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PubMedDate not supplied

[Immunologic thrombopenic purpura and HIV infection in heroin addicts].

The authors have studied the clinical aspects and mechanism of the thrombocytopenia observed in heroin addicts in the light of recently published data. This relatively frequent complication of intravenous drug addiction must be related to the immunological disturbances caused by carriage of the HIV virus. The evolutive characteristics of thrombocytopenia in such cases and the therapeutic implications of this association between thrombocytopenic purpura and acquired immunodeficiency are discussed.

Acquired Immunodeficiency Syndrome↗

PubMed1999

[Cytomegalovirus myeloradiculitis in pregnancy].

INTRODUCTION: Cytomegalovirus neurological complications are frequent in immunocompromised patients specially in HIV positive patient. In immunocompetent patient these complications are infrequent. EXEGESIS: We describe a case of cytomegalovirus myeloradiculitis during pregnancy in a 25-year-old woman, HIV negative. The evolution was favorable with foscarnet therapy. CONCLUSION: A spinal complication during cytomegalovirus infection in immunocompetent patient should lead to a therapy with a specific antiviral to reduce neurologic involvement.

Abortion, Induced↗

PubMed1999

Sequence clusters in human immunodeficiency virus type 1 reverse transcriptase are associated with subsequent virological response to antiretroviral therapy.

Many amino acid (aa) sites in reverse transcriptase (RT) have been implicated in resistance to nucleoside (NRTI) and nonnucleoside antiretrovirals. Interactions between these in response to combination therapy remain poorly understood. In a trial (ACTG 241) of zidovudine/didanosine (ddI) versus zidovudine/ddI/nevirapine in nucleoside-experienced patients, baseline sequence data from the RT coding region was analyzed from 55 individuals. Sequences were clustered by use of a parsimony method and the virological responses (ratio of baseline viral load to viral load after of therapy) for each cluster were analyzed at week 8 and week 48. Both clusters and genotype at aa 215 were significantly associated with virological response at both time points, whereas viral load showed a stronger association with sequence clusters. Sequence clusters identified one group of patients who never developed high-level resistance to NRTIs despite prior nucleoside exposure and poor suppression of viral replication.

Acquired Immunodeficiency Syndrome↗

PubMed2001

HIV-1 and HIV-2 LTR nucleotide sequences: assessment of the alignment by N-block presentation, "retroviral signatures" of overrepeated oligonucleotides, and a probable important role of scrambled stepwise duplications/deletions in molecular evolution.

Previous analyses of retroviral nucleotide sequences, suggest a so-called "scrambled duplicative stepwise molecular evolution" (many sectors with successive duplications/deletions of short and longer motifs) that could have stemmed from one or several starter tandemly repeated short sequence(s). In the present report, we tested this hypothesis by focusing on the long terminal repeats (LTRs) (and flanking sequences) of 24 human and 3 simian immunodeficiency viruses. By using a calculation strategy applicable to short sequences, we found consensus overrepresented motifs (often containing CTG or CAG) that were congruent with the previously defined "retroviral signature." We also show many local repetition patterns that are significant when compared with simply shuffled sequences. First- and second-order Markov chain analyses demonstrate that a major portion of the overrepresented oligonucleotides can be predicted from the dinucleotide compositions of the sequences, but by no means can biological mechanisms be deduced from these results: some of the listed local repetitions remain significant against dinucleotide-conserving shuffled sequences; together with previous results, this suggests that interspersed and/or local mononucleotide and oligonucleotide repetitions could have biased the dinucleotide compositions of the sequences. We searched for suggestive evolutionary patterns by scrutinizing a reliable multiple alignment of the 27 sequences. A manually constructed alignment based on homology blocks was in good agreement with the polypeptide alignment in the coding sectors and has been exhaustively assessed by using a multiplied alphabet obtained by the promising mathematical strategy called the N-block presentation (taking into account the environment of each nucleotide in a sequence). Sector by sector, we hypothesize many successive duplication/deletion scenarios that fit our previous evolutionary hypotheses. This suggests an important duplication/deletion role for the reverse transcriptase, particularly in inducing stuttering cryptic simplicity patterns.

Algorithms↗

PubMed2001

The inference of stepwise changes in substitution rates using serial sequence samples.

It is frequently true that molecular sequences do not evolve in a strictly clocklike manner. Instead, substitution rate may vary for a number of reasons, including changes in selection pressure and effective population size, as well as changes in mean generation time. Here we present two new methods for estimating stepwise changes in substitution rates when serially sampled molecular sequences are available. These methods are based on multiple rates with dated tips (MRDT) models and allow different rates to be estimated for different intervals of time. These intervals may correspond to the sampling intervals or to a priori--defined intervals that are not coincident with the times the serial samples are obtained. Two methods for obtaining estimates of multiple rates are described. The first is an extension of the phylogeny-based maximum-likelihood estimation procedure introduced by Rambaut. The second is a new parameterization of the pairwise distance least-squares procedure used by Drummond and Rodrigo. The utility of these methods is demonstrated on a genealogy of HIV sequences obtained at five different sampling times from a single patient over a period of 34 months.

Anti-HIV Agents↗

PubMed2001

The proteasome: a new target for novel drug therapies.

The proteasome is an enzyme present in all cells, from yeast to human, and has a central role in the proteolytic degradation of the vast majority of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in controlling inflammatory processes, cell cycle regulation, and gene expression. As such, agents that inhibit the proteasome have been shown to be active in numerous animal models of inflammation and cancer Two proteasome inhibitors are under clinical evaluation. PS-519 is being studied for the treatment of reperfusion injury that occurs following cerebral ischemia and myocardial infarction. The other, PS-341, has recently entered multiple phase 2 clinical trials for the treatment of multiple myeloma, chronic lymphocytic leukemia, and a variety of solid tumors. The proteasome may have an important role in the evolution of HIV-related disorders including AIDS and inflammatory disorders. Therapeutic strategies using proteasome inhibitors for the treatment of these conditions have now entered preclinical development.

Acetylcysteine↗

PubMed2004

HIV/AIDS epidemics in Vietnam: evolution and responses.

The goal of this study was to describe the evolution of the HIV epidemic in Vietnam and its responses. Surveillance was conducted in 8 provinces in 1994, expanded to 12 in 1995, 20 in 1996, and 30 in 2001. Sentinel populations were sexually transmitted disease (STD) patients, female sex workers (FSWs), injection drug users (IDUs), tuberculosis (TB) patients, antenatal women, and military conscripts. Vietnam is in the concentrated epidemic stage. HIV prevalence had increased significantly in all surveillance population groups in the 1990s. HIV prevalence in the south is higher than in other regions of the country. The national HIV prevalence increased from 10.1% in 1996 to 32% in 2002 among IDUs, from 0.6% in 1994 to 6.6% in 2002 among FSWs, from 0.4% in 1994 to 2.4% in 2002 among STD patients, from 0.03% in 1994 to 0.34% in 2002 among pregnant women, from 0% in 1994 to 0.7% in 2002 among army military recruits, and from 0.5% in 1994 to 3.6% in 2002 among TB patients. The government has a strong commitment to control the epidemic and has implemented many activities for HIV prevention and control. Vietnam's HIV epidemic is predominantly among IDUs. Current intervention activities have not been sufficient to reduce HIV transmission. Vietnam needs to strengthen responses by scaling up the best practices in the most affected population groups by implementing internationally recognised effective interventions appropriately.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Skin manifestations in AIDS patients.

Skin lesions occur in virtually all patients during the unfolding evolution of their HIV infection--usually a succession of conditions reflecting the gradual decline of immunity. Hairy leucoplakia can occur at any stage and in all risk groups. Kaposi's sarcoma is seen only in homosexually acquired AIDS. A transient rash may accompany the initial HIV seroconversion illness, but may go unnoticed. Documented examples show macular red oval lesions, similar to pityriasis rosea, but extending onto the face, palms and soles, preceded by a flu-like illness with lymphadenopathy and lymphopenia simulating glandular fever. Seroconversion occurs within weeks. During the following weeks or years the gradually declining immunity may only be documented by decreasing numbers of CD4 positive lymphocytes with the emergence of 'idiopathic' inflammatory skin conditions (eg, seborrhoeic dermatitis, psoriasis), as well as autoimmune conditions (eg, thrombocytopenia, morphoea or alopecia areata). As immunity itself declines, skin infections emerge. Shingles affects over 25% of HIV-positive patients--sometimes involving numerous dermatomes, accompanied by multiple distant chicken pox lesions and followed by post-herpetic neuralgia. Onychomycosis and tinea pedis are universal, but sometimes occult patterns with follicular lesions due to Trichophyton rubrum may spread widely over the beard and chest. Uncomfortable mucosal candidosis, sometimes with oesophageal extension, may only become controllable with oral imidazoles. Molluscum contagiosum may be seen in hundreds over large areas, whole soles can be shod in verrucae and vulgar warts appear in the most unusual sites, for example on the palate or up nostrils. Dry skin develops into acquired ichthyosis and eczema crackelé.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗

PubMed2003

Influence of reverse transcriptase variants, drugs, and Vpr on human immunodeficiency virus type 1 mutant frequencies.

The evolution of drug resistance is a major complication of human immunodeficiency virus type 1 (HIV-1) chemotherapy. HIV-1 reverse transcriptase (RT) is a major target of antiretroviral therapy and ultimately the target of drug resistance mutations. Previous studies have indicated that drug-resistant HIV-1 RTs can alter HIV-1 mutant frequencies. In this study, we have tested a panel of HIV-1 RT variants for their ability to influence virus mutant frequencies. The RT variants tested included drug-resistant RT variants as well as other variants analyzed in enzyme fidelity studies with the lacZalpha gene as a mutation target and/or implicated as being important for enzyme fidelity by structural studies. Combinations of mutations that alone had a statistically significant influence on virus mutant frequencies resulted in different mutant frequency phenotypes. Furthermore, when virus replication occurred in the presence of drugs [e.g., 3'-azido-3'-deoxythymidine, (-)2/,3'-dideoxy-3'-thiacytidine, hydroxyurea, thymidine, or thioguanine] with selected RT variants, virus mutant frequencies increased. Similarly, Vpr variants deficient for binding to the uracil DNA glycosylase repair enzyme were observed to influence HIV-1 virus mutant frequencies when tested alone or in combination with RT variants. In summary, these observations indicate that HIV-1 mutant frequencies can significantly change by single amino acid substitutions in RT and that these effects can be altered by additional mutations in RT, by drugs, and/or by expression of Vpr variants. Such altered virus mutant frequencies could impact HIV-1 dynamics and evolution in small population sizes.

Amino Acid Substitution↗

PubMed2001

Evolution and transmission of stable CTL escape mutations in HIV infection.

Increasing evidence indicates that potent anti-HIV-1 activity is mediated by cytotoxic T lymphocytes (CTLs); however, the effects of this immune pressure on viral transmission and evolution have not been determined. Here we investigate mother-child transmission in the setting of human leukocyte antigen (HLA)-B27 expression, selected for analysis because it is associated with prolonged immune containment in adult infection. In adults, mutations in a dominant and highly conserved B27-restricted Gag CTL epitope lead to loss of recognition and disease progression. In mothers expressing HLA-B27 who transmit HIV-1 perinatally, we document transmission of viruses encoding CTL escape variants in this dominant Gag epitope that no longer bind to B27. Their infected infants target an otherwise subdominant B27-restricted epitope and fail to contain HIV replication. These CTL escape variants remain stable without reversion in the absence of the evolutionary pressure that originally selected the mutation. These data suggest that CTL escape mutations in epitopes associated with suppression of viraemia will accumulate as the epidemic progresses, and therefore have important implications for vaccine design.

Adult↗

PubMed2004

Coevolution of RANTES sensitivity and mode of CCR5 receptor use by human immunodeficiency virus type 1 of the R5 phenotype.

The evolution of human immunodeficiency virus type 1 (HIV-1) coreceptor use has been described as the acquisition of CXCR4 use linked to accelerated disease progression. However, CXCR4-using virus can be isolated only from approximately one-half of individuals with progressive HIV-1 disease. The other half continue to yield only CCR5-using viruses (R5 phenotype) throughout the course of disease. In the present work, the use of receptor chimeras between CCR5 and CXCR4 allowed us to study the evolution of HIV-1 with the R5 phenotype, which was not revealed by studies of wild-type coreceptor use. All together, 246 isolates (173 with the R5 phenotype) from 31 individuals were tested for their ability to infect cells through receptor chimeras. R5(narrow) virus was able to use only wild-type CCR5, whereas R5(broad(1)) to R5(broad(3)) viruses were able to use one to three chimeric receptors, respectively. Broad use of chimeric receptors was interpreted as an increased flexibility in the mode of receptor use. R5(broad) isolates showed higher infectivity in cells expressing wild-type CCR5 than R5(narrow) isolates. Also, the increased flexibility of R5(broad) isolates was concomitant with a lower sensitivity to inhibition by the CC chemokine RANTES. Our results indicate a close relationship between HIV-1 phenotypic changes and the pathogenic process, since the mode and efficiency of CCR5 use as well as the decrease in the RANTES sensitivities of isolated viruses are significantly correlated with CD4(+)-T-cell decline in a patient. One possible explanation is that ligand competition at the CCR5 receptor or changed CCR5 availability may shape the outcome of HIV-1 infection.

Cell Line, Tumor↗

PubMed1992

[Seroepidemiologic study of human herpesvirus-6 in intravenous drug addicts, with and without infection caused by human immunodeficiency virus type 1].

BACKGROUND: The human herpesvirus-6 (HHV-6) may be a cofactor of infection by the human immunodeficiency virus type 1 (HIV-1). However, there are discrepancies with respect to the possible epidemiological relation between both viruses. The aim of the present study was to study the prevalence of infection by the HHV-6 in intravenous drug addicts (IVDA) with and without HIV-1 infection. METHODS: IgG antibodies vs HHV-6 (anti-HHV-6-IgG) were determined by indirect immunofluorescence in 100 IVDA (29 seronegative and 71 seropositive for HIV-1 of which 45 were in stage II and 26 in IV-C1 of CDC) as well as in 100 healthy subjects of a similar age (control group). RESULTS: The prevalence of anti-HHV-6-IgG was much higher in the whole group of IVDA than in the control group and was equal in the IVDA with HIV-1 infection and in those patients without infection. There was no significant difference between the latter and the control group with the same being seen between the IVDA in different stages of HIV-1 infection. CONCLUSIONS: The results of this study suggest the existence of an epidemiological relation between human herpes virus-6 (HHV-6) infection and human immunodeficiency virus -1 (HIV-1). However, infection by the HHV-6 has no relation with the evolutive degree of the HIV-1 infection nor with intravenous drug addiction.

Acquired Immunodeficiency Syndrome↗

PubMed1989

Is HIV unique or merely different?

The HIV epidemic is similar to previous human epidemics, and our early responses to the HIV epidemic have likewise been similar. Furthermore, HIV is similar to other single-stranded RNA viruses in its evolution. Like other RNA viruses, HIV has a high mutation rate and thus evolves rapidly. This rapid evolution may make it difficult to develop a successful vaccine against HIV, and perhaps may also limit the usefulness of drugs because of the appearance of resistant mutants. However, most of the variation in HIV nucleotide sequences is neutral, not adaptive. Other viruses in the same retrovirus subfamily as HIV (lentiviruses) are also successful pathogens in animals and are difficult to control without the added problem of the social factors that exist for HIV. These social factors involved in HIV transmission make HIV hard to control by usual public health measures. The prevalence of syphilis and hepatitis B in the United States shows that neither a successful drug treatment nor an effective vaccine is sufficient to stop some infectious diseases when social factors are involved. For these reasons, I conclude that the HIV/AIDs epidemic is different, but not unique.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Evolution of lamivudine resistance in human immunodeficiency virus type 1-infected individuals: the relative roles of drift and selection.

Human immunodeficiency virus type 1 (HIV-1) rapidly develops resistance to lamivudine during monotherapy, typically resulting in the appearance at position 184 in reverse transcriptase (RT) of isoleucine instead of the wild-type methionine (M184I) early in therapy, which is later replaced by valine (M184V). M184V reduces viral susceptibility to drug in vitro by approximately 100-fold, but also results in a lower processivity of RT. We show that a drop in absolute viral fitness associated with the outgrowth of M184V results in a drop in viral load only in individuals with high CD4(+) counts, from whom we estimate the relative fitness of M184V in the presence of drug to be approximately 10% of that of the wild type prior to therapy. The timing of emergence of the M184V mutant varies widely between infected individuals. From analysis of the frequency of M184I and M184V mutants determined at multiple time points in seven individuals during lamivudine therapy, we estimated the fitness advantage of M184V over M184I during therapy to be approximately 23% on average. We have also estimated the average ratio of the frequencies of the two mutants prior to therapy to be 0. 2:1, with a range from 0.12:1 to 0.33:1. We have found that the differences between individuals in the rate of evolution of lamivudine resistance arise due to genetic drift affecting the relative frequency of M184I and M184V prior to therapy. These results show that stochastic effects can be significant in HIV evolution, even when there is large fitness difference between mutant and wild-type variants.

Anti-HIV Agents↗

PubMed2006

Longitudinal analysis of human immunodeficiency virus type 1 nef/long terminal repeat sequences in a cohort of long-term survivors infected from a single source.

We studied the evolution of human immunodeficiency virus type 1 (HIV-1) in a cohort of long-term survivors infected with an attenuated strain of HIV-1 acquired from a single source. Although the cohort members experienced differing clinical courses, we demonstrate similar evolution of HIV-1 nef/long-terminal repeat (LTR) sequences, characterized by progressive sequence deletions tending toward a minimal nef/LTR structure that retains only sequence elements required for viral replication. The in vivo pathogenicity of attenuated HIV-1 is therefore dictated by viral and/or host factors other than those that impose a unidirectional selection pressure on the nef/LTR region of the HIV-1 genome.

Adaptation, Physiological↗

PubMed1995

[The calculation of AIDS costs in Spain by simulation technics].

BACKGROUND: The aim of this study was to elaborate a quantitative model integrating the clinical, and epidemiologic characteristics of the economic costs of the treatment of HIV infected and AIDS patients in Spain to determine the future evolution of the treatment of HIV infected and AIDS patients in Spain to determine the future evolution of the disease and predict the costs of the treatments for the Spanish health care system in 1995. METHODS: A model based on the calculation of probabilities in which the classification of AIDS patients was designed in three phases: early, intermediate and AIDS and established the relations of changes among the phases and included the economic costs of each of the treatments. The model was programmed on a calculation sheet to allow possibilities of disease evolution to be configured in addition to the costs. RESULTS: In 1995 the health care system will treat 22,000 AIDS patients together with those with HIV infection leading to three million hospital stays, equivalent to 8,000 hospital beds dedicated to each treatments with a budget repercussion of close to 90,000 million pesetas. The number of consultations to specialists will increase to up to 570,000 with the total cost of health care treatments being up to 113,000 million pesetas. CONCLUSIONS: The results of this model indicate high health care costs derived from the treatment of AIDS and HIV infection. Given the fact that it is possible to perform simulations with the model under other hypothesis, basic clinical, epidemiologic and economic data are required to determine the most realistic possibilities to thereby orient global policies concerning this disease.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Gene defects clustered at the C-terminus of the vpr gene of HIV-1 in long-term nonprogressing mother and child pair: in vivo evolution of vpr quasispecies in blood and plasma.

Earlier studies on HIV-1 strains from HIV-1-infected long-term nonprogressors (LTNP) have reported that nef deletions and/or attenuations may be crucial in the survival of these patients. Other reports have suggested that the nef gene may not be the only gene involved, but attenuations in other accessory genes (vif, vpr, vpu), which play an important role in the viral life cycle, may be similarly important in chronic HIV-1 infection in LTNPs. Here we show the molecular and phylogenetic analyses of the vpr gene in HIV-1 strains derived from both blood and plasma of an HIV-1 infected long-surviving mother-child pair which has survived for > 13 years with HIV infection: both have maintained stable CD4+ T-cell counts. Analyses of blood-and plasma-derived HIV-1 vpr clones indicated the presence of defects (insertions and deletions) and length polymorphisms. Interestingly, all the vpr defects in PBMCs and plasma were clustered at the C-terminus of the Vpr protein, between amino acid residues 83 and 89, which has been implicated in the G2 cell cycle arrest as a step to early HIV-1 infection. In contrast, the vpr sequence analysis of HIV-1 strains derived from 30 different patients, who either died of AIDS-related illnesses or have AIDS, showed neither C-terminal defects nor length polymorphism in the vpr gene. Also, secondary structure predictions suggest that the naturally occurring mutations at the C-terminal region (aa 83-89) have the potential to affect the secondary structure of the Vpr protein. Also, in some cases, the out-of-frame mutations and the length polymorphisms affect the tat gene reading frame. Together, these mutations may have potential significance in conferring chronic HIV-1 infection in this long-surviving nonprogressing mother-child pair.

Adolescent↗

PubMed2005

In HIV type 1-infected children cytotoxic T lymphocyte responses are associated with greater reduction of viremia under antiretroviral therapy.

The evolution of the HIV-specific CD8+ T cell response in patients receiving potent combination therapy has been well documented in adult patients. However, no study reported whether baseline HIV-specific CD8+ T cell response is linked to treatment outcome. The aims of this study were to investigate both the impact of baseline memory cytotoxic T lymphocytes (CTL) on treatment outcome and the effect of potent therapy on memory HIV-specific CTL in HIV-1-infected pediatric patients. The study group comprised 30 children who started a first-line combination treatment including at least three drugs from two different classes and were longitudinally followed during treatment. Their memory HIV-specific responses were measured at baseline and during treatment, as well as their plasma viremia and CD4+ levels. The intensity of memory Gag-specific CTL and the breadth of the CTL response at the beginning of treatment were significantly correlated with lower plasma viral load during treatment, independently of baseline plasma viral load, CD4+ counts, and age. Children with partially controlled viral replication had enhanced Gag-specific CTL compared to their baseline value. This improvement of antiviral responses during treatment was not observed when viral replication was either fully suppressed or uncontrolled. In conclusion, our results show that higher baseline HIV-specific CTL are linked to lower viremia under combination therapy. This result adds further support to the hypothesis that cooperation between the antiviral immune response and antiviral drugs could be helpful for therapeutic management of HIV-infected patients.

Acquired Immunodeficiency Syndrome↗