Immune control of HIV-1 infection after therapy interruption: immediate versus deferred antiretroviral therapy

Abstract Background The optimal stage for initiating antiretroviral therapies in HIV-1 bearing patients is still a matter of debate. Methods We present computer simulations of HIV-1 infection aimed at identifying the pro et contra of immediate as compared to deferred Highly Active Antiretroviral Therapy (HAART). Results Our simulations highlight that a prompt specific CD8+ cytotoxic T lymphocytes response is detected when therapy is delayed. Compared to very early initiation of HAART, in deferred treated patients CD8+ T cells manage to mediate the decline of viremia in a shorter time and, at interruption of therapy, the virus experiences a stronger immune pressure. We also observe, however, that the immunological effects of the therapy fade with time in both therapeutic regimens. Thus, within one year from discontinuation, viral burden recovers to the value at which it would level off in the absence of therapy. In summary, simulations show that immediate therapy does not prolong the disease-free period and does not confer a survival benefit when compared to treatment started during the chronic infection phase. Conclusion Our conclusion is that, since there is no therapy to date that guarantees life-long protection, deferral of therapy should be preferred in order to minimize the risk of adverse effects, the occurrence of drug resistances and the costs of treatment.</p

Retroviral transfer of donor MHC class I or MHC class II genes into recipient bone marrow cells can induce operational tolerance to alloantigens in vivo.

Infusion of allogeneic, donor bone marrow (BM) can induce specific immunological unresponsiveness in vivo resulting in long-term acceptance of subsequent fully allogeneic, donor-type solid organ grafts, but this may be associated with graft-versus-host disease. We hypothesize that transfer of donor MHC gene(s) to recipient-type BM or hematopoietic stem cells would enable delivery of donor alloantigens to the recipient without the risk of graft-versus-host disease. This strategy could also potentially take advantage of linked suppression to induce specific unresponsiveness to additional alloantigens expressed by the solid organ graft. We found that infusion of 5 x 10(6) CBA (H-2(k)) recipient mouse BM cells transduced with a recombinant replication-defective retrovirus encoding either a single donor MHC class I or class II gene (H-2K(b) or H-2IA(b)) in combination with anti-CD4 monoclonal antibody resulted in long-term survival of C57BL/10 (H-2(b)) but not third-party NZW (H-2(z)) heart grafts. BM cells (3 x 10(3)) enriched for hematopoietic stem cells by sorting for c-Kit(+), lineage-negative cells, were able to induce long-term allograft survival in 50% of recipients after transduction with the vector encoding a single donor MHC class I gene. These results have important implications for future strategies to enhance clinical allograft survival by delivery of donor alloantigens

Immunology of solid tumors beyond tumor-infiltrating lymphocytes: The role of tertiary lymphoid structures

Immune cells and other constituents of the immune system make up an important part of the tumor microenvironment. Due to increased knowledge on the biology of the immune system in solid tumors and the successes with the treatment of patients with drugs that target its function, interest in immuno-oncology has increased enormously since the first successful trials. The first part of this chapter gives an overview of our current understanding of the role of the immune system in solid tumors, with a focus on the role of tumor-infiltrating lymphocytes (TILs) and their organization in structures called tertiary lymphoid structures (TLS). The increased interest in immuno-oncology has also triggered the search for predictive and prognostic biomarkers. One of the best characterized tissue-based biomarkers of the immune response in solid tumor is the presence of TILs. The second part of the chapter, which focuses on breast cancer, describes currently available data on TILs as a prognostic biomarker, challenges on the assessment of TILs, and TLS and the efforts of the International Immuno-Oncology Biomarker Working Group on standardization of its assessment.SCOPUS: ch.binfo:eu-repo/semantics/publishe