Human Immunodefiency Virus Research Articles

Neurotoxicity and dysfunction of dopaminergic systems associated with AIDS dementia.

Infection with the human immunodeficiency virus (HIV) selectively targets the basal ganglia resulting in loss of dopaminergic neurons. Although frequently asymptomatic, some patients may develop signs of dopamine deficiency de novo. Accordingly, they are highly susceptible to drugs that act on dopaminergic systems. Both neuroleptics and psychostimulants may exacerbate these symptoms. Experimental evidence suggests that viral proteins such as gp120 and Tat can cause toxicity to dopaminergic neurons, and this toxicity is synergistic with compounds such as methamphetamine and cocaine that also act on the dopaminergic system. In addition, other neurotransmitters that modulate dopaminergic function, such as glutamate and opioids, may also modify the susceptibility of the dopamine system to HIV. Therefore, a thorough understanding of the mechanisms that lead to this selective neurotoxicity of dopaminergic neurons would also likely lead to the development of therapeutic modalities for patients with HIV dementia.

Morphine inhibits human microglial cell production of, and migration towards, RANTES.

The beta-chemokine RANTES has recently been implicated in the neuropathogenesis of the human immunodeficiency virus. Based upon previous studies of the effects of morphine on microglial cell production of cytokines and chemotaxis towards the activated complement component C5a, we tested the hypothesis that this opiate would alter the production of and migration towards RANTES by human microglia. Treatment of highly purified microglial cell cultures with morphine (10(-8)-10(-6) M) potently inhibited RANTES production by lipopolysaccharide- and interleukin-1beta-stimulated cells. Using a chemotaxis chamber to assess directed migration towards RANTES, treatment of microglial cells with morphine (10(-10)-10(-6) M) was found to suppress chemotaxis. The inhibitory effects of morphine on RANTES production and on chemotaxis were blocked by naloxone and beta-funaltrexamine, indicating that morphine mediated its suppressive effects via activation of microglial p-opioid receptors. Morphine's inhibitory effect on chemotaxis did not appear to be associated with an alteration in RANTES-induced [Ca2+]i mobilization. While the clinical significance of these in-vitro findings is unknown, they suggest that mu-opioid receptor agonists could alter certain neurodegenerative and inflammatory processes within the brain.

Peripheral Blood Mononuclear Cells of HIV- and HCV-Antibody-Positive Individuals Contain HCV RNA but No HCV DNA despite Evidence for Reverse Transcription of HIV RNA into DNA

Following reports of the finding of cDNA of RNA viruses in cells containing an endogenous retrovirus-encoded reverse transcriptase, we looked for the presence of hepatitis C virus (HCV) DNA in peripheral blood mononuclear cells (PBMC) of injecting drug users seropositive for both HCV and human immunodefiency virus (HIV). We tested serial PBMC samples from four HCV infected individuals; one was seronegative for HIV, two seroconverted for HIV during follow-up, and one was seropositive for HIV throughout the study period. HCV RNA was found in PBMC and plasma samples at all time points tested. Similarly, HIV RNA was found in all PBMC and plasma samples following HIV seroconversion. In contrast, no HCV DNA was detected in any PBMC sample, whereas HIV DNA was found in all tested PBMC samples following HIV seroconversion, indicative of active HIV reverse transcriptase in these PBMC samples. These results do not support the hypothesis that HCV viraemia is related to retrotranscription of the HCV RNA genome into DNA in peripheral blood mononuclear cells coinfected with HIV. The potential of HIV RT to retrotranscribe HCV RNA into DNA awaits studies of liver cells coinfected with HCV and HIV.

The histologic pattern of non-Hodgkin's lymphomas in Ethiopians

Non-Hodgkin's lymphomas (NHLs) are among the malignancies that can arise in advanced stages of infection in patients with human immunodefiency virus (HIV). However, the pattern of this malignancy has not been reported in Ethiopia. A sixteen year retrospective review has been carried out to determine the trend, age, sex distribution, and histological types of non-Hodgkin's lymphoma from January 1982 to December 1997. A total of 544 cases of non-Hodgkin's lymphoma were available for analysis. An increasing trend is observed from 1995 onwards. The male-to-female ratio was 2.8:1 and the peak occurence was in the age group of 50-54 years. The most frequent histologic grade was high grade accounting for 237 (43.6%) followed by 162 (29.9%) low grade and intermediate grade of 139 (25.5%). Diffuse growth pattern was seen in 96% of cases and follicular in only 4%. The most frequent histological type was immunoblastic (30.3%) followed by small lymphocytic lymphoma (26.5%). Extranodal involvement was observed in one fourth (24.6%) of cases. This study showed that NHLs are a heterogeneous collection of lymphoreticular malignancies having a wide age coverage and various peculiar histological types. Unlike in the Western Countries, follicular NHLs are much less common here. A properly designed prospective study is recommended to observe the stage, prognostic markers, and treatment outcome of various types of non-Hodgkin's lymphoma. (Ethiopian Journal of Health Development, 2000, 14(3): 345-352)

Epithelial application of Pseudomonas aeruginosa exotoxin A results in a selective targeting to cells in the liver, spleen and lymph node

Pseudomonas aeruginosa exotoxin A (PE) is a 67-kDa protein expressed under the selective pressure of a low iron environment. Previous studies using non-toxic PE chimeras containing a viral surface antigen, the V3 loop of MN gp120 from human immunodefiency virus type 1 (HIV-1), resulted in not only an effective mucosal immunization but also a striking systemic immune response following epithelial application. Presently, we have examined the possibility that such a strong dual immune response was generated by the efficient targeting of critical cells of the immune system. Mice were dosed with 10 μg of toxic PE or a non-toxic mutant of PE (ntPE) by intratracheal instillation. Examination of lung, liver and spleen tissues isolated 4, 8 and 12 h following intratracheal instillation with PE demonstrated specific cell damage in these tissues which was not observed in mice dosed with ntPE. Based upon the location and characteristics of observed responses, the cells targeted by PE appear to be involved in the antigen presentation arm of the immune response. Since ntPE chimeras with inserted peptide antigen epitopes from a wide variety of pathogens are easy to prepare and administer, these results support this approach for mucosal immunization.

Biosafety considerations for flow cytometric analysis of human immunodeficiency virus-infected samples.

Since the recognition of human-immunodefiency virus (HIV-1, -2) infection as a separate disease entity, flow cytometry has been an invaluable tool for the study of the effects of these viruses on cellular parameters. As early as 1983, before the identification of the causative agents of the disease, immune abnormalities in circulating T lymphocyte subpopulations in patients affected with the Acquired Immunodeficiency Syndrome (AIDS) were noted (2,31). Most importantly, these patients presented with decreased numbers of CD4-bearing T lymphocytes; subsequently, CD4 cell frequencies as measured by flow cytometry were found to be highly prognostic for prediction of disease survival (32). Commercial availability of monoclonal antibodies to various cell surface antigens and the generation of different fluorochromes for multi-color flow cytometry provided the possibility of in-depth analysis of the alteration of immune cell subsets observed during HIVinfection (reviewed in 12,15) and has also led to the identification of alternate markers for disease progression (13,18). Thus, flow cytometers are utilized frequently in research and clinical laboratories to analyze HIV-infected samples. However, previous reports about the hazards associated with the use of flow cytometers have focused on cell sorting (10,11,21), because flow sorters generate droplets and aerosols during their normal operation and thus may expose operators to toxins or to pathogens contained in the samples to be sorted. Recently, the Biohazards Working Group of the International Society for Analytical Cytology (ISAC) has generated biosafety guidelines for cell sorting of unfixed, viable cells (30). The document contains recommendations for sample handling, operator training and protection, laboratory design, instrument setup and maintenance, and testing for instrument aerosol containment and is available in the full-text version on the internet from the webpage of the ISAC Biosafety Committee at http://www.isac-net.org/committees/biosafety/biosafety.html. The general recommendations as set forth in the ISAC biosafety guidelines are also applicable to cell sorting of samples known to contain HIV. In contrast, the current document focuses specifically on the practical safety aspects of flow cytometric analysis of HIV-infected samples and addresses areas that require special attention in laboratories which process known biohazardous samples and analyze them on flow cytometers.

Apport de l'épidémiologie clinique à la prise en charge de l'infection par le VIH

The objective of this publication is to make clinicians more aware of clinical epidemiology through our experience in the field of human immunodefiency virus (HIV) infection. Clinical epidemiology is aimed at studying diagnostic, therapeutic and prognostic aspects of diseases, and their consequences, with the objective of improving both scientific knowledge and patient's management. Examples, including longitudinal studies and clinical trials, illustrate the value of clinical epidemiology. Beyond HIV infection, the importance of both multidisciplinary collaboration and education of clinicians in regard to biostatistical and epidemiological methods is emphasized.

Haematologic features of the human immunodeficiency virus (HIV) infection in adult Zimbabweans.

To describe the haematologic features of the HIV infection in adult Zimbabweans and compare the features in the different clinical stages of the disease. Descriptive cross sectional study. Parirenyatwa Hospital, a tertiary and referral medical centre in Harare, and the blood donor clinics of the Blood Transfusion Service in Harare. Patients attending HIV outpatients clinics or receiving inpatient care at Parirenyatwa Hospital and asymptomatic persons donating blood at the BTS Harare. Full blood counts and bone marrow cell counts and morphology. Blood cytopenia was found in 47.5% of adults with HIV infection. The most frequent abnormalities were lymphopenia (31.5%); anaemia (30.8%); neutropenia (29.6%); thrombocytopenia (24.7%); eosinophilia (23.5%) and leucopenia (11.7%). Frequency of anaemia in the AIDS and symptomatic groups (43.4% and 24.5% respectively) was greater than in the carriers (6.7%), while the frequency of other cytopenias and of eosinophilia was about the same in all groups. There was also a general lack of association between the severity of haematologic abnormalities and the clinical stage of the disease. Severe haematologic changes occur frequently in HIV infection and AIDS but routine full blood count may not be helpful in the monitoring of the disease or the prediction of onset of AIDS.

HIV and people with serious mental illness: the public sector's role in reducing HIV risk and improving care.

The paper discusses issues related to the detection, prevention of transmission, and treatment of human immunodeficiency virus (HIV) infection among persons with serious mental illness and suggests ways public mental health systems can address these issues. MEDLINE was searched from 1980 through 1998, and all pertinent references were reviewed. Persons with severe mental illness are at greatly increased risk of HIV infection due to increased likelihood of high-risk sexual behaviors and injection drug use. The formidable barriers to detection and effective treatment of HIV that exist in this population can be attributed to the unique characteristics of this population, lack of knowledge and expertise among mental and physical health care providers, and fragmented mental and physical health care systems. In the last five years, treatments for HIV that are far more efficacious than earlier treatments have become available, making it more important for HIV infection be detected and treated among persons with serious mental illness. Public mental health systems need to implement active prevention policies and practices, educate both mental health and physical health care providers about key treatment issues, and develop effective linkages between mental and physical health care providers and systems.

External Quality Assessment of Transporting Infectious Substances in Canada

To determine the degree of compliance with Transport Canada's Transportation of Dangerous Goods Regulations for transporting infectious substances in Canada. A three-phase study including observation of packages arriving at the British Columbia Centre for Disease Control (BCCDC) provincial laboratory; observation of requested samples of either an Escherichia coli culture or serum, not human immunodeficiency virus (HIV) or HbsAg positive, from laboratories; and a questionnaire concerning training and certification of packers in laboratories. During phase 1, 500 packages arriving at the BCCDC provincial laboratory were assessed. All arrived intact, with 384 (76.8%) in a firm outer package. Only 178 (35.6%) contained absorbent material. Six samples were known to contain human immunodefiency virus or hepatitis B; all were appropriately packaged. Of the remainder, 11 (2.2%) were considered overpackaged, 192 (38.4%) acceptably packaged and 191 (38.2%) inadequately packaged. In phase 2, 138 requested packages were assessed. All arrived intact, 132 (95.7%) in a firm outer package. Ninety-six (69.6%) contained absorbent material. Only six (4.3%) were considered inadequately packaged. In phase 3, 171 laboratories responded to a questionnaire. Fifty-nine were from small laboratories, 53 from intermediate laboratories and 23 from large laboratories. Most laboratories (55.4%) relied on in-house resources to train packers. Only 26 (15.3%) facilities had no certified packers, and 60.8% noted they had a formal copy of the regulations available in the laboratory. Laboratory characteristics associated with the likelihood of overpackaging included number of technologists (χ(2)=5.72; P=0.058), number of samples processed by laboratories (χ(2)=8.46; P=0.015) and being a private laboratory as opposed to being a hospital laboratory (Fisher Exact two-tailed 0.040). Canadian laboratories tend to package safely and within the acceptable range of regulation, although not within the precision of regulation. Most laboratories have trained and certified packers. The most common error is the use of outer packaging that is not firm. Larger laboratories tend to overpackage resulting in increased costs.

Prevalence and clinical significance of intestinal microsporidiosis in human immunodeficiency virus-infected patients with and without diarrhea in Germany: a prospective coprodiagnostic study.

The prevalence of intestinal microsporidiosis among human immunodefiency virus (HIV)-infected persons with chronic diarrhea varies from 7% to 50%; thus, microsporidia are a significant source of morbidity and, occasionally, mortality among these patients. Anecdotal reports suggest that intestinal microsporidiosis is also an important infection in patients with AIDS in Germany. To determine the prevalence of microsporidiosis among HIV-infected patients in Germany, we performed a prospective coprodiagnostic study of 97 consecutive HIV-infected patients. Microsporidia were the most common enteropathogen identified in 18 (36.0%) of 50 patients with diarrhea and 2 (4.3%) of 47 patients without diarrhea (P < .001; chi2 test). Microsporidia were present in 60% of patients with chronic diarrhea and 5.9% of patients with acute diarrhea. The etiologic agent was Enterocytozoon bieneusi in 18 patients and Encephalitozoon intestinalis in two patients. The prevalence of intestinal microsporidiosis in this cohort of German patients with AIDS and diarrhea is one of the highest to be reported anywhere in the world. Microsporidiosis seems to represent one of the most important causes of diarrhea in HIV-infected patients in Germany and thus must be considered in the differential diagnosis for all AIDS patients presenting with diarrhea.

Orthopaedic Surgery in Hemophilic Patients With Human Immunodefiency Virus

Patients registered at the author's hemophilia center between 1982 and 1994 were studied to establish whether major orthopaedic surgical procedures accelerate the fall of CD4 lymphocyte counts of patients with hemophilia who are infected with the human immunodeficiency virus, and whether patients who had surgery had different rates of development of acquired immune deficiency syndrome or death when compared with patients who did not have surgery. The patients were divided into four groups: Group 1, 22 patients who were human immunodeficiency virus positive undergoing orthopaedic surgery; Group 2, 89 patients who were human immunodeficiency virus positive not undergoing orthopaedic surgery; Group 3, 18 patients who were human immunodeficiency virus negative undergoing orthopaedic surgery; and Group 4, 135 patients who were human immunodeficiency virus negative not undergoing orthopaedic surgery. There was no significant difference between the rates of decline of CD4 lymphocyte counts for patients who were human immunodeficiency virus positive who underwent surgery when compared with human immunodeficiency virus positive patients who did not undergo surgery, nor was there any significant difference between the two human immunodeficiency virus negative groups. There were no significant differences in the rate of development of acquired immune deficiency syndrome or mortality rates between patients who had surgery and those who did not.

1-Aryl-1H,3H-thiazolo[3,4-a]benzimidazole Derivatives

The structural features of some 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles active against human immunodefiency virus (HIV) are reported. The diffractometric analysis reveals that the title compounds, 1-(2,4-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole, C15H10F2N2S, 1-(2,6-dichlorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole, C15H10Cl2N2S, and 1-(2-chloro-4-fluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole, C15H10ClFN2S, all adopt a butterfly like conformation which appears to be particularly important for the inhibition of HIV-1 reverse transcriptase (RT), an enzyme which plays a key role in the viral life cycle.

Sulfadiazine-associated nephrotoxicity in patients with the acquired immunodeficiency syndrome.

We performed a computerized search on sulfadiazine-associated nephrotoxicity reported in human immunodefiency virus (HIV)-infected patients in the international literature. Including an original case report, we summarized 35 acquired immunodefiency syndrome (AIDS) patients from 1987 to 1995 in an analysis comparing their features to historical HIV-negative controls from the 1940s and 1950s. Likely due to a high prevalence of potential risk factors, incidence of sulfadiazine-associated renal impairment was 1.9%-7.5% in AIDS patients and 1%-4% in HIV-negative controls. Its occurrence appeared to be delayed in HIV-infected patients with a median of about 3 weeks of medication compared with about 10 days in HIV-negative subjects. Correspondingly, the cumulative sulfadiazine dose at manifestation doubled in AIDS patients with a median of 84 g versus 40 g in controls. Patients usually presented with flank or lumbar pain, oliguria, and (macro) hematuria. Urinalysis showed typical "sheaves of wheat" crystalluria, erythrozyturia, and, less commonly, leukozyturia and proteinuria. Echogenic (mostly peripelvic) densities, renal stones, and hydronephrosis are frequent findings on ultrasound examination, whereas X-ray examination possesses a low diagnostic sensitivity. The principle aim of therapy in these patients is to (re)institute the physicochemical urinary solubility of sulfadiazine and its metabolites. For this purpose, forced rehydration and, most importantly, urine alkalinization proved to be effective measures without an absolute need to withhold the drug. Provided prophylactic and therapeutic recommendations are complied with, outcome of this drug-related side effect is usually excellent, and rare relapses will similarly respond well.

AIDS risk among black male adolescents: Implications for nursing interventions

Acquired immunodeficiency syndrome (AIDS) is a devastating disease the incidence of which is increasing in the black heterosexual community. Only 12% of the nation's population is black, yet 28% of the people with AIDS are black. AIDS currently threatens black adolescents because of their high risk sexual behavior. No cure exists for AIDS nor is a vaccine available. However, AIDS is preventable. Presently, teaching people how to avoid becoming infected with the human immunodefiency virus is the only strategy for reducing the spread of AIDS. Nurses can be an important link in the chain of AIDS prevention in this country. Minimal information is available to assist nurses in learning how to effectively intervene with adolescents, especially black male adolescents, regarding AIDS prevention. This article reviews research on AIDS knowledge, attitudes, and high risk sexual behavior among black male adolescents, suggests strategies for using the nursing process as an AIDS education model in working with black male adolescents, and provides guidelines for nurses to use when working with black male adolescents concerning the issue of sexuality education and AIDS prevention.

Several CD4 domains can play a role in human immunodeficiency virus infection in cells

The human immunodefiency virus (HIV) uses the human CD4 glycoprotein as a receptor for infection of susceptible cells. Cells expressing a series of mutated forms of the CD4 gene have shown a variability in their ability to support replication of three HIV type 1 (HIV-1) and three HIV-2 strains. Moreover, when different stages of virus production were examined by a variety of assays, a consistent delay was observed in all cell lines containing CD4 mutants compared with those with intact full-length CD4. Cells expressing the CD4.415 mutant (modified at the serine 415 corresponding to a phosphorylation site of the cytoplasmic domain) showed only a minimal effect on virus replication. Cells expressing CD4.403 and CD4.401 mutants (lacking the whole cytoplasmic domain) manifested a moderate delay in production of virus progeny. The most substantial effect on HIV replication was observed in cells expressing a chimeric hybrid containing sequences corresponding to the first 177 residues of the N-terminal CD4 fused to CD8 sequences encoding the hinge, transmembrane, and cytoplasmic domains of the human CD8. Furthermore, in a cell-to-cell contact assay, fusion was absent when the CD4 proximal membrane domain was replaced by the CD8 counterpart. In addition, a strong correlation between the down-modulation of the surface CD4 and HIV expression was observed. These observations suggest that in addition to the known binding region, other domains of CD4 could play an important role in regulating HIV entry of cells.

A human immunodeficiency virus peer education program for adolescent females

Black adolescent females living in urban environments are at high risk for human immunodefiency virus (HIV) infection. Our objectives were to develop an HIV peer education program and to pilot-test its effect on knowledge and sexual behavior. Between September 1989 and March 1990, all females aged 12–19 years attending an inner-city, hospital-based adolescent clinic were invited to meet individually with trained peer educators (10 females aged 16–19 years) to discuss acquired immunodeficiency syndrome (AIDS) and its prevention. Each participant completed a modified version of the AIDS Knowledge and Attitudes Survey immediately before and 2–6 weeks after the counseling session. Of the 283 counseled patients, 241 (85%) completed the follow-up questionnaire and comprised the study sample. Mean age was 15.6 years, mean Hollingshead (parental occupational) score was 3.4, and 216 (90%) patients were black. Baseline knowledge about routes of transmission was high and did not improve on follow-up. Comparison of individual baseline and follow-up responses revealed improvements ( p < 0.05) in routes by which HIV is not transmitted, methods of prevention, individuals at risk, and general information about AIDS. The improvement in total score between baseline and follow-up was 38% for patients with low baseline scores, 13% for middle scores, and 3% for high scores ( p < 0.05). At baseline, 50 (21%) patients reported sexual intercourse within the preceding 2 weeks, compared to 33 (14%) at follow-up ( p < 0.05). Of the sexually active patients, 22 (44%) reported no condom use at baseline, compared to 11 (33%) at follow-up ( p < 0.05). We conclude that peer education for adolescent females improves knowledge about HIV infection and diminishes high-risk sexual behavior.

Localization of immunogenic domains in the human immunodeficiency virus type 2 envelope

Highly immunogenic domains have not yet been defined in the extracellular protein of the human immunodefiency virus type 2 (HIV-2) envelope. In this study, six contiguous segments covering the entire HIV-2ST envelope were amplified and cloned into a bacterial expression vector to localize the relative immunogenic reactivity of different regions of the molecule by Western blot (immunoblot) analysis. Our results demonstrate that the extracellular protein of the HIV-2 envelope contains highly immunogenic epitopes with potential value as type-specific markers for HIV-2 infection.

Chemotherapy of the acquired immune deficiency syndrome (AIDS): Non-nucleoside inhibitors of the human immunodeficiency virus type 1 reverse transcriptase

Several classes of non-nucleoside analogues (i.e. TIBO and HEPT derivatives) have been identified that specifically interact with the reverse transcriptase (RT) of human immunodefiency virus type 1 (HIV-1). These derivatives inhibit the replication of HIV-1 in various cell lines, including peripheral blood lymphocytes and monocytes/macrophages, at concentrations that are 10,000- to 100,000-fold lower that the cytotoxic concentrations. At the HIV-1 RT level, they appear to interact with a specific allosteric “TIBO” site, which may be functionally and also structurally associated with the substrate binding site. The TIBO and TIBO-like compounds are orally bioavailable. In vivo they sustain plasma drug levels that are well above the concentrations required to inhibit virus replication in vitro.

Characterization of monoclonal antibodies to human immunodefiency virus type 1 gp41 by HIV-1 polypeptides expressed inEscherichia coli

Two monoclonal antibodies (MAbs) were produced in Balb/c mice by immunization with recombinant gp41 derived from expression of lambda-BH10 cDNA of the human immunodeficiency virus-1 (HIV-1) in the prokaryotic expression vector pEX-41. Characterization of the epitopes recognized by these MAbs was done with HIV-1 envelope (env) fusion proteins expressed in Escherichia coli encoding ten distinct segments of the env proteins. In comparison, another mouse MAb, M25, a human MAb directed against gp41, which was produced by the xeno hybridoma line 3D6 and a pool of human patient sera containing antibodies to HIV-1 were tested. We were able to demonstrate that the epitopes recognized by our MAbs are located between arg732 and ser759 of the HIV-1 env glycoprotein gp160 of HTLV-III strain B. M25 reacted with epitopes between ser647 and pro731, which includes the hydrophobic transmembrane region of gp41. The human MAb against gp41, 3D6 reacts with epitopes between ile474 and trp646, a polypeptide stretch consisting of gp120 and gp41 specific amino acids. The human serum pool, positive for HIV-1 antibodies, reacted predominantly with antigenic determinants located between ile474 and leu863. The recombinant env fusion proteins were initially produced to test the immunoreactivity with patient sera and to characterize epitopes which are relevant for immunodiagnostic purposes. In this study, we showed that the set of recombinant env proteins is also a simple and accurate tool for the characterization of MAbs directed to the HIV envelope proteins.