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

We report, to our knowledge, the first HIV type 1 (HIV-1) transgenic (Tg) r at. Expression of the transgene, consisting of an HIV-1 provirus with a fun ctional deletion of gag and pol, is regulated by the viral long terminal re peat. Spliced and unspliced viral transcripts were expressed in lymph nodes , thymus, liver, kidney, and spleen, suggesting that Tat and Rev are functi onal. Viral proteins were identified in spleen tissue sections by immunohis tochemistry and gp120 was present in splenic macrophages, T and B cells, an d in serum. Clinical signs included wasting, mild to severe skin lesions, o paque cataracts, neurological signs, and respiratory difficulty. Histopatho logy included a selective loss of splenocytes within the periarterial lymph oid sheath, increased apoptosis of endothelial cells and splenocytes, folli cular hyperplasia of the spleen, lymphocyte depletion of mesenteric lymph n odes, interstitial pneumonia, psoriatic skin lesions, and neurological, car diac, and renal pathologies. Immunologically, delayed-type hypersensitivity response to keyhole limpet hemocyanin was diminished. By contrast, Ab tite rs and proliferative response to recall antigen (keyhole limpet hemocyanin) were normal. The HIV-1 Tg rat thus has many similarities to humans infecte d with HIV-1 in expression of viral genes, immune-response alterations, and pathologies resulting from infection. The HIV-1 Tg rat may provide a valua ble model for some of the pathogenic manifestations of chronic HIV-1 diseas es and could be useful in testing therapeutic regimens targeted to stages o f viral replication subsequent to proviral integration.