Inhibition of HIV-1 expression by HIV-2

HIV-1 and HIV-2 are co-endemic in certain geographic areas. HIV-2 is more weakly pathogenic than HIV-1, and progression to AIDS occurs less frequently and over a longer period of time. Recent epidemiologic studies suggest that individuals infected with HIV-2 have a lower risk of HIV-1 infection. Both immune mechanisms and various modes of viral interference have been proposed to account for these results. Our findings, described in this paper, suggest that HIV-2 inhibits HIV-1 replication. To study the molecular interactions between HIV-1 and HIV-2, proviral clones were transfected alone or in combination into the human T cell line CEM. LTR-CAT indicator constructs were included for the purpose of monitoring viral promoter activity. Viral replication in transfected cells was monitored by p24 antigen capture assay of cell culture supernatants and Western blot analysis of cell extracts. HIV-2 inhibited HIV-1 replication as determined by intracellular and extracellular p24 antigen levels. Similar results were obtained with simultaneous virus infection using HIV-1 and HIV-2, rather than transfections of proviral DNA. Using cotransfection of HIV-1 and HIV-2 LTR indicator gene constructs, the mechanism of inhibition was found to be suppression of the HIV-1 LTR by HIV-2. The inhibitory effect of HIV-2 is not due to Tat-2, but appears to discriminate between the HIV-1 and HIV-2 LTRs based on differences in the Tat activation response element, TAR. These results suggest both a molecular mechanism for HIV-2 interference with HIV-1 replication and a potential molecular approach to therapy.     

Neutralization of HIV-1

A Workshop on Neutralization of HIV-1: Technology and reagents for analysis of prophylactic vaccines clinical trials, sponsored by the Food and Drug Administration (FDA) and the Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), was held on April 19-20, 1993, in Bethesda, Maryland. This workshop brought together researchers who are involved in the development, testing, and evaluation of HIV-1 prophylactic vaccines. The major objectives were (1) to discuss critically the different neutralization and binding assays that are currently used in the evaluation of immune sera; (2) to identify assays that will measure the "most relevant" antibodies, which are likely to predict neutralization of primary isolates; and (3) to identify well-characterized reference reagents, which could be used to standardize neutralization assays used in laboratories around the world.     

HIV-1-specific cytotoxic T lymphocytes and the control of HIV-1 replication

The present study examined the effect of perceived problem-solving ability (self-identified effective and ineffective) operationalized by Heppner and Petersen's Problem Solving Inventory (PSI) and random feedback (success vs. failure) on participants' attributions. A total of 30 female and 30 male teacher trainees who had scored in the top and bottom distribution of the PSI dealt with three unexpected classroom disruptions during a lecture presentation. After their presentation, they received randomized feedback concerning their performance during disruptions. Following feedback, they completed Baumgardner's Attribution Questionnaire (AQ). Results indicated a significant PSI x Feedback interaction for ability and effort but not for task difficulty and luck. Perceived efficacious problem solvers' internal attributions depended on whether they received success or failure feedback. Similar to the self-enhancing tendency reported in the literature, this group attributed success versus failure more to ability and effort. The perceived ineffective problem solvers' attributions did not differ based on the feedback they received. Results are discussed in terms of prior research and theory.     

HIV-1 and bleach

The high proportion of diabetic patients is partly responsible for the high frequency of chronic renal failure in Reunion. The confection and maintenance of an arterio-venous fistule is a major problem in those patients. We report herein our experience with temporary vascular access by internal jugular vein catherization with subcutaneous tunnelization using silastic catheters. The mean duration of utilisation of these accesses is 107 days for diabetic patients and 98 days for nondiabetic patients. The major complication observed is sepsis (18.36%). Diabetes mellitus which represent a traditional risk factor does not seem to be responsible here, the climatic and hygienic conditions prevailing in this part of the world could be a contributing factor. Nevertheless, we find the utilisation of these catheters a suitable solution during the waiting period because it is an easy operation, of the good quality of the material used and the comfort brought to the patient.     

Pediatric HIV-1 infection

Although there is optimism that with the prospective identification and treatment of HIV-1-infected pregnant women the incidence of pediatric infection can be diminished, currently the number of HIV-1-infected children continues to rise. Improvements in early diagnosis provide the potential for early intervention, and the advent of more potent antiretroviral agents provides the hope of better treatment strategies to slow disease progression in HIV-1-infected children.     

Haloperidol-based irreversible inhibitors of the HIV-1 and HIV-2 proteases

The proteases expressed by the HIV-1 and HIV-2 viruses process the polyproteins encoded by the viral genomes into the mature proteins required for virion replication and assembly. Eight analogs of haloperidol have been synthesized that cause time-dependent inactivation of the HIV-1 protease and, in six cases, HIV-2 protease. The IC50 values for the analogues are comparable to that of haloperidol itself. Enzyme inactivation is due to the presence of an epoxide in two of the analogues and carbonyl-conjugated double or triple bonds in the others. Irreversible inactivation is confirmed by the failure to recover activity when one of the inhibitors is removed from the medium. At pH 8.0, the agents inactivate the HIV-1 protease 4-80 times more rapidly than the HIV-2 protease. Faster inactivation of the HIV-1 protease is consistent with alkylation of cysteine residues because the HIV-1 protease has four such residues whereas the HIV-2 protease has none. Inactivation of the HIV-2 protease requires modification of non-cysteine residues. The similarities in the rates of inactivation of the HIV-2 protease by six agents that have intrinsically different reactivities toward nucleophiles suggest that the rate-limiting step in the inactivation process is not the alkylation reaction itself. At least five of the agents inhibit polyprotein processing in an ex vivo cell assay system, but they are also toxic to the cells.     

Detection of human immunodeficiency virus type 1 (HIV-1) RNA in pools of sera negative for antibodies to HIV-1 and HIV-2

A total of 234 pools were prepared from 10,692 consecutive serum samples negative for antibodies to human immunodeficiency virus type 1 (HIV-1) and HIV-2 collected at five virological laboratories (average pool size, 45 serum samples). Pools were screened for the presence of HIV-1 RNA by a modified commercial assay (Amplicor HIV-1 Monitor test) which included an additional polyethylene glycol (PEG) precipitation step prior to purification of viral RNA (PEG Amplicor assay). The sensitivity of this assay for HIV-1 RNA detection in individual serum samples within pools matches that of standard commercial assays for individual serum samples, i.e., 500 HIV-1 RNA copies per ml. Five pools were identified as positive, and each one contained one antibody-negative, HIV-1 RNA-positive serum sample, corresponding to an average of 1 infected sample per 2,138 serum samples. Retrospective analysis revealed that the five HIV-1 RNA-positive specimens originated from individuals who had symptomatic primary HIV-1 infection at the time of sample collection and who were also positive for p24 antigenemia. We next assessed the possibility of performing the prepurification step by high-speed centrifugation (50,000 x g for 80 min) of 1.5-ml pools containing 25 microl of 60 individual serum samples, of which only 1 contained HIV-1 RNA (centrifugation Amplicor assay). The sensitivity of this assay also matches the sensitivities of standard commercial assays for HIV-1 RNA detection in individual serum samples. The results demonstrate that both assays with pooled sera can be applied to the screening of large numbers of serum samples in a time- and cost-efficient manner.     

Field evaluation of alternative testing strategies for diagnosis and differentiation of HIV-1 and HIV-2 infections in an HIV-1 and HIV-2-prevalent area

OBJECTIVE: To identify cost-efficient alternative antibody testing strategies for screening, confirmation and discrimination of HIV-1 and HIV-2 infections, including rapid simple tests (RST) as well as enzyme-linked immunosorbent assays (ELISA), in a HIV-1 and HIV-2-prevalent area. DESIGN: Evaluation and comparison of anti-HIV-1/2 assays, adhering to the World Health Organization recommendations for alternative confirmatory strategies, using banked and prospectively collected specimens in Guinea-Bissau. METHODS: A total of 1110 consecutive sera from Bissau were included in the first phase, of which 198 (17.8%) were HIV-seropositive: 52 (4.7%) HIV-1, 120 (10.8%) HIV-2, and 26 (2.3%) HIV-1/HIV-2 dually reactive. In addition, 95 selected HIV-positive specimens were included for study of sensitivity and cross-reactivity between HIV-1 and HIV-2. Western blot was used as a gold standard for confirming the reactivity of the specimens. All specimens were screened by two assays. Enzygnost ELISA and Capillus RST. Samples reactive by any of the screening assays were further tested by assays chosen for confirmation: UBI ELISA, Innotest ELISA Recombigen RST, Multispot RST and Immunocomb RST. The confirmatory RST as well as Wellcozyme Recombinant HIV-1 ELISA, PEPTI-LAV and INNO-LIA were also used to study differentiation between HIV-1 and HIV-2. RESULTS: The sensitivities of all assays were 100%. The specificities of the screening assays at initial and repeated testing were 98.0 and 99.7%, respectively, for Enzygnost and 99.8 and 99.9%, respectively, for Capillus. The various combinations of two or three assays showed specificities of 99.2-100%. Several possible combinations of assays were identified where a specificity of 100% and good differentiation between HIV-1 and HIV-2 was achieved. Significant differences in the capacity to discriminate were noted; Immunocomb and PEPTI-LAV had the lowest number of dual-reactive results. A follow-up study of 1501 consecutive samples tested with the strategy chosen for routine use showed a sensitivity and specificity comparable to ELISA and Western blot. CONCLUSION: High sensitivities and specificities were obtained with various combinations of assays including RST as well as ELISA, and these procedures are well suited for field use in Africa. Serodiagnostic strategies for HIV can be based on RST alone and differentiation between HIV-1 and HIV-2 can be achieved as part of these strategies. Large differences in the capacity of individual assays to discriminate between HIV-1 and HIV-2 were observed.     

Pathogenesis of HIV-1 associated neurodegeneration

A significant number of people infected with the human immunodeficiency virus (HIV) develop neurologic complications. The AIDS dementia complex is frequently accompanied by HIV encephalitis, which is characterized at the neuropathologic level by loss of neuronal subpopulations in the neocortex, limbic system, and basal ganglia in association with synaptic and dendritic damage, astrogliosis, and formation of microglial nodules and multinucleated giant cells. Recent studies have shown that the extent of neurodegeneration in this condition correlates directly with the amount of HIV-1 antigen in the brain. HIV-1 infection of the brain could result in neurodegeneration via neurotoxic effects of viral products (e.g., gp 120, Nef, Tat) and/or via alterations in the expression of host factors. The latter may include increased production of potentially detrimental factors such as cytokines, excitotoxic amino acids, free oxygen radicals, and bioactive lipid mediators as well as interference with the production or action of neurotrophic/protective factors. Derangements of the neuronal calcium homeostasis, lipid peroxidation, and induction of programmed cell death (apoptosis) may all play a role as final common pathogenetic pathways in HIV-1-induced neurodegeneration. Recent studies in transgenic mice (over)expressing HIV- or host-derived proteins in their central nervous system indicate that distinct neuronal populations may differ in their susceptibility to specific pathogenic factors. For example, glutamate-receptor-bearing pyramidal neurons were particularly susceptible to neurodegeneration promoted by HIV-1 products, whereas interneurons were more sensitive to the neurotoxic effects mediated by cytokines. For the design of effective treatments for the HIV-1-associated cognitive/motor complex, it will be important to determine whether the neurologic deficits in this entity result from global neuronal dysfunction or relate more specifically to the impairment of distinct neuronal subpopulations. It will also be critical to examine diverse in vitro and in vivo models to help decide which of the many pathogenetic processes that may be at work in this complex disease constitute the most promising therapeutic targets.     

Psychoneuroimmunology and HIV-1.

Recent psychoneuroimmunologic findings have suggested that it may be useful to evaluate the influence of behavioral factors on immune functioning and disease progression among human immunodeficiency virus-Type 1 (HIV-1) infected individuals. Behavioral interventions with immunomodulatory capabilities may help restore competence and thereby arrest HIV-1 disease promotion at the earliest stages of the infectious continuum. Evidence describing benefits of behavioral interventions such as aerobic exercise training on both psychological and immunological functioning among high-risk HIV-1 seronegative and very early stage seropositive gay men is presented. The HIV-1 infection is cast as a chronic disease for which early immunomodulatory behavioral interventions may have important physical and psychological impact. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Apoptosis in HIV-1 Infection

We have studied apoptosis in lymph node and peripheral blood mononuclear cells (PBMCs) from HIV-infected children and adults and SIV-infected rhesus macaques. In lymph nodes, we found that apoptosis and productive infection occurred only rarely in the same cell. There was, however, a direct correlation between the numbers of apoptotic and productively-infected cells. In HIV-infected children, we found a direct correlation between disease severity and percentage CD4+ T cell apoptosis (p = 0.001). Both CD4+ and CD8+ T cell apoptosis were directly related to CD4+ T cell depletion (p = 0.006 and p = 0.01, respectively). In addition, we found a trend towards diminished CD4+ T cell apoptosis on anti-retroviral agents. These findings suggest that apoptosis of uninfected cells may be important in HIV pathogenesis and that measurement of apoptosis may be a useful marker of disease activity.     

Long-term survivors of HIV-1 infection

The clinical course and outcome of HIV-1 infection are highly variable. A full spectrum of pathology has been observed, from rapid progression to AIDS within months of HIV-1 seroconversion, to asymptomatic survival for more than a decade. This phenomenon probably reflects the multiphasic and multifactorial nature of the virus-host interactions. Obviously, interest in the extremes now recognized in HIV-1 disease progression is growing, with the hope that mechanisms of protection may be found.     

Ultrastructure of HIV-1 genomic RNA

The traditional acute care health care environment does not meet the needs of chronically ill patients and their families. The classic paternalistic approach encourages dependence on the health care team. This report reviews several innovative types of patient care delivery models, including patient-focused care, family-centered care, cooperative care, and Program Planetree. The core concepts of these various models are described and compared. Related research is presented. A synthesis of these existing models to meet the needs of chronically ill medical patients holistically is proposed. The implementation of the holistic model with chronically ill patients and their families is depicted.     

Quantification by additive RT-PCR of HIV-1 RNA plasma levels in different stages of HIV-1 infection

Recent reports have shown an association between an intronic polymorphism of the presenilin-1 (PSEN1) gene and late-onset (age at onset > 65) familial and sporadic (no family history) Alzheimer disease (AD). The reported association was independent of the effect of the only previously identified gene associated with late-onset AD, APOE. Blood samples were obtained from members of 122 multiplex AD families, 42 unrelated cases of AD with positive family histories of dementia, 456 sporadic cases of AD, and 317 controls of similar ages at examination to the cases. These samples were genotyped for an intronic polymorphism of the PSEN1 gene, located 3' to exon 8, and the data analyzed for evidence of association or linkage. The samples were also genotyped for APOE and the data analyzed to see if the association or linkage changed when controlling for APOE genotype. There was no statistically significant increase (at alpha = .01) in allele 1 (199 bp) or genotype 1/1 in the sporadic AD cases, or in a random sample of one affected from each multiplex family, compared to controls. When examining the effect of the PSEN1 polymorphism while controlling for APOE genotype, APOE genotype was strongly associated with AD, but the PSEN1 polymorphism genotype was not. Model-trait dependent (lod score) and independent (Sim1BD) methods detected no evidence of linkage between PSEN1 and AD. In this independent dataset, the previously reported association between the intronic PSEN1 polymorphism and AD cannot be confirmed, and the conclusion that PSEN1 is a major susceptibility gene for late-onset AD is not supported.     

Comparative analysis of HIV-1 and HIV-2 indeterminate western blot patterns

A comparison of HIV-1 and HIV-2 indeterminate Western blot patterns of Ghanaian sera collected between 1989 and 1990 was made. Antibodies to group specific antigen (GAG) gene products were most frequently detected both HIV-1 and HIV-2 indeterminate sera. HIV-2 GAG gene product p26 was shown to be a non-specific indicator of infection. Antibody to gp120, and envelope gene product of HIV-1 never occurred in indeterminate sera whereas antibodies to all the envelope gene products of HIV-2 were detected in indeterminate sera.     

A case of primary HIV-1 infection

Effects of oleic acid or triolein on lymphatic recovery of docosahexaenoic acid (DHA) given as an ethyl ester were examined in rats with cannulated thoracic ducts. Lymphatic recovery of ethyl DHA given with oleic acid or triolein was significantly higher than in rats given ethyl DHA alone. DHA distributed almost exclusively at the 1- and 3-position of triglyceride in lymph collected at 0-3 h after the administration, when it was given with oleic acid or triolein. A small part of DHA distributed at the 2-position when ethyl DHA was the sole fatty acid given. Oleic acid given as free acid or triolein with ethyl DHA was a major fatty acid at the 2-position. Intramolecular distribution of DHA and oleic acid in lymph triglyceride was similar when ethyl DHA was given with oleic acid or triolein.