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PubMed1990

[Estimate of the number of HIV-seropositive persons in The Netherlands; implications for the evolution of the AIDS epidemic].

In this article we estimate the total number of HIV seropositives in the Netherlands with an extended version of the Fast Back Calculation model. As a result we found between 5500 and 6500 seropositives for the end of 1987. This is considerably lower than earlier expectations. The distribution of incidence over time suggests that the HIV epidemic has passed its summit. We argue that the total number of HIV infected persons halfway 1990 lies somewhere between 7500 and 9000. With the estimated number of HIV seropositives we also predict minimum values for the AIDS incidence in future years. We expect the number of new AIDS cases to increase to over 600 per year in the mid-nineties. We briefly discuss the consequences of our findings for AIDS control. We underline the desirability of a policy directed at risk groups and apart from continuing existing preventive measures aimed at these groups we advocate paying more attention to i.v. drug users, visitors of STD clinics and travellers to and applicants for political asylum from endemic areas.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Mouse serum factor(s) down-modulate the CD4 and CXCR4 molecules on human T cells conferring resistance to HIV infection in NOG mice.

Human cells have developed innate immunity, exploiting several means to block virus infection, and viruses have evolved diverse strategies to resist these. We show here that the human immunodeficiency virus 1 (HIV-1) could neither progressively infect engrafted human leukemic T cells nor repress their growth in NOG mice. However, ED-40515(-) cells infected with HIV-1 before inoculation were found to significantly delay the onset of tumor growth and increased the survival period of NOG mice. ED-40515(-) tumor cells showed resistance to HIV-1 which was apparently correlated with the down-regulation of CD4 and CXCR4 molecules in NOG mice. Serum from three different mouse strains, including NOG, retained a suppressive effect on the CD4 molecule of ED-40515(-) cells in vitro. ED-40515(-) cells obtained from mice re-expressed CD4 and CXCR4 molecules upon in vitro culture and were again successfully infected with HIV-1. These findings indicate that HIV-1 may initially successfully delay or regress tumor growth in NOG mice, but eventually fails to do so because of the evolution of HIV-resistant cells due to a rapid down-modulation of CD4 and CXCR4. Our data also demonstrated that some unknown soluble factor(s) present in mouse serum was responsible for conferring resistance to HIV infection to human T cells.

Animals↗
PubMed2000

Some statistical issues in the design of HIV-1 vaccine and treatment trials.

This article summarizes material on statistical issues in the design of HIV-1 preventive vaccine trials and antiretroviral HIV-1 treatment trials that was presented at the first school on Modern Statistical Methods in Medical Research, held at the International Centre for Theoretical Physics in Trieste, in September 1999. Design issues for the two trial types are discussed separately and are compared, which highlights the relative complexity of vaccine trials. Vaccine trial designs for assessing various vaccine effects are considered, including classical double-blind individual-randomized designs for evaluating biological vaccine effects on susceptibility to infection, and augmented partners, cluster-randomized, and infant designs for evaluating biological vaccine effects on infectiousness as well as on susceptibility. Within these designs, covered topics include surrogate endpoints for measuring vaccine effects on secondary transmission and on HIV-1 disease progression, and exploratory and confirmatory methods for assessing host immune and viral genotypic or phenotypic correlates of vaccine protection against infection or disease. For antiretroviral trials, covered topics include endpoint selection and structured designs such as fractional factorial and Latin square designs for rapidly screening combination drug regimens and for identifying patterns of HIV-1 genomic evolution that predict loss of drug efficacy.

AIDS Vaccines↗
PubMed1990

Therapy may explain recent deficits in AIDS incidence.

Since the middle of 1987, fewer consistently defined AIDS cases have been reported than expected among homosexual and bisexual men in the United States. This "AIDS deficit" was greater among homosexual and bisexual men in New York City, San Francisco, and Los Angeles, but was also striking among all homosexual and bisexual men in the United States. Deficits were virtually absent among intravenous drug users (IVDUs) in the United States. Three independent sources of data--placebo-controlled trials, pharmaceutical company reports, and the San Francisco Men's Health Study--were used to demonstrate that the amounts of zidovudine (AZT) given prophylactically to those at highest risk of AIDS since March 1987 have been sufficient to account for most of the observed AIDS deficits. Other advances in the medical care of pre-AIDS patients may have combined with AZT to produce the deficits. Other hypothesized explanations were examined and found insufficient to account for the observed AIDS deficits, including: (a) a sudden halt in new human immunodeficiency virus (HIV) infections during the early or mid-1980s; (b) misspecification of the distribution of AIDS incubation times following HIV infection; (c) increasing delays in the reporting of AIDS cases; (d) changes in the surveillance definition of AIDS in 1987; and (e) evolution of attenuated HIV strains. The hypothesis that therapy is affecting national AIDS rates has important implications. Failure to take the effects of therapy into account can lead to serious underestimates by back-calculation of the cumulative numbers infected with HIV and of AIDS incidence over the longer term. Moreover, it appears that AIDS incidence could be retarded in underserved groups, such as IVDUs, by making AZT and other state-of-the-art treatments readily available to AIDS-free patients with advanced immunodeficiency.

Acquired Immunodeficiency Syndrome↗
PubMed1988

"Artificial" HIV?

Explore the source record for details and available documents.

Biological Evolution↗
PubMed1995

Distinct HIV-1 long terminal repeat quasispecies present in nervous tissues compared to that in lung, blood and lymphoid tissues of an AIDS patient.

OBJECTIVE: To investigate the phylogenetic relationship of HIV-1 proviral long terminal repeat (LTR) variants present in postmortem samples of lymph node, spleen, lung, dorsal root ganglion and spinal cord as well as in the peripheral blood of an HIV-1-infected patient dying with AIDS. DESIGN AND METHODS: Postmortem tissues were studied by a combination of histology, cell culture and molecular analyses. The patient had a stable CD4 count of 10 x 10(6)/I during the 12 months preceding death. A 540 base-pair fragment of the LTR including U3/R/U5 was amplified using polymerase chain reaction on proviral DNA from the five postmortem tissues and peripheral blood mononuclear cells obtained 2 months prior to death. The population of viral variants was determined by sequencing at least five plasmid clones of the amplicons. The relationship between the variants present in different body sites was investigated using molecular phylogeny methods. RESULTS: HIV-1 was present in all organs analysed and correlated with the presence of abnormal histology. Genetic variation leading to divergence from the consensus sequence was more frequently present in characterized transcription factor binding sites within the LTR (P < 0.0001) although the HIV-1 LTR quasispecies in the different body sites showed similar, relatively low levels of divergence (intra-organ median heterogeneity ranging from 0.0094 to 0.017). Phylogenetic analysis showed that the spinal cord and dorsal root ganglion harboured an LTR population genetically distinct from that present in other organs and more closely related to a previously characterized neurotropic strain of HIV (strain JRcsf). CONCLUSION: The independent clustering of HIV-1 LTR variants present in spinal cord and dorsal root ganglion shows that HIV-1 LTR evolution can occur in a compartmentalized fashion. The data show that the LTR is an important region to analyse in sequence variation studies of HIV since it may play a role in nervous tissue adaptation of HIV-1 and neuropathogenicity. Outgrowth of HIV-1 LTR variants that are most fit for the utilization of tissue-specific transcription factors can occur in the nervous tissue.

Acquired Immunodeficiency Syndrome↗
PubMed1998

The Western Australian HIV Cohort Study, Perth, Australia.

The efficacy of primary prophylactic treatment for opportunistic infections can be estimated in an observational cohort study by adjusting for clinical and laboratory markers of the immunodeficiency (e.g., oral candidiasis, CD4%, lymphocyte cell counts) as time-dependent co-variates (providing that the treatment does not directly alter the markers). However, the CD4 cell count provides an incomplete measure of the protective immune response, and the efficacy of treatment may be underestimated if there is inadequate adjustment for the severity of immunodeficiency. Unlike prophylactic therapies, the efficacy of which remains relatively constant over time, antiretroviral therapy may produce only transient or time-limited benefits. This problem can be minimized by allowing the effect of antiretroviral therapy to vary over time in Cox proportional hazards models (i.e., to allow the antiretroviral therapy coefficient to change over time). Another difficulty is that CD4 cell counts may underestimate the degree of immunodeficiency after prolonged zidovudine (AZT) monotherapy. If post-antiretroviral therapy CD4 cell counts are used to adjust for the stage of immunodeficiency, it may therefore be helpful to adjust for the duration of antiretroviral therapy with the CD4 cell count at the time of starting antiretroviral therapy. It is interesting to consider statistical models of progressive HIV-induced immunodeficiency in the context of the evolution of host immunity. HIV infection results in the loss of the relatively recently evolved adaptive CD4 T cell-mediated immunity to intracellular parasites. The infected host may compensate for this by making greater use of phylogenetically ancient, more innate protective responses. Because these compensatory responses are polymorphic, this results in the appearance of differences between individuals in the immune response to HIV as the disease progresses. Data from the Western Australia HIV Cohort Study support a two-stage model of immunopathology. The first stage of this model involves a loss of mucosal immunity and occurs at a variable CD4 cell count (of between 400 cells/mm3 and zero), and is marked by a loss of cutaneous delayed-type hypersensitivity responses and oral candidiasis, seborrheic dermatitis, and Pneumocystis carinii pneumonia. The second stage of the model involves a loss of systemic immunity and requires profound CD4 T-cell lymphopenia (CD4 cell count <50 cells/mm3), and is marked by infections such as cytomegalovirus and disseminated Mycobacterium avium infection. The influence of HLA type on the risk for such opportunistic infections becomes apparent during this late phase.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

[The role of C-reactive protein (CRP) determination in the early diagnosis of infections with opportunistic microorganisms in HIV-infected children].

The levels of C-reactive protein (CRP) in sera of 71 HIV-seropositive children and of 71 apparently healthy children were determined by Mancini method. The results demonstrate that HIV-infection per se doesn't increase the concentration of CRP in serum. After this we wanted to determine the relationship between CRP and evolution of HIV-infection. For this we used a set of 8 children in different stages of HIV-infection. For each child we had at least 2 sera, used for diagnosis and CRP assay. Three children (one with AIDS [correction of SIDA] and 2 in intermediate stage) had elevated levels of CRP. The reason for these elevations were an acute salmonellosis, a febrile episode of unknown origin and for the last child, once a staphylococcal infection of the skin and once an acute bronchiolitis clinically but not microbiologically documented. In conclusion, HIV-infection per se doesn't induce increased levels of the CRP, in any stage; this protein could be used as a marker of bacterial, parasitic and cytomegalovirus infections.

AIDS-Related Opportunistic Infections↗
PubMed1992

Development of a quasispecies of human immunodeficiency virus type 1 in vivo.

During treatment with one specific batch of blood clotting factor IX, a number of hemophilia B patients in Germany recently became infected with human immunodeficiency virus type 1 (HIV-1). The nucleotide sequences of cloned HIV-1 envelope gene regions including the variable V3 loop and the V4 region derived from short-term virus cultures and directly from peripheral blood cells of these patients were shown to be highly homologous. Based on the assumption that the corresponding consensus sequence (termed HIV-1MBK) was identical to the genotype of the initially infecting virus, we were able to construct phylogenetic trees of the developing quasispecies in two patients studied in detail. True intermediates between input and multiply mutated genotypes were found in individual blood samples. Except for the initially infecting variant HIV-1MBK, variants found at 11 months postinfection had replaced those seen at 5 months postinfection. Variability early after infection was shown to cluster in two small regions located 3' of the V3 loop (i.e., outside the loop) and within the V4 region. This communication therefore describes the evolution of an HIV-1 quasispecies in humans starting from a single genotype.

Amino Acid Sequence↗
PubMed2005

Infection of human and non-human cells by a highly fusogenic primary CD4-independent HIV-1 isolate with a truncated envelope cytoplasmic tail.

Truncation of the envelope cytoplasmic tail has enabled FIV, SIV, and some laboratory HIV-1 strains to acquire broader cellular tropism and enhanced fusogenicity. Here we have characterized a primary CD4-independent HIV-1 isolate (92UG046-T8) with a truncated cytoplasmic tail that was able to infect and induce syncytia in primary lymphocytes from human, chimpanzee, and monkey, as well as CD4-negative cell lines from human and monkey. Increased syncytia were also noticeable with 293 cells expressing the cloned envelope from the 92UG046-T8 isolate suggesting envelope-mediated cellular fusion. Except pooled serum from HIV-1-infected individuals, monoclonal anti-envelope antibodies or antibodies/antagonists against CD4, CXCR4, and CCR5 were not able to prevent infection by the 92UG046-T8 isolate. This is the first report showing a primary HIV-1 variant with truncated cytoplasmic tail which is highly fusogenic and can infect a broad range of cells from human and non-human origins. In vivo evolution of similar HIV-1 mutants may have important implications in AIDS pathogenesis.

Animals↗
PubMed1997

Forced evolution of a regulatory RNA helix in the HIV-1 genome.

The 5'and 3'end of the HIV-1 RNA genome forms a repeat (R) element that encodes a double stem-loop structure (the TAR and polyA hairpins). Phylogenetic analysis of the polyA hairpin in different human and simian immunodeficiency viruses suggests that the thermodynamic stability of the helix is fine-tuned. We demonstrated previously that mutant HIV-1 genomes with a stabilized or destabilized hairpin are severely replication-impaired. In this study, we found that the mutant with a destabilized polyA hairpin structure is conditionally defective. Whereas reduced replication is measured in infections at the regular temperature (37 degrees C), this mutant is more fit than the wild-type virus at reduced temperature (33 degrees C). This observation of a temperature-dependent replication defect underscores that the stability of this RNA structure is critical for function. An extensive analysis of revertant viruses was performed to further improve the understanding of the critical sequence and structural features of the element under scrutiny. The virus mutants with a stabilized or destabilized hairpin were used as a starting point in multiple, independent selections for revertant viruses with compensatory mutations. Both mutants reverted to hairpins with wild-type stability along various pathways by acquisition of compensatory mutations. We identified 19 different revertant HIV-1 forms with improved replication characteristics, providing a first look at some of the peaks in the total sequence landscape that are compatible with virus replication. These experiments also highlight some general principles of RNA structure building.

Base Sequence↗
PubMedDate not supplied

[Structural and functional relationships demonstrated by the study of V3 loop heterogeneity].

Data obtained from genomic sequence analysis of the gp 120 V3 loop show that some of the phenotype features depend on the modifications produced in the amino acid sequence of this region. Phenotypical characterization of HIV isolates is based on their sensitivity to neutralizing antibodies, the appearance of virus variants showing unusual tropism, higher cytopathogenicity in vitro and modified virulence in vivo, etc. Sequencing data published since now concern strains from the Euro-American area only, the other geographical areas being neglected. So, these informations support some relations between structure and function, but don't allow a prediction about the evolutive capacity of HIV strains, the distinction between conserved and variable regions nor the understanding of medical signification of some specific genomic changes. Three aspects important for clinical evolution of the disease are discussed in detail: genomic changes in V3 encoding sequence associated with virulence, changes associated with neurotropism for macrophages, changes conditioning sensitivity to neutralizing antibodies.

Antigenic Variation↗
PubMed1989

Isotype, distribution and target analysis of lymphocyte reactive antibodies in patients with human immunodeficiency virus infection.

Anti-lymphocyte (ALA) antibodies were investigated by using both microcytotoxicity and immunofluorescence analyses in 87 subjects with different clinical features of human immunodeficiency virus (HIV) infection. A similar mean percentage of killing in microcytotoxicity assays using heterologous lymphocytes as cellular target was recorded in four groups of patients, including 36 HIV-seropositive asymptomatic subjects, 34 patients with HIV-induced lymphadenopathy syndrome (LAS), 13 with acquired immunodeficiency syndrome (AIDS)-related complex (ARC), and 4 patients with the full-blown AIDS. Conversely, an increasing percentage of ALA-positive subjects paralleled the evolution of the HIV infection. The majority of ALA were IgM isotype with a significant reactivity against T cells. This specificity was indifferently directed to CD3+, CD4+, and CD8+ lymphocytes. In additional experiments employing enzymatic digestion of lymphocyte membrane antigens, we demonstrated that CD4 and CD8 receptors were digested by the pronase, whereas CD3 molecules were highly resistant. Subsequent flow cytometry analyses using these pronase-digested T cells showed that reactivity of ALA for their target was unchanged. Our data suggest that antigenic specificities of ALA in HIV infection are resistant to pronase treatment and are not related to CD4 and CD8 molecules.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2006

HIV-1 entry inhibitors: classes, applications and factors affecting potency.

Antiviral agents targeting human immunodeficiency virus type-1 (HIV-1) attachment, co-receptor engagement and fusion, collectively referred to as entry inhibitors, are emerging as promising therapeutic agents in the treatment of HIV-1 infection. Viral evolution and concomitant emergence of resistant strains will continue to be an important consideration in the development of any new therapeutic against HIV-1. However, unique challenges facing the development of entry inhibitors center around the highly variable and flexible nature of the HIV-1 envelope protein (Env). For example, the evolution of Env during the course of HIV-1 infection increases the efficiency of Env-CCR5 interactions, which consequently increases Env-mediated fusogenicity and decreases sensitivity to entry inhibitors. This points to a relationship between co-receptor interactions and fusogenicity that merits further consideration in the design of HIV-1 entry inhibitors. It also underscores the importance of considering the biological properties of late-emerging HIV-1 variants in the design of new therapeutics. This review examines the various entry inhibitors that are undergoing preclinical or clinical testing or which are in the early stages of clinical use, their applications in a clinical setting and possible factors that may affect potency against HIV-1.

Anti-HIV Agents↗
PubMed1999

CXCR4 utilization is sufficient to trigger CD4+ T cell depletion in HIV-1-infected human lymphoid tissue.

The human chemokine receptors CCR5 and CXCR4 have emerged as the predominant cofactors, along with CD4, for cellular entry of HIV-1 in vivo whereas the contribution of other chemokine receptors to HIV disease has not been yet determined. CCR5-specific (R5) viruses predominate during primary HIV-1 infection whereas viruses with specificity for CXCR4 (R5/X4 or X4 viruses) often emerge in late stages of HIV disease. The evolution of X4 viruses is associated with a rapid decline in CD4+ T cells, although a causative relationship between viral tropism and CD4+ T cell depletion has not yet been proven. To rigorously test this relationship, we assessed CD4+ T cell depletion in suspensions of human peripheral blood mononuclear cells and in explants of human lymphoid tissue on exposure to paired viruses that are genetically identical (isogenic) except for select envelope determinants specifying reciprocal tropism for CXCR4 or CCR5. In both systems, X4 HIV-1 massively depleted CD4+ lymphocytes whereas matched R5 viruses depleted such cells only mildly despite comparable viral replication kinetics. These findings demonstrate that the coreceptor specificities of HIV-1 are a causal factor in CD4+ T cell depletion ex vivo and strongly support the hypothesis that the evolution of viral envelope leading to usage of CXCR4 in vivo accelerates loss of CD4+ T cells, causing immunodeficiency.

Animals↗
PubMedDate not supplied

Romanian HIV-AIDS epidemic after a decade of evolution.

Situated in Southeastern Europe, with a surface of 237,500 km2 and a population of over 22 million, Romania was a special case in the evolution of global AIDS crisis. After the first reported case in a homosexual male in 1985, five years elapsed till the epidemiological investigations done in the Institute of Virology, Bucharest (1-4) provided strong evidence for what may represent the world's largest iatrogenic transmission of blood-borne pathogens in children. On the basis of Epidemiological Fact Sheet concerning Romania provided by UNAIDS/WHO Working Group on Global HIV/AIDS and STD Surveillance we offer a couple of graphics which are considered important for informed decision-making and planning at national and regional levels. We emphasize the lack of availability of many specific data both on epidemiological and socio-behavioral indicators. Structural collapse in Eastern Europe sets the scene for the rapid spread of HIV/AIDS among young people and the lack of information may contribute to an unexpected rebound of the epidemic.

Acquired Immunodeficiency Syndrome↗