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PubMed2005

[Clinical and epidemiological study of a series of HIV-infected patients over 50 years old].

INTRODUCTION: The epidemiology of human immunodeficiency virus (HIV) infection has changed in recent years. Cases in persons over the age of 50 have increased, and the most frequent mode of transmission is sexual contact. The objective of this study is to analyse the epidemiological, clinical and evolution characteristics of a clinical series of HIV-infected patients over 50 years old at the time of diagnosis. METHODS: 165 HIV-infected patients over the age of 50, attended at Hospital Clinic (Barcelona) and Corporació Parc Taulí (Sabadell) during the period of 1985 to 2001, were studied. RESULTS: Among the total, 81% of the patients were men, mean age at the time of diagnosis was 58.5 years, and 81.8% had acquired the disease by sexual contact. The median initial CD4 T cell count was 216 cells/microl. Initial viral load was 1,000-100,000 copies/ml in 45.2% of the patients, whereas 52.3% had > 100,000 copies/ml. At the time of diagnosis, 30.9% had an AIDS-defining disease. The main opportunistic diseases were pulmonary tuberculosis, Kaposi's sarcoma, P. jiroveci (before carinii) pneumonia and non-Hodgkin lymphoma. Mortality due to AIDS was 32.7%. CONCLUSIONS: Subjects over 50 years old diagnosed with HIV-infection were predominantly men, who acquired the infection by sexual contact. A high percentage of patients were diagnosed with the development of an opportunistic disease.

AIDS-Related Opportunistic Infections↗
PubMed2002

Selection of drug-resistant HIV-1 mutants in response to repeated structured treatment interruptions.

BACKGROUND: A new HIV-1 treatment strategy based on repeated structured treatment interruptions (STI) is currently being evaluated in clinical trials to determine whether immune cell-mediated control of viral replication can be stimulated by intermittent periods of viral replication. The potential for selection of drug-resistant quasi-species remains a major concern of such a treatment strategy. METHODS: Plasma and peripheral blood lymphocyte (PBL) samples from 12 patients who had three consecutive STIs were studied. Genotypic analysis was based on population and clonal sequencing. Drug susceptibility and their corresponding replication capacities were evaluated by a single-cycle growth assay. RESULTS: Consistent with a loss of phenotypic susceptibility to lamivudine, the M184V mutation was detected by genotypic analysis (direct and clonal sequencing) in plasma samples collected from two patients at the end of the second or third STI. Longitudinal analysis of patient samples revealed a step-wise increase in the M184V mutation in each patient virus population over successive STIs, despite the lower replicative capacity associated with this mutation in the absence of antiviral agents. CONCLUSION: Drug-resistant virus can rise to high frequencies in chronically HIV-1 infected individuals during consecutive STIs. Evolution of resistance is likely to be more important in patients with prior suboptimal therapies, particularly when few mutations are required for resistance. Maximum care should be taken in designing STI protocols that minimize development of drug-resistant mutations that may lead to treatment failure. Thus, drug-resistance testing may be useful before restarting treatment during STI studies.

Adult↗
PubMed1998

A novel mutation (F227L) arises in the reverse transcriptase of human immunodeficiency virus type 1 on dose-escalating treatment of HIV type 1-infected cell cultures with the nonnucleoside reverse transcriptase inhibitor thiocarboxanilide UC-781.

Treatment of wild-type human immunodeficiency virus [HIV-1(IIIB)]-infected cell cultures with the thiocarboxanilide UC-781 under low selective pressure (i.e., 0.01 microg/ml) resulted in the emergence of V106A RT mutant virus. On increasing drug concentrations (stepwise up to 30 microg/ml) the virus retained the V106A RT mutation but acquired the novel F227L mutation in the RT genome in addition to the L100I, K1O1I, and Y181C mutations. This multiple-mutant virus proved highly resistant to virtually all nonnucleoside RT inhibitors (NNRTIs) (e.g., nevirapine, delavirdine, and loviride), but retained full sensitivity to nucleoside analogs such as AZT, ddI, (-)FTC, and 3TC. The F227 amino acid is highly conserved in HIV-1 strains and forms part of the NNRTI-binding pocket. Our model suggests a hydrophobic interaction between F227 and the chloro atom of UC-781.

Anilides↗
PubMed1992

Nephropathy associated with infection by human immunodeficiency virus: a report on 11 cases including 6 treated with zidovudine.

The human immunodeficiency virus (HIV) was recently suggested to be involved in generating kidney lesions in HIV-associated nephropathy (HIVN). The possibility that antiretroviral agents can slow down the usually explosive evolution of HIVN to end-stage renal failure (ESRF) has not been studied in many of the series of cases published. The present work is a retrospective analysis of 11 patients with histologically proven HIVN, 6 of whom were treated with zidovudine. Seven patients (group 1) either required dialysis at the outset, when HIVN was diagnosed, or progressed very fast to ESRF within 15-45 days. Two patients of this group were treated with zidovudine, but it had no effect on kidney function. In the remaining 4 patients (group 2), HIVN progressed more slowly than in group 1. All 4 patients were treated with zidovudine at an earlier stage of the disease than ESRF. Only 1 deteriorated to ESRF in 9 months. The 3 others, who did not have ESRF, were followed up for 13, 10 and 32 months, respectively. Although this is a preliminary study, its results do suggest that zidovudine can slow down the evolution of HIVN to ESRF. They highlight the need to screen HIV-positive patients regularly for proteinuria, in order to detect HIVN by renal biopsies at an early stage of renal lesion formation.

AIDS-Associated Nephropathy↗
PubMed1999

Directed evolution of thymidine kinase for AZT phosphorylation using DNA family shuffling.

The thymidine kinase (TK) genes from herpes simplex virus (HSV) types 1 and 2 were recombined in vitro with a technique called DNA family shuffling. A high-throughput robotic screen identified chimeras with an enhanced ability to phosphorylate zidovudine (AZT). Improved clones were combined, reshuffled, and screened on increasingly lower concentrations of AZT. After four rounds of shuffling and screening, two clones were isolated that sensitize Escherichia coli to 32-fold less AZT compared with HSV-1 TK and 16,000-fold less than HSV-2 TK. Both clones are hybrids derived from several crossover events between the two parental genes and carry several additional amino acid substitutions not found in either parent, including active site mutations. Kinetic measurements show that the chimeric enzymes had acquired reduced K(M) for AZT as well as decreased specificity for thymidine. In agreement with the kinetic data, molecular modeling suggests that the active sites of both evolved enzymes better accommodate the azido group of AZT at the expense of thymidine. Despite the overall similarity of the two chimeric enzymes, each contains key contributions from different parents in positions influencing substrate affinity. Such mutants could be useful for anti-HIV gene therapy, and similar directed-evolution approaches could improve other enzyme-prodrug combinations.

Amino Acid Sequence↗
PubMed1994

Blood monocytes infected in vivo by HIV-1 variants with a syncytium-inducing phenotype.

Extensive data have been obtained on sequence changes in the V3 region of the HIV-1 envelope protein that are associated with in vitro biological properties such as cell tropism and syncytium-inducing capacity. However, so far this concerned viruses isolated from peripheral blood mononuclear cells and thus did not discriminate between variants present in T lymphocytes or in monocytes. In this study, we analyzed viral sequences derived separately from uncultured T lymphocytes, blood monocytes, and plasma of an HIV-1-infected patient showing a neurological evolution of the disease. Sequences related to the V3 region and 18 amino acids downstream were obtained from 48 clones after PCR amplification. One predominant viral sequence close to the monocytotropic/non-syncytium-inducing (NSI) consensus sequence was observed in the three blood sources. Two viral species were specifically identified in monocytes (43% of the clones), showing clear differences from the consensus sequence and exhibiting the genetic determinants associated with the SI phenotype. Plasma-derived viruses with a similar V3 loop were obtained on in vitro isolation. Analysis of the biological properties of these selected viruses confirmed their monocytotropism and the syncytium-inducing phenotype as expected by the cell type in which the sequences were observed and the charge of the V3 loop. Structural analysis of these variants suggested an intermediate structure between NSI/monocytotropic and SI/lymphotropic V3 loops. Thus, in vivo circulating monocytes could be a reservoir for distinct HIV-1 variants with potential SI characteristics, at least in later stages of infection. Studying such variants over the course of the infection may shed light on their involvement in disease manifestations.

Amino Acid Sequence↗
PubMed2003

Characterization of novel recombinant HIV-1 genomes using the branching index.

We have characterized six novel genomes of human immunodeficiency virus type 1 (HIV-1) sampled from individuals infected in Uganda and former Zaire. Four isolates (SE6954, SE8603, UG035, and UG266) had clear recombination patterns that included subtypes A1, D and C. The two remaining strains (SE8646 and SE9010) also appeared to be recombinant but had a more complex pattern. To facilitate the classification of these two genomes we developed a metric, the branching index, for characterization of "problematic" sequence fragments that associate to a subtype cluster with a high bootstrap value but are only distantly related to the reference sequences. The branching index is able to signal when parental representatives may be missing and a subtype classification thus is not meaningful. Several fragments of SE8646 and SE9010 had a branching index below the subtype defining cutoff value (0.55) and, therefore, these genomes could not be unequivocally classified. The branching index, with a cutoff value defined from analyses of HIV-1 reference sequences, may be a useful approach not only for more conservative classifications of HIV-1 subtypes but also for analyzing relationships among other types of sequences.

Evolution, Molecular↗
PubMed1999

Mosaic structure of the human immunodeficiency virus type 1 genome infecting lymphoid cells and the brain: evidence for frequent in vivo recombination events in the evolution of regional populations.

In addition to immunodeficiency, human immunodeficiency virus type 1 (HIV-1) can cause cognitive impairment and dementia through direct infection of the brain. To investigate the adaptive process and timing of HIV-1 entry into the central nervous system, we carried out an extensive genetic characterization of variants amplified from different regions of the brain and determined their relatedness to those in lymphoid tissue. HIV-1 genomes infecting different regions of the brain of one study subject with HIV encephalitis (HIVE) had a mosaic structure, being assembled from different combinations of evolutionarily distinct lineages in p17(gag), pol, individual hypervariable regions of gp120 (V1/V2, V3, V4, and V5), and gp41/nef. Similar discordant phylogenetic relationships were observed between p17(gag) and V3 sequences of brain and lymphoid tissue from three other individuals with HIVE. The observation that different parts of the genome of HIV infecting a particular tissue can have different evolutionary histories necessarily limits the conclusions that can be drawn from previous studies of the compartmentalization of distinct HIV populations in different tissues, as these have been generally restricted to sequence comparisons of single subgenomic regions. The complexity of viral populations in the brain produced by recombination could provide a powerful adaptive mechanism for the spread of virus with new phenotypes, such as antiviral resistance or escape from cytotoxic T-cell recognition into existing tissue-adapted virus populations.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Isolation of human immunodeficiency virus-related simian immunodeficiency viruses from African green monkeys.

We have isolated lentivirus strains that are related to the human immunodeficiency virus (HIV) from African green monkeys (Cercopithecus aethiops; AGM). Although immunologically related, these SIVagm are clearly distinct from other simian immunodeficiency virus (SIV) isolates, including isolates from Macaca mulatta (SIVmac) or even from other AGM. The SIVagm strains described in this communication grow well in a limited number of human T-lymphoma lines. Virus density, morphology, and reverse transcriptase activity are characteristic of the lentivirus group. SIVagm exhibits the following pattern of major virus proteins: p18, p28, gp45, p64, gp140. They appear to bind to the target cell via the CD4 or its primate analogue. Four virus isolates have already been molecularly cloned for detailed genomic analysis and within this SIV agm group they exhibit the genomic variability that is typical of lentiviruses. AGMs infected with this virus apparently remain healthy and therefore SIVagm not only provides a virus model for vaccine studies but also allows investigation of the defense mechanisms (immunological and others) that keep the AGMs healthy. Furthermore, precise genomic analysis of these and other SIV strains will lead to a better understanding of the evolution and pathogenicity of human lentiviruses like HIV.

Animals↗
PubMed1995

Evaluation of secular trends in CD4+ lymphocyte loss among human immunodeficiency virus type 1 (HIV-1)-infected men with known dates of seroconversion.

The rate at which immunodeficiency develops in untreated human immunodeficiency virus type 1(HIV-1)-infected persons might be increasing or decreasing over time because of viral evolution or other factors. Beginning in 1984, Multicenter AIDS Cohort Study investigators recruited HIV-1-seronegative homosexual/bisexual men from four US metropolitan areas and examined them semiannually for HIV-1 seroconversion. To assess possible secular changes in the natural history of HIV-1 infection, the authors examined CD4+ lymphocyte data from 354 men who seroconverted between 1984 and 1991. To control for measurement differences among centers and over time, the authors adjusted CD4+ lymphocyte values to those of persistently seronegative participants. CD4+ lymphocyte percentage measurements at the first seropositive visit formed a U-shaped pattern, with the lowest values observed in 1988 and 1989. The authors observed no consistent secular pattern of CD4+ percentages at later visit dates, except that mean CD4+ percentages were consistently lowest in men who seroconverted in 1988. In a proportional hazards model, the time to the adjusted CD4+ lymphocyte count of < 500 cells/mm3 was not associated with the secular time of seroconversion (relative hazard = 1.05, 95% confidence interval 0.97-1.13). The authors' data do not suggest a major change in the natural history of HIV-1 infection of this population.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Evolution of human and non-human primate CC chemokine receptor 5 gene and mRNA. Potential roles for haplotype and mRNA diversity, differential haplotype-specific transcriptional activity, and altered transcription factor binding to polymorphic nucleotides in the pathogenesis of HIV-1 and simian immunodeficiency virus.

Polymorphisms in CC chemokine receptor 5 (CCR5), the major coreceptor of human immunodeficiency virus 1 (HIV-1) and simian immunodeficiency virus (SIV), have a major influence on HIV-1 transmission and disease progression. The effects of these polymorphisms may, in part, account for the differential pathogenesis of HIV-1 (immunosuppression) and SIV (natural resistance) in humans and non-human primates, respectively. Thus, understanding the genetic basis underlying species-specific responses to HIV-1 and SIV could reveal new anti-HIV-1 therapeutic strategies for humans. To this end, we compared CCR5 structure/evolution and regulation among humans, apes, Old World Monkeys, and New World Monkeys. The evolution of the CCR5 cis-regulatory region versus the open reading frame as well as among different domains of the open reading frame differed from one another. CCR5 cis-regulatory region sequence variation in humans was substantially higher than anticipated. Based on this variation, CCR5 haplotypes could be organized into seven evolutionarily distinct human haplogroups (HH) that we designated HHA, -B, -C, -D, -E, -F, and -G. HHA haplotypes were defined as ancestral to all other haplotypes by comparison to the CCR5 haplotypes of non-human primates. Different human and non-human primate CCR5 haplotypes were associated with differential transcriptional regulation, and various polymorphisms resulted in modified DNA-nuclear protein interactions, including altered binding of members of the NF-kappaB family of transcription factors. We identified novel CCR5 untranslated mRNA sequences that were conserved in human and non-human primates. In some primates, mutations at exon-intron boundaries caused loss of expression of selected CCR5 mRNA isoforms or production of novel mRNA isoforms. Collectively, these findings suggest that the response to HIV-1 and SIV infection in primates may have been driven, in part, by evolution of the elements controlling CCR5 transcription and translation.

Animals↗
PubMed2005

A genotypic assay for the amplification and sequencing of gag and protease from diverse human immunodeficiency virus type 1 group M subtypes.

In human immunodeficiency virus type 1 (HIV-1), an interaction exists between the in vivo evolution of Gag protein and protease to escape from antiretroviral drug selective pressure. Therefore, it was decided to develop a genotypic assay for the amplification and sequencing of HIV-1 gag and protease. As the HIV-1 pandemic is characterised by a large genetic diversity, the assay developed was evaluated on a panel of 28 genetically divergent samples belonging to the following subtypes A1, B, C, D, F1, F2, G, H, J, CRF01-AE, CRF02-AG and CRF13-cpx. The assay displayed a detection limit ranging between 500 RNA copies/ml and 5000 RNA copies/ml plasma. Full-length sequences could be obtained for 25 samples. The population sequences of the three other samples lacked a part of the sequence because of heterogeneous signal, probably due to the presence of quasi-species with insertions/deletions of a different length.

DNA Primers↗
PubMed2003

Evolution of R5 and X4 human immunodeficiency virus type 1 gag sequences in vivo: evidence for recombination.

Human immunodeficiency virus type 1 (HIV-1) infection is in general established by CCR5-utilizing (R5) virus variants, which persist throughout the course of infection. R5 HIV-1 variants evolve into CXCR4-utilizing (X4) HIV-1 variants in approximately half of the infected individuals. We have previously observed an ongoing genetic evolution with a continuous divergence of envelope gp120 sequences of coexisting R5 and X4 virus variants over time. Here, we studied evolution of gag p17 sequences in two patients who developed X4 variants in the course of infection. In contrast to the envelope gp120 sequences, gag p17 sequences of R5 and X4 virus populations intermingled in phylogenetic trees and did not diverge from each other over time. Statistical evaluation using the Shimodaira-Hasegawa test indicated that the different genomic regions evolved along different topologies, supporting the hypothesis of recombination. Therefore, our data imply that recombination between R5 and X4 HIV-1 variants occurs in vivo.

Cell Line↗
PubMed1993

Divergent evolution may link human immunodeficiency virus GP41 to human CD4.

A local sequence similarity of HIV envelope proteins (gp120 and gp41) to immunoglobulins suggests that a mimicry phenomenon may form the basis of the HIV-cell membrane interaction and of HIV-induced autoimmune reaction. We explored the hypothesis of any deeper relationship between HIV env proteins and immunoglobulin family members. An overall DNA sequence similarity between gp41 coding region of env gene and the HIV-receptor CD4 gene was observed and a 14-base-long oligonucleotide, almost unique in the GenBank, was found in gp41 and CD4 genes. The alignment of env gene to CD4 gene and to 84 different sequences showed a significantly higher homology score and a nonrandom similarity in the CD4-env alignment. A significant similarity was also found between the env protein and the sequence encoded by an alternate reading frame of CD4 gene. Our observations suggest that gp41 coding region might have a different origin than the gp120 coding region of the env gene, and that a divergent evolution might link gp41 to CD4 or immunoglobulin family members. In this study the analysis of alternate-reading-frame products is also proposed as a novel approach to investigate evolutionary links and structure-function relationships.

Amino Acid Sequence↗
PubMed2005

[Infectious pulmonary complications in HIV-infected patients in the high by active antiretroviral therapy era in Spain].

Pulmonary complications in HIV-infected patients are at present a first-rate problem. They are the main cause of hospital admission of these patients in our country. Most HIV-patients have a pulmonary complication during the evolution of the infection. The main etiologic diagnosis is bacterial pneumonia, especially pneumococcal pneumonia; the second most frequent cause is Pneumocystis jiroveci (previously named P. carinii) pneumonia and the third cause is mycobacteriosis, particularly Mycobacterium tuberculosis. From early studies, important changes in the epidemiology of HIV-related pulmonary complications have occurred. General prescription of P. jiroveci primary prophylaxis is probably one of the main causes, and, more recently, the use of highly active antiretroviral therapy may also be an underlying explanation. In this review, epidemiology, diagnosis and outcome of HIV-related pulmonary complications in our country are update.

Antiretroviral Therapy, Highly Active↗
PubMed2005

When to initiate antiretroviral therapy in HIV-1-infected adults: a review for clinicians and patients.

One of the most controversial topics in the medical management of HIV disease is the optimal time to initiate highly active antiretroviral therapy (HAART) in HIV-1-infected adults. Premature exposure to antiretrovirals may precipitate early evolution of resistance and unnecessary side-effects, whereas remaining off HAART until late in the course of HIV disease may lead to reduced therapeutic benefits and elevated mortality. The lack of a randomised clinical trial to consider this issue has resulted in ongoing revision of expert recommendations and substantial variability between international consensus guidelines regarding the optimal time to initiate therapy. Since this uncertainty is a source of unease for both patients and clinicians, we summarise the latest evidence regarding the optimal time to initiate HAART with consideration of the potential benefits and drawbacks of starting HIV treatment at the different levels presently recommended in leading consensus guidelines.

Anti-HIV Agents↗
PubMed1995

[Clinico-radiologic characteristics of 8 cases of brain tuberculoma].

Several problems are presented in differential diagnosis between cerebral tuberculomas and other brain lesions. Eight cases of cerebral tuberculomas diagnosed in our hospital between 1962 and 1992 were studied. Data about age, sex, HIV antibodies, clinical manifestation, tomographic images, non cerebral locations, diagnostic method, evolution and treatment resolution were collected. Eight cases were diagnosed, seven men and one woman, age 40.75 +/- 10 HIV antibodies in three patients were positive. Meningitis (4 cases) and weight loss (4 cases) were the first clinical features. Confusional state, fever and seizures were presented in three cases one (37.5%), ataxia in two cases (25%) and headache in one (12.5%). Lesions were sole in 62.5% of cases, and several in 37.5%. Were high density in 25.9% and low density in 75%. All patients presented a other localization of tuberculosis. Mycobacterium tuberculosis was isolated in sputum in 75% of cases. After six month, most of the lesions improved.

Adult↗