Contribution of immune activation to the pathogenesis and transmission of human immunodeficiency virus type 1 infection

Abstract

The life cycle of human immunodeficiency virus type 1 (HIV-1) is intricately related to the activation state of the host cells supporting viral replication. Although cellular activation is essential to mount an effective host immune response to invading pathogens, paradoxically the marked systemic immune activation that accompanies HIV-1 infection in vivo may play an important role in sustaining phenomenal rates of HIV-1 replication in infected persons. Moreover, by inducing CD4+ cell loss by apoptosis, immune activation may further be central to the increased rate of CD4+ cell turnover and eventual development of CD4+ lymphocytopenia. In addition to HIV-1-induced immune activation, exogenous immune stimuli such as opportunistic infections may further impact the rate of HIV-1 replication systemically or at localized anatomical sites. Such stimuli may also lead to genotypic and phenotypic changes in the virus pool. Together, these various immunological effects on the biology of HIV-1 may potentially enhance disease progression in HIV-infected persons and may ultimately outweigh the beneficial aspects of antiviral immune responses. This may be particularly important for those living in developing countries, where there is little or no access to antiretroviral drugs and where frequent exposure to pathogenic organisms sustains a chronically heightened state of immune activation. Moreover, immune activation associated with sexually transmitted diseases, chorioamnionitis, and mastitis may have important local effects on HIV-1 replication that may increase the risk of sexual or mother-to-child transmission of HIV-1. The aim of this paper is to provide a broad review of the interrelationship between immune activation and the immunopathogenesis, transmission, progression, and treatment of HIV-1 infection in vivo.

FIG. 1

Consequences of immune activation in HIV-1 infection in vivo. This conceptual diagram highlights the broad consequences of immune activation on the biology of HIV-1 and on lymphoid cell populations in vivo and their subsequent effect on HIV-1 transmission, disease progression, and survival in HIV-1-infected persons.

FIG. 2

Replication and intercellular transmission of HIV-1 is increased during antigen presentation. Macrophages serve as long-lived reservoirs of HIV-1 infection. During antigen presentation (both HIV-1 antigens and other antigens), activation of macrophages and CD4⁺ T lymphocytes leads to potent upregulation of proinflammatory cytokine secretion and HIV-1 transcription. This provides the ideal microenvironment for transmission of HIV-1 to CD4⁺ cells and for rapid HIV-1 replication in an expanding pool of activated memory (CD45RO⁺) cells. Selective infection of antigen-specific memory CD4⁺ cells may also lead to selective loss of this clone of cells.

FIG. 3

Cellular transcription factors that bind to the HIV-1 LTR. The HIV-1 promoter is functionally divided into the modulatory enhancer region and the core promoter region, which both lie upstream of the transcription start point, and the transactivation response region (TAR), which lies downstream. The interaction of these cellular transcription factors with the HIV-1 promoter results in the tight coordination of HIV-1 replication to the activation state of the host cell.