CD8+ T-cell immunity to HIV infection.

Fifteen years after the first, definitive reports of HIV-1-specific, CD8+ T cells [147,148], there is ample evidence for the importance of these cells in control of HIV-1 infection. As much is known of their role in the natural history of HIV-1 infection and their cellular and molecular mechanisms of reactivity than of T-cell responses to any other human virus. Indeed, HIV-1-related research has led the scientific field in revealing many new, fundamental principles of cellular immunity in the last 15 years. From these data, there are multiple, posited mechanisms for loss of CD8+ T-cell control of HIV-1 infection. These include both intrinsic defects in T-cell function and loss of T-cell recognition of HIV-1 because of its extraordinary genetic diversity and disruption of antigen presentation. Efforts have begun on devising approaches to reverse these immune defects in infected individuals and develop vaccines that induce T-cell immunity for protection from infection. Combination antiretroviral drug regimens now provide exceptional, long-lasting control of HIV-1 infection, even though they do not restore anti-HIV-1 T-cell immunity fully in persons with chronic HIV-1 infection. Very encouraging results show that such treatment can maintain normal T-cell reactivity specific for this virus in some persons with early HIV-1 infection. Unfortunately, the antiviral treatment does not cure the host of this persistent, latent virus. This has led to new strategies for immunotherapeutic intervention to enhance the level and breadth of the T-cell repertoire specific for the host's residual virus in persons with chronic HIV-1 infection. Although the principles of immunotherapy stem from early in the last century, modern era approaches are integrating highly sophisticated, molecular and cell biology reagents and methods for control of HIV-1 infection. The most promising immunotherapies are autologous virus activated in vivo by STI or administered in autologous DC that have been engineered ex vivo. There are also compelling rationales supported by animal models and early clinical trials for use of cytokines and chemokines as recombinant proteins or DNA to augment anti-HIV-1 T-cell reactivity and trafficking of T cells and APC to tissue sites of infection. For prevention of HIV-1 infection, the discouragingly poor results of vaccine development in the late 1980s and early 1990s have led to very encouraging, recent studies in monkeys that show partially protective and possibly sterilizing immunity. Finally, clinical trials of new-generation DNA and live vector vaccines already have indications of improved induction of HIV-1-specific T-cell responses. Knowledge of HIV-1-specific T-cell immunity and its role in protection from HIV-1 infection and disease must continue to expand until the goal of complete control of HIV-1 infection is accomplished.