In an effort to go beyond immune-based therapies, researchers are now considering the implications of apoptosis dysregulation during HIV-induced immunodeficiency. This work provides the first comprehensive compendium of the progress made in understanding the process of cell death related to HIV and the potential breakthroughs in treatment that offer much promise. Combining the work of more than two-dozen top researchers, this seminal volume provides clinicians and researchers with an excellent reference, while also serving as an incubator to stimulate future research. It explains the fundamental biology involved with apoptosis, explains its clinical impact in HIV, and examines the newest therapeutic approaches.

In the past decade, the global efforts in the control of HIV disease were basically concentrated on the search for anti-retroviral agents. So far, anti-HIV therapies have been shown to be disappointing because of rapid development of drug-resistant mutant variants. Despite this drawback in the therapeutic fight against HIV infection, antiviral research should be actively pursued. However, failure of antiviral therapy indicates that other avenues of research should be rapidly explored with the same energy. In this setting, striking advances have been recently made in the dissection and understanding of the viro-immunological processes governing the progressive destruction of lymphoid organs associated with AIDS develop ment, and HIV-induced activation and apoptosis have been identified as key phenomena of the immune system destruction. This book assembles the most recent advances on basic and clinical aspects ofT-cell activationiapoptosis in HIV infection and their implications for immunotherapy. These data were presented at an international symposium held on July 11-12, 1994, in Paris. The book is partitioned into 21 chapters covering four comprehensive fields: 1) T-celllmacrophage activation and HIV infection; 2) Apoptosis and viropathogenesis of HI V disease; 3) Apop tosis and immunopathogenesis ofHIV disease; 4) Mediators ofT-cell activationiapoptosis and therapeutic applications. We hope that this book will assist the readers in understanding recent advances in the viro-immunopathogenesis of HI V disease as well as the rationales for potential immune cell-targeted therapeutic interventions.

Progression to AIDS is driven by HIV depletion of CD4 T cells. Most CD4 T cells residing in lymphoid tissues die from abortive HIV infection. During abortive infection, HIV fuses normally to quiescent cells but the elongation step of reverse transcription is very inefficient leading to cytoplasmic accumulation of short DNA transcripts. The host DNA sensor IFI16 detects these incomplete viral DNAs triggering both interferon-[beta] expression and the assembly of inflammasomes containing caspase 1. Caspase 1 activation induces pyroptosis, a highly inflammatory form of programmed cell death. We studied whether this mechanism also promotes the death of quiescent, non-permissive CD4 T cells circulating in the blood. Here we report that blood CD4 T cells are highly resistant to pyroptosis at least in part because they lack expression of the DNA sensor, IFI16. However, blood CD4 T cells undergo HIV induced pyroptosis when co-cultured with lymphoid tissue-derived CD4 T, CD8 T, or B cells. The interactions between these co-cultured cells induce IFI16 expression likely by mimicking events occurring within lymphoid organs. These results highlight a fundamental biological difference between blood and lymphoid tissue-derived CD4 T cells and underscore AIDS as a disease of lymphatic tissue.

This volume has gathered some of the experts in the field to review aspects of our understanding of CMV and to offer perspectives of the current problems associated with CMV. The editors and authors hope that the chapters will lead to a better understanding of the virus that will assist in the development of new and unique antivirals, a protective vaccine, and a full understanding of CMV's involvement in human disease.

During the last 5 years, major advances have been made in our understanding of the pathogenesis of human immunodeficiency virus (HIV) disease and in the development of new potent antiviral agents. With regard to HIV pathogenesis, several recent observations have not only changed our perspectives of HIV disease, but have been critical for the design of therapeutic strategies.

The eradication of Human Immunodeficiency Virus (HIV) from infected patients is one of the major medical problems of our time, primarily due to HIV reservoir formation. Macrophages play important roles in HIV reservoir formation: once infected, they shield HIV against host anti-viral immune responses and anti-retroviral therapies, help viral spread and establish infection in anatomically protected sites. Thus, it is imperative to selectively induce the apoptosis of HIV-infected macrophages for a complete cure of this disease. I hypothesize that HIV infection dysregulates the expression of some specific genes, which is essential to the survival of infected host cells, and these genes can be targeted to selectively induce the apoptosis of HIV-infected macrophages. My objective is to identify the genes that can be targeted to eradicate HIV reservoir in macrophages, and to briefly elucidate the mechanism of cell death induced by targeting one of the identified genes. A four-step strategy was proposed to reach the goal. First, 90k shRNA lentivirus pool technology and microarray analysis were employed in a genome-wide screen of genes and 28 promising genes were found. Second, siRNA silencing was applied to validate these genes with 2 different HIV-1 viruses; as a result, 4 genes, Cox7a2, Znf484, Cdk2, and Cstf2t, were identified to be novel gene targets. Third, the 4 validated genes were characterized by literature review. Lastly, I briefly elucidated the mechanism of apoptosis induced by targeting one of the identified gene, Cox7a2. The results of this study can help to understand the mechanisms of HIV reservoir formation in macrophages and propose promising therapeutic targets for the eradication of HIV-infected macrophages from patients.