OBJECTIVE:To identify disease patterns in AIDS-related focal brain lesions (FBL) and to design a decision-making strategy for differential diagnosis. DESIGN:Prospective study. Probabilities of CNS disorders were calculated using Bayes' theorem according to clinical variables (mass effect at CT or MRI, Toxoplasma serology, anti-Toxoplasma prophylaxis) and to the results of polymerase chain reaction (PCR) assays. PATIENTS:136 consecutive HIV-infected patients with a definitive diagnosis of FBL-causing disorder observed from 1991 to 1995 in a single clinical setting. INTERVENTIONS:Patients underwent empiric anti-Toxoplasma therapy. After 3 weeks, patients with progressive/stable disease underwent brain biopsy. In 66 patients Epstein-Barr virus (EBV)-DNA, JC virus (JCV)-DNA, and T gondii-DNA amplification was performed by PCR in CSF. Diagnostic criteria were histopathologic examination of bioptic or autoptic tissue specimens for all disorders and complete/partial resolution of FBL after empiric therapy for toxoplasmic encephalitis (TE). RESULTS:Neuroradiologic characteristics did not discriminate between TE and primary CNS lymphoma (PCNSL). Probability of TE was 0.87 in Toxoplasma-seropositive patients with mass effect who were not receiving anti-Toxoplasma prophylaxis, but only 0.59 if prophylaxis was performed. In seronegative patients with mass effect, the likelihood of PCNSL was 0.74. If EBV-DNA or T gondii-DNA tests were positive, the probability of PCNSL or TE increased to more than 0.96. The absence of T gondii-DNA did not exclude the possibility of a TE diagnosis. Among FBL without mass effect, the probability of progressive multifocal leukoencephalopathy (PML) was 0.81; this increased to 0.99 if JCV-DNA testing was positive. Sensitivity of brain biopsy was 93%, with a perioperative morbidity of 12% and a mortality of 2%. CONCLUSIONS:Due to the low diagnostic capability of clinical variables, PCR amplifications in CSF, especially for EBV-DNA and for JCV-DNA, represent, in most cases, an essential step in the differential diagnosis of AIDS-related FBL. This is particularly true in patients with FBL without mass effect or with mass effect and who are either seronegative or undergoing anti-Toxoplasma prophylaxis. Brain biopsy remains a necessary procedure in EBV-DNA-positive cases and in seronegative patients with FBL displaying a mass effect. Positive JCV-DNA testing may obviate the need for brain biopsy in patients with FBL without mass effect. An advanced diagnostic strategy based on combined clinical criteria and PCR tests may allow rapid and accurate identification of patients for prompt brain biopsy or specific therapy.

The Cdk2 kinase has long been known to be involved in the progression of mammalian cells past the G1 phase restriction point and through DNA replication in the cell cycle. The Rb family of proteins, consisting of pRb, p107, and pRb2/p130, has also been shown to monitor progression of G1 phase, mostly through their interaction with E2F family members. p107 is able to inhibit Cdk2 kinase activity through this interaction via a p21-related domain present in the C terminus of the protein. We show here that pRb2/p130 also possesses this activity, but through a separate domain. Moreover, we correlate the increased expression of pRb2/p130 during various cellular processes with the decreased kinase activity of Cdk2. We hypothesize that pRb2/p130 may act not only to bind and modify E2F activity, but also to inhibit Cdk2 kinase activity in concert with p21 in a manner different from p107.

Transgenic mice harboring the early genome from the human neurotropic JC virus, ICV, develop massive abdominal tumors of neural crest origin during 6-8 months after birth and succumb to death a few weeks later. The viral early protein, T-antigen, which possesses the ability to transform cells of neural origin, is highly expressed in the tumor cells. Immunoblot analysis of protein extract from tumor tissue shows high level expression of the tumor suppressor protein, p53, in complex with T-antigen. Expression of p21, a downstream target for p53, which controls cell cycle progression by regulating the activity of cyclins and their associated kinases during the G1 phase, is extremely low in the tumor cells. Whereas the lever of expression and activity of cyclin D1 and its associated kinase, cdk6, was modest in tumor cells, both cyclin A and E, and their kinase partners, cdk2 and cdk4, were highly expressed and exhibited significant kinase activity. The retinoblastoma gene product, pRb, which upon phosphorylation by cyclins:cdk induces rapid cell proliferation, was found in the phosphorylated slate in tumor cell extracts, and was detected in association with ICV T-antigen. The transcription factor, E2F-1, which dissociates from the pRb-E2F-1 complex and stimulates S phase-specific genes upon phosphorylation of pRb and/or complexation of pRb with the viral transforming protein, was highly expressed in tumor cells. Accordingly, high level expression of the E2F-1-responsive gene, proliferating cell nuclear antigen (PCNA), was detected in the tumor cells. These observations suggest a potential regulating pathway that, upon expression of ICV T-antigen, induces formation and progression of tumors of neural origin in a whole animal system. (C) 1997 Wiley-Liss, Inc.

The histone H4 gene promoter provides a paradigm for defining transcriptional control operative at the G1/S phase transition point in the cell cycle. Transcription of the cell cycle-dependent histone H4 gene is upregulated at the onset of S phase, and the cell cycle control element that mediates this activation has been functionally mapped to a proximal promoter domain designated Site II. Activity of Site II is regulated by an E2F-independent mechanism involving binding of the oncoprotein IRF2 and the multisubunit protein HiNF-D, which contains the homeodomain CDP/cut, CDC2, cyclin A, and the tumor suppressor pRb. To address mechanisms that define interactions of Site II regulatory factors with this cell cycle control element, we have investigated these determinants of transcriptional regulation at the G1/S phase transition in FDC-P1 hematopoietic progenitor cells. The representation and activities of histone gene regulatory factors were examined as a function of FDC-P1 growth stimulation. We find striking differences in expression of the pRb-related growth regulatory proteins (pRb/p105, pRb2/p130, and p107) following the onset of proliferation. pRb2/p130 is present at elevated levels in quiescent cells and declines following growth stimulation. By contrast, pRb and p107 are minimally represented in quiescent FDC-P1 cells but are upregulated at the G1/S phase transition point. We also observe a dramatic upregulation of the cellular levels of pRb2/p130-associated protein kinase activity when S phase is initiated. Selective interactions of pRb and p107 with CDP/cut are observed during the FDC-P1 cell cycle and suggest functional linkage to competency for DNA binding and/or transcriptional activity. These results are particularly significant in the context of hematopoietic differentiation where stringent control of the cell cycle program is requisite for expanding the stem cell population during development and tissue renewal.

p53 mutations are among the most frequent genetic alterations reported in human lung cancer. Although the prognostic value of altered p53 expression is still debated, it is accepted widely that estimation of the proliferation rate has an important prognostic role. Moreover, an association between certain types of human lung cancers and tobacco use is well known. Drawing from this background, we investigated the immunohistochemical expression of mutant oncogenic p53 protein, and related it to the smoking history of 61 patients with non-small cell lung carcinoma (NSCLC) and to the expression pattern of proliferating cell nuclear antigen (PCNA), which is considered to be an important negative prognostic factor in several neoplasms. We found p53 overexpression in 22 (36.1%) specimens, including 16 squamous carcinomas (41%) and six (27.2%) adenocarcinomas. PCNA nuclear staining was detected in 98.4% of the specimens, and a significantly higher PCNA expression score was found in all of the p53-positive samples. When the patient survival time was compared, p53 accumulation had a statistically significant negative prognostic value (P < .001). This was supported by a Kaplan-Meier survival percentage plot of immunohistochemically p53-undetectable specimens and p53-detectable specimens. These latter patients had a greatly reduced survival time. A relationship was established between p53 immunohistochemical detection and the smoking history of the patients. None of the specimens from the nonsmoking patients expressed immunohistochemically detectable p53 protein. Altered p53 expression was detected in 40.7% of smoking patients. Our findings support the hypothesis of involvement of p53 mutations in tobacco-induced carcinogensis and indicate that altered p53 expression plays an important prognostic role in NSCLC in smokers.

We investigated the PCNA immunoreactivity in 35 specimens of malignant mesothelioma and 20 specimens of mesothelial hyperplasia in order to evaluate the usefulness of this parameter in differentiating between these two mesothelial proliferations, and to determine whether PCNA has any prognostic significance in mesotheliomas. Eleven of the 35 investigated malignant mesotheliomas displayed up to 25% of positive cells for PCNA expression. The remaining 24 specimens showed high percentages of positive cells ranging from 26% to 95%. All specimens of reactive hyperplasia had less than 25% of PCNA positive cells. The difference between malignant mesothelioma and mesothelial hyperplasia for PCNA immunoreactivity was statistically significant (p < 0.01). A positive relationship was also found between PCNA expression level and the overall survival of those affected by malignant mesothelioma (p = 0.0032). Our results suggest on important role for PCNA in differentiating diagnosis of mesothelial proliferations. It remains unclear whether PCNA expression truly correlates with the proliferation rate of the malignant mesotheliomas and with the overall survival of patients affected by this neoplasm.

Despite its potential role as a tumor suppressor, p27 gene, a member of the Cip/Kip family of cyclin-dependent kinase inhibitor genes, has never been found mutated in human tumors. We investigated p27 protein expression in a series of 108 non-small cell lung cancers (57.4% stage 1, 16.7% stage 2, and 25.9% stage 3) to determine whether the lack or altered expression of this protein correlates with neoplastic transformation and/or progression. We performed immunohistochemistry and Western blot analysis of each specimen. We found that tumors expressing low to undetectable levels of p27 contained high p27 degradation activity. When we evaluated the outcome of the patients in relationship to p27 expression, we found p27 to be a prognostic factor correlating with the overall survival times (P = 0.0012). The possibility of a simple assay, such as the immunohistochemical analysis of p27 expression on routinely formalin-fixed, paraffin-embedded specimens, has considerable value for the prognosis of patients who undergo surgical resection. In addition, confirmation of the involvement of the proteasome-mediated proteolysis in p27 degradation should stimulate new strategies of nonsurgical treatments of non-small cell lung cancer.

We evaluated tissues for the overexpression of p53 protein in 35 malignant mesotheliomas and 20 reactive pleural hyperplasias, obtained from open biopsies or pleurectomies. Of the 35 neoplasms investigated, 30 (85.7%) displayed positive nuclear staining for p53. No staining was seen in any specimens of hyperplasia. We found no significant statistical difference in p53 expression when we compared p53 overexpression in the different histological subtypes of mesotheliomas. Moreover, p53 overexpression did not correlate in a statistical manner with survival. We conclude that p53 overexpression is a frequent feature of pleural mesothelioma and is useful for routine differentiating between malignant and non-neoplastic mesothelial alterations. The reason for p53 overexpression in mesothelioma, however, remains to be determined.

Neuroblastoma cells can undergo neural differentiation upon treatment with a variety of chemical inducers and growth factors. During this process, many cell cycle–related genes are downregulated while differentiation-specific genes are triggered. The retinoblastoma family proteins, pRb, p107, and pRb2/p130, are involved in transcriptional repression of proliferation genes, mainly through their interaction with the E2F transcription factors. We report that pRb2/p130 expression levels increased during differentiation of neuroblastoma cell line LAN-5. On the other hand, both pRb and p107 decreased and underwent progressive dephosphorylation at late differentiation times. The expression of B-myb and c-myb, two targets of the retinoblastoma family proteins, were downregulated in association with the increase of pRb2/p130, which was detected as the major component of the complex with E2F on the E2F site of the B-myb promoter in differentiated cells. Interestingly, E2F4, a preferential partner of p107 and pRb2/p130, was upregulated and underwent changes in cellular localization during differentiation. In conclusion, our data suggest a major role of pRb2/p130 in the regulation of B-myb promoter during neural differentiation despite the importance of cofactors in modulating the function of the retinoblastoma family proteins. J. Cell. Biochem. 67:297–303, 1997. © 1997 Wiley-Liss, Inc.

Background: Studies on the survival of AIDS-related primary central nervous system lymphoma(PCNSL) suggest the need of new strategies to better select patients to brain biopsy shortening time to diagnosis. The value of in vivo detection of EBV-DNA in CSF, highly correlated to AIDS-related PCNSL in retrospective studies, has still not been assessed. Objectives of the study were:1) to prospectively evaluate the efficiency of EBV-DNA detection in CSF in the diagnosis of AIDS-related PCNSL; 2) to assess the value of lumbar puncture (LP) for a non-invasive diagnostic approach for PCNSL; 3) to correlate several baseline variables to CSF expression of EBV-DNA. Methods: All pts with focal brain lesions (FBL) at CT/MRI observed during a 18-months period, underwent LP. if not contraindicated. Nucleic acids of EBV have been detected by EBER-1 in situ hybridization (RNA) and nested PCR with EBNA-1 primers (DNA, detection limit: 10 viral copies) on tissue samples (EBER-ISH) and on CSF obtained by either lumbar or ventricular puncture or during intrathecal chemotherapy (PCR). Epidemiological, clinical and neuroradiological features were collected. Factors as age 35aa, sexual transmission, CD4 level<50/µl, previous AIDS diagnosis, KPS level <50, presence of multiple or deep lesions at CT/MRI were all investigated for correlation to CSF expression of EBV-DNA and to response to therapy of PCNSI, using univariate analysis and multiple logistic regression. Results: 107 HIV-pts with FBL have been included: 29 had a histologic diagnosis of PCNSL and 4 were presumptive PCNSL; the other diagnoses were: PML=30; TE=32; others=12, EBER-1 viral transcripts were detected in 26 out of 28 patients analyzed (93%). In 94 pts(32 PCNSL) a CSF sample was available ("overall CSF"), and in 86 pts LP was performed (24 PCNSL), EBV-DNA was detected in 27/32 PCNSL with an "overall" sensitivity, specificity, PPV and NPV respectively of 84% (95%CI 66-94), 100% (95%CI 93-100), 100% (95%CI 84-100), 93% (95%CI 83-97). In 17 out of 24 PCNSL with lumbar CSF, EBV-DNA ws detected with a sensitivity of 71% (95%CI 49-87), a specificity of 100% (95%CI 93-100), a PPV of 100% (95%CI 77-100) and a NPV of 90% (95%CI 80-95). Therefore, in 17 out of 29 pts (sensitivity 59%) a non-invasive diagnosis of PCNSL could had been achievable with the detection of EBV-DNA after LP; in 62 out of 74 pts (84%) with FBL a diagnosis of PCNSL could had been excluded with the negativity of EBV-DNA drawn by LP. Among all the variables analyzed, we found at multivariate analysis that a sexual route of HIV transmission was the only factor correlated to CSF expression of EBV-DNA(O.R.=8.0; p=0.006). Considering response to treatment (radiation and/or chemotherapy), positivity of EBV-DNA in CSF is strongly correlated to a progression of disease (O.R.=7.5;p=0.007) at multivariate analysis. Conclusions: EBV-DNA in CSF is confirmed to be a sensitive and highly specific diagnostic marker of AIDS-related PCNSL; it allows a rapid selection of pts for brain biopsy. Because of the high specificity of the test it should be considered for a non-invasive diagnostic approach to PCNSL. More acquisitions regarding the pathogenesis of EBV lymphomagenesis in AIDS-related PCNSL are necessary to define not only the correlation between EBV-DNA in CSF and sexual transmission but also to evaluate factors related to a lack of CSF expression of EBV as well as its prognostic value.

Mammalian cell cycle progression is regulated by sequential activation and inactivation of cyclin-dependent kinases (cdks). Recently, several new members of the cdk family were cloned, and some of these were shown to complex with different cyclins and to be active at discrete stages of the cell cycle. PITALRE, a new member of this family, was cloned by our laboratory and was shown to be able to phosphorylate pRb protein in vitro. In the current work, we found that PITALRE kinase activity phosphorylated pRb at sites similar to those phosphorylated by the CDC2 kinase, which itself is known to mimic, in vitro, the in vivo phosphorylation of pRb. Phosphorylation of pRb by the PITALRE-associated kinase activity was on Ser residues exclusively. Moreover, we investigated the expression pattern of PITALRE in normal human tissues, using immunohistochemical techniques so as to gain additional data on the characteristics of this new cdk family member. The protein was widely expressed, although a different tissue distribution and/or level of expression was found in various organs. Some specialized tissues such as blood, lymphoid tissue, ovarian cells, and the endocrine portion of the pancreas showed a high expression level of PITALRE. The specific expression pattern found suggests that PITALRE may be involved in specialized functions in certain cell types. (C) 1997 Wiley-Liss, Inc.

Two proteins, p107 and pRb2/p130, which are structurally and functionally similar to the product of the retinoblastoma gene (pRb), were cloned by taking advantage of their ability to bind transforming proteins of DNA tumor viruses through a particular region called the "pocket domain." Like pRb, both proteins play a fundamental role in growth control. Using immunocytochemical techniques, we examined a variety of normal human tissues for the expression of pRb2/p130 and p107. Both proteins were expressed ubiquitously, although a different tissue distribution and/or level of expression were found in various organs. Terminally differentiated cells, such as neurons and skeletal muscle, showed high expression levels for Rb2/p130, whereas p107 was expressed at higher levels in other cell types such as epithelia of the breast and prostate. We then examined the expression pattern of Rb2/p130 in 158 specimens of human lung cancer and found an inverse correlation between the histological grading of the tumors, the development of metastasis, and the level of expression of Rb2/p130.

Recent evidence suggested a role for the cell cycle dependent kinases cdc2 and cdk2 in apoptosis. An important mechanism by which many cell types could undergo apoptosis is through the activation of the Fas molecule on the cell membrane. To investigate whether Fas-induced cell death activated cdc2 and cdk2 kinases inappropriately, the human T lymphoma cells HUT-78, which express a high copy number of Fas, and two other previously characterized subclones of the same cell line which express mutant, cell death-deficient dominant-negative forms of Fas, were Fas-challenged and the changes in cdc2 and cdk2 kinase activity monitored. In both wild-type and Fas-mutated HUT-78 cells, apoptosis was associated simultaneously with decreased cdc2 and increased cdk2 activity. This association suggested that changes in cdc2 and cdk2 kinase activity are secondary events in cell death mediated by Fas.

The human Rb2/p130 gene shares many structural and functional features with the retinoblastoma gene and the retinoblastoma-related p107 gene. In the present study, we have cloned and partially sequenced the gene coding for the Rb2/p130 protein from human genomic libraries. The complete intron-exon organization of this gene has been elucidated. The gene contains 22 exons spanning over 50 kb of genomic DNA. The length of individual exons ranges from 65 to 1517 bp. The largest intron spans over 9 kb, and the smallest has only 82 bp. The 5' flanking region revealed a structural organization characteristic of promoters of "housekeeping" and growth control-related genes. A typical TATA or CAAT box is not present, but there are several GC boxes and potential binding sites for numerous transcription factors. This study provides the molecular basis for understanding the transcriptional control of the Rb2/p130 gene and for implementing a comprehensive Rb2/p130 mutation screen using genomic DNA as a template.

Journal of Eukaryotic MicrobiologyVolume 43, Issue 5 p. 118S-119S Detection of T.gundii-DNA by PCR in AIDS-related toxoplasmic encephalitis. ANTONELLA CINGOLANI, ANTONELLA CINGOLANI Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this authorANDREA DE LUCA, ANDREA DE LUCA Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this authorADRIANA AMMASSARI, ADRIANA AMMASSARI Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this authorRITA MURRI, RITA MURRI Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this authorANGELA LINZALONE, ANGELA LINZALONE Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this authorRITA GRILLO, RITA GRILLO Department of Microbiology, Catholic University, Rome, ItalySearch for more papers by this authorMARIA LETIZIA GIANCOLA, MARIA LETIZIA GIANCOLA Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this authorANDREA ANTINORI, ANDREA ANTINORI Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this author ANTONELLA CINGOLANI, ANTONELLA CINGOLANI Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this authorANDREA DE LUCA, ANDREA DE LUCA Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this authorADRIANA AMMASSARI, ADRIANA AMMASSARI Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this authorRITA MURRI, RITA MURRI Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this authorANGELA LINZALONE, ANGELA LINZALONE Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this authorRITA GRILLO, RITA GRILLO Department of Microbiology, Catholic University, Rome, ItalySearch for more papers by this authorMARIA LETIZIA GIANCOLA, MARIA LETIZIA GIANCOLA Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this authorANDREA ANTINORI, ANDREA ANTINORI Department of Infectious Diseases, Catholic University, Rome, ItalySearch for more papers by this author First published: September 1996 https://doi.org/10.1111/j.1550-7408.1996.tb05035.xCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References 1 Aurelius E., Johansson B., Skoldenberg B., Staland A., Forsgren M. Lancet (1990) 337: 189– 192. 2 Bacellar H., Munoz A., Miller EN Choen BA, Besley D., Selnes OA, Becker JT, McArthur JC Neurology (1994) 44: 1892– 1900. 3 Centers for Disease Control., Morbid Mortal Weekl Rep (1993) 41 (RR17): 1– 19. 4 De Luca A., Cingolani A., Linzalone A., Ammassari A., Murri R., Giancola ML, Maiuro G., Antinori A. Improved detection of JCV-DNA in cerebrospinal fluid for the diangosis of AIDS-related progressive rnultifocal leucoencephalopathy. J Clin Microbiol (1996) 34: 1343– 46. 5 Dupon M., Cazenave J., Pellegrin JL, Ragnaud JM, Cheyrou A., Fischer I., Leng B., Lacut JY. J CIin Microbiol (1995) 33: 2421– 2426. 6 Eggers C., Gross U., Klinker H., Schalke B., Stellbrink HJ, Kunze K. J Neurol (1994) 242: 644– 649. 7 Novati R., Castagna A., Morsica G., Vago L., Tambussi G., Ghezzi S., Gervasoni C., Bisson C., D'Arminio Monforte A., Lazzarin A. AIDS 1994; 8: 1691– 1694. Citing Literature Volume43, Issue5September 1996Pages 118S-119S ReferencesRelatedInformation

Toxoplasmic encephalitis (TE) is one of the major opportunistic infections of the central nervous system (CNS) and the most frequent cause of focal brain lesions (FBL) in patients with acquired immunodeficiency syndrome (AIDS) (Luft et al. 1993). CNS toxoplasmosis is rapidly progressive and fatal without treatment and has been reported to be the AIDS index diagnosis in 22%-51% of patients infected with human immunodeficiency virus (HIV) (Leport et al. 1988; Cohn et al. 1989; Dannemann et al. 1991; Zangerle et al. 1991; Porter and Sande 1992).

Seventy-eight asymptomatic HIV-seropositive (aHIV) subjects were examined by means of an extensive neuropsychological test battery in comparison with 32 HIV-seronegative controls. They were also tested with regard to CD4+ and serum p24 antigen. Fifty-six of them completed a clinical follow-up of 12 up to 36 months and 35 also underwent a second session of neuropsychological, CD4+ and p24 antigen assessments at a 12- to 18-month interval from the first session. Results obtained lead to the following conclusions: (a) even among aHIV subjects there is a significant prevalence (28.2%) of cognitive abnormalities for which no cause other than HIV can be found, and therefore this suggests the possible development of HIV-related brain damage since the earliest stages of infection; (b) most sensitive to early HIV-related cognitive impairment are timed psychomotor tasks and memory tasks which require attention, learning and 'active' monitoring or retrieval of information; (c) during the early asymptomatic stages of HIV infection, there is no clear-cut evidence of a cross-sectional relationship between cognition and immunological/ virological markers (at least in the high ranges of CD4+ cell counts considered here); only in relatively more advanced stages does this relationship become evident in the subgroup of aHIV subjects with cognitive abnormalities; (d) the presence of cognitive abnormalities in early HIV infection is predictive of a further decrease in cognitive functioning and faster progression to AIDS-this latter reflected by a faster rate of decline in the number of CD4+ cells and by an increase in positivity of serum p24 antigen.