Publications

To determine whether neurological and neuropsychological abnormalities are associated with clinical manifestations of human immunodeficiency virus type 1 (HIV-1) infection in men who do not have acquired immunodeficiency syndrome (AIDS), we performed a historical prospective and cross-sectional study. One hundred HIV-1 seropositive homosexual or bisexual men, of whom 26 had AIDS-related complex, 31 had generalized lymphadenopathy, and 43 had no signs or symptoms of HIV-1 infection, and 157 HIV-1 seronegative men were enrolled from a cohort of 6,701 men who were originally recruited between 1978 and 1980 for studies of hepatitis B virus infection. Evaluation included medical history, physical examination, and neuropsychological tests. Of 26 HIV-1 seropositive subjects with AIDS-related complex, 11 (42%) reported neurological, cognitive, or affective symptoms compared with 30 (19%) of 157 HIV-1 seronegative subjects (relative risk = 2.2, p = 0.02). On neuropsychological testing, subjects with AIDS-related complex performed at a significantly lower level than the HIV-1 seronegative group (p = 0.001). A significantly higher percentage of subjects with AIDS-related complex (8[31%]of 26) than HIV-1 seronegative subjects (19 [12%] of 157) had abnormal results on two or more neuropsychological tests (rate ratio = 2.5, p = 0.03). Symptoms and impairment on neuropsychological tests were correlated only within the group who had AIDS-related complex. Subjects with generalized lymphadenopathy and subjects who had no signs or symptoms of HIV-1 infection were not different from HIV-1 seronegative subjects with respect to symptoms or performance on neuropsychological tests.(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated the biochemical basis for negative regulation of interleukin 2 receptor alpha-chain (IL-2R alpha) gene expression. Transient transfection studies employing internally deleted forms of the IL-2R alpha promoter localized a negative regulatory element (NRE) between nucleotides -400 and -368 relative to the major distal transcription start (cap) site. This 31-base-pair (bp) element is involved in the attenuation of both basal and inducible IL-2R alpha promoter activity. Comparison of this IL-2R alpha NRE with other known regulatory motifs revealed an 11-bp core element (TTCATCCCAGG) that was strikingly similar to a protein-binding domain within the long terminal repeat of the type 1 human immunodeficiency virus (HIV-1). This viral domain has been previously implicated in the negative control of HIV-1 gene expression. In vitro protein-DNA binding studies demonstrated that the same constitutively expressed approximately 50-kDa protein (SP-50) specifically bound to both the IL-2R alpha and HIV-1 NRE core elements. Mutation of the 11-bp IL-2R alpha NRE core element, which disrupted protein binding, significantly augmented basal as well as Tax protein- or phorbol ester-induced IL-2R alpha promoter activity in vivo, suggesting that SP-50 functions as a transcriptional silencer.

The factors operative during normal and disease states which govern the degradation of the glomerular extracellular matrix (ECM, glomerular basement membrane and mesangial matrix) remain poorly understood. These structures consist primarily of types IV and V collagen, which are highly resistant to the action of classical interstitial collagenases. Here we report that an intrinsic glomerular cell type, the human mesangial cell, secretes: 1) a neutral proteinase with specific activity against type IV basement membrane collagen and, 2) an inhibitory protein with the characteristics of the tissue inhibitor of metalloproteinases (TIMP). The purified enzyme has a neutral pH optimum, consists of a basic (pI 8.4) protein doublet with molecular weight of 66 and 68 kilodaltons, and is inhibited by calcium and zinc chelators. The enzyme degrades both soluble and basement membrane type IV collagen, but does not specifically degrade types I or V collagen or casein. Immunohistochemistry of cultured cells demonstrated homogeneous staining for the neutral proteinase antigen, while the TIMP antigen was detected in fewer than one-third of cultured cells. These findings suggest that the synthesis of these proteins may be independently regulated. The secretion of these factors may play an important role in the turnover of the glomerular ECM under basal or pathologic conditions.