent BM transplantation (BMT) from a CCR5 Δ32 homozygous donor (with decreased binding to R5-tropic HIV strains) as treatment for acute leukemia. 12 HIV viral loads in this patient have remained undetectable even in the absence of antiretroviral therapy.…”

“…Questions abound at multiple levels: Are the increased numbers of CD4 + T cells functional, and have these patients regained ‘meaningful' T-cell help? 11 Ex vivo assays of T-cell function could provide some indication of this. An even more basic question is whether de novo production of CD4 + T cells following ABM infusion is responsible for the observed increase?…”

“…This is unlikely based on studies of T-cell kinetics with highly active antiretroviral therapies (HAART) alone. 11 Past studies have tested the effects of infusion of autologous CD8 + T cells in HIV patients with some therapeutic effect; 18 however, this is unlikely to explain the increase in CD4 + T cells. Does the coupling of HAART with ABM infusion lead to a more significant effect, allowing the infused hematopoietic cells to persist and to generate new CD4 + T cells?…”