Role of CD8+ Lymphocytes in Control of Simian Immunodeficiency Virus Infection and Resistance to Rechallenge after Transient Early Antiretroviral Treatment

The typical course of infection observed in susceptible hosts infected with pathogenic primate immunodeficiency viruses is characterized by persistent progressive infection with continuous unrelenting viral replication. Various factors and mechanisms have been invoked to explain this, including the capability of these viruses to integrate into the host genome; to establish latent infection; to evade immune responses by mutation, concealment of key antigenic determinants, downregulation of major histocompatibility complex proteins, or other strategies to thwart immune mechanisms; and to attack, kill, or disable cells critically involved in coordinating the antiviral host immune response (5, 6, 25, 26). We and others have proposed that compromise of host immune responses during the critical interval of early infection results in an inability to establish an immune response capable of clearing or controlling the infection in the long term (1, 2, 15, 19, 29, 42, 43, 45). In particular, the loss of effective CD4 help for establishment of virus-specific memory CD8 cells capable of persisting even in the face of declining or very low levels of antigen is proposed as a key feature contributing to the establishment of persistent, progressive infection (1, 2, 15, 19, 42, 43, 45). According to this model, although it may take years for the process to progress to clinically manifest disease, much of the outcome may be largely determined during the critical first few weeks of infection, when the dynamic equilibrium between viral replication and host responses is established (16, 23, 36, 41). To evaluate the hypothesis that the dynamics of the virus-host interaction during the early stages of initial infection exert a profound influence on the subsequent immunologic, virologic, and clinical course of infection, we recently conducted a study using transient postinoculation antiretroviral treatment of simian immunodeficiency virus (SIV)-infected macaques to modulate viral replication during the immediate postinoculation period (15). Prior studies had established that certain regimens of short-term postinoculation (p.i.) antiretroviral treatment could prevent the emergence of measurable plasma viremia following cessation of drug administration (39, 40), but the detailed viral dynamics and host immune responses, particularly cellular immune responses, underlying this protection remained unexplored. Similarly, it remained unclear whether protection from emergent viremia following termination of antiretroviral treatment in this model was associated with protection from rechallenge with infectious pathogenic SIV. We addressed these questions in a recent study and demonstrated that in rhesus macaques inoculated with a highly pathogenic strain of SIV, certain transient postinoculation treatment regimens prevented the emergence of measurable plasma viremia following discontinuation of the treatment (15). Interestingly, this protective effect was associated with the development of SIV-specific lymphoproliferative responses, despite the absence of measurable amounts of virus or seroconversion during treatment or in the initial period following treatment (15). Strikingly, animals that appeared to have established control of their infections following only transient drug treatment also resisted a subsequent intravenous homologous rechallenge with SIV 6 weeks after discontinuation of drug treatment. Both the delay to initiation of treatment and the duration of treatment affected the outcome. However, even in animals in which measurable plasma virus was observed after treatment termination, peak levels of virus were often markedly blunted in comparison to those in untreated control animals. Many animals showed spontaneous progressive declines in plasma viremia, eventually to below the level of quantitation (100 copy Eq/ml of plasma), in the absence of any further experimental manipulation (15). In aggregate, these results strongly suggested that limitation of virus replication by drug treatment during the critical first weeks of infection permitted a more effective sensitization of the host than occurs during typical untreated infection. This drug-induced suppression of viral replication appeared to have allowed the establishment of host responses capable of controlling the infection, at least in the near term, despite the comparatively low levels of immune responses measured in the peripheral blood. Important questions that were not addressed in this earlier study include the durability of this control of viral replication, the durability of the resistance to rechallenge, the breadth of resistance to rechallenge with heterologous virus strains, and the underlying mechanism(s) responsible for control of the infection and resistance to rechallenge. We have conducted extended follow-up and further testing on a subset of animals from our previous study. The results clearly indicate that the protective effects observed extend for more than a year following the initial infection and drug treatment, that at least partial protection is conferred against rechallenge with highly heterologous virus isolates, and that control of the infection is mediated at least in part by CD8+ T lymphocytes. In aggregate, these results strongly suggest that limitation of virus replication by drug treatment during the critical first weeks of infection can permit a more effective sensitization of the immune system, allowing the establishment of an immune response capable of controlling the infection and resisting rechallenge. These findings have important implications both for understanding the pathogenesis of the primate lentiviruses and for developing vaccines for the prevention of AIDS.