Perspectives on inducing efficient immune control of HIV-1 replication - anew goal for HIV therapeutics?

Objectives: A goal for long-term therapy of HIV infection is immune control of virus replication rather than the somewhat unrealistic aim of complete viral elimination. This paper will review the evidence that the control of viral infection can be achieved by an active CD8+ T-cell-mediated response. Design: This review will draw on both experimental and clinical sources to discuss the potential mechanisms of the immune control. Results: Data indicate that HIV infection can be effectively controlled by HIV-specific CD8+ T-cell-mediated responses. In infected individuals, the d evelopment of active cytotoxic T lymphocytes (CTLs, as measured by lyric ac tivity) is associated with the control of viral replication. Within the sim ian immunodeficiency virus infection model in rhesus macaques, strong CTL r esponses are similarly associated with effective viral control. In addition , depletion by antibodies of CD8+ T cells within infected macaques results in rapid increases in viral load. However, in most HIV-infected individuals , the CD8+ T-cells response is inefficient at low antigen dose, probably du e to the lack of an effective HIV-specific CD4+ T-cell response. If this CD 4+ T-cell response is lost due to viral induced anergy, rather than clonal deletion, such responses may he generated by interruptions in antiretrovira l treatment, and/or therapeutic immunization in chronically infected patien ts. A strong immune response stimulated at low-antigen dose early during vi ral rebound may be critical in preventing accumulation of toxic viral produ cts that might inhibit effective CD4+ T-cel[ responses. Conclusion: immune control of HIV infection is a realistic goal. Understand ing both the basic immune mechanisms of in vivo viral replication and ident ifying practical therapeutic regimens to activate HIV CD4+ and CD8+ T-cell responses may allow the development of efficient immune control of HIV repl ication in chronically infected patients. (C) 2001 Lippincott Williams & Wi lkins.