Development of Lymphoid Hyperplasia in Transgenic Mice Expressing the HIV tat Gene

HIV infection is accompanied by an early immune dysfunction limiting host control of virus and likely contributing to difficulties in achieving a successful vaccine against HIV. We report here that the HIV Tat protein is strongly immunosuppressive, both immediately after immunization of mice with soluble protein (sTat), and in seroconverting humans, and propose that Tat-induced suppression cripples immune surveillance to HIV infection. We show that macrophages are sensitive to sTat stimulation at concentrations 1,000-fold lower (500 pM) than T cells, and this stimulation is accompanied by the immunosuppressive induction of Fas ligand on the macrophage. T cell proliferative defects induced by sTat in vitro can be completely (at lower concentrations of sTat) or partially (at higher concentrations) reversed by antagonists to Fas͞Fas ligand interaction. We further report a method to preserve immunogenicity while inactivating Tat immunosuppression through oxidation, which advances the use of oxidized Tat as a component of an anti-HIV vaccine. These observations define additional methods to study the immunosuppressive functions of sTat that now may be rapidly applied to primary isolates from individuals with differing clinical courses. Our findings have immediate relevance for vaccine development, by describing and supporting a strategy that includes inactivated sTat in a multicomponent, anti-HIV vaccine.

Section: Discussionmentioning

confidence: 99%

Pronounced acute immunosuppression in vivo mediated by HIV Tat challenge

Cohen

Ding

et al. 1999

“…A Tat transgene was reported to cause dermal lesions resembling Kaposi sarcoma (13) or lymphoid hyperplasia in spleen and lymph nodes, and B cell lymphoma (14) when expression was regulated by the viral long terminal repeat (LTR) or a heterologous promoter, respectively. Expression of a nef transgene driven by the HIV-1 LTR also resulted in dermal lesions (15).…”

mentioning

confidence: 99%

An HIV-1 transgenic rat that develops HIV-related pathology and immunologic dysfunction

Reid

Sadowska

Denaro

et al. 2001

331

407

We report, to our knowledge, the first HIV type 1 (HIV-1) transgenic (Tg) rat. Expression of the transgene, consisting of an HIV-1 provirus with a functional deletion of gag and pol, is regulated by the viral long terminal repeat. Spliced and unspliced viral transcripts were expressed in lymph nodes, thymus, liver, kidney, and spleen, suggesting that Tat and Rev are functional. Viral proteins were identified in spleen tissue sections by immunohistochemistry and gp120 was present in splenic macrophages, T and B cells, and in serum. Clinical signs included wasting, mild to severe skin lesions, opaque cataracts, neurological signs, and respiratory difficulty. Histopathology included a selective loss of splenocytes within the periarterial lymphoid sheath, increased apoptosis of endothelial cells and splenocytes, follicular hyperplasia of the spleen, lymphocyte depletion of mesenteric lymph nodes, interstitial pneumonia, psoriatic skin lesions, and neurological, cardiac, and renal pathologies. Immunologically, delayed-type hypersensitivity response to keyhole limpet hemocyanin was diminished. By contrast, Ab titers and proliferative response to recall antigen (keyhole limpet hemocyanin) were normal. The HIV-1 Tg rat thus has many similarities to humans infected with HIV-1 in expression of viral genes, immune-response alterations, and pathologies resulting from infection. The HIV-1 Tg rat may provide a valuable model for some of the pathogenic manifestations of chronic HIV-1 diseases and could be useful in testing therapeutic regimens targeted to stages of viral replication subsequent to proviral integration.

“…It is actively released from HIV-infected cells as a biologically active protein (3,4). Expression of the tat gene in transgenic mice induces hyperplasia in lymphoid tissues and tumors of different histotypes, including lymphoma, suggesting that Tat could play a direct role in causing cancer (5)(6)(7). Extracellular Tat and basic fibroblast growth factor synergize in inducing Kaposi sarcoma (8).…”

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confidence: 99%

Reciprocal modulations between p53 and Tat of human immunodeficiency virus type 1.

Wang

Friedman

et al. 1995

112

Infection by human immunodeficiency virus type 1 (HIV-1) causes acquired immunodeficiency syndrome (AIDS) after a long clinical latency. This disease is associated with a spectrum of cancers. Here we report that wild-type p53 is a potent suppressor of Tat, a major transactivator of HIV-1. Reciprocally, Tat inhibits the transcription of p53. Downregulation of p53 by upregulated tat may be important for the establishment of productive viral infection in a cell and also may be involved in the development of AIDS-related malignancies.