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PubMed2001

Epidemiology, evolution, and future of the HIV/AIDS pandemic.

We used mathematical models to address several questions concerning the epidemiologic and evolutionary future of HIV/AIDS in human populations. Our analysis suggests that 1) when HIV first enters a human population, and for many subsequent years, the epidemic is driven by early transmissions, possibly occurring before donors have seroconverted to HIV-positive status; 2) new HIV infections in a subpopulation (risk group) may decline or level off due to the saturation of the susceptible hosts rather than to evolution of the virus or to the efficacy of intervention, education, and public health measures; 3) evolution in humans for resistance to HIV infection or for the infection to engender a lower death rate will require thousands of years and will be achieved only after vast numbers of persons die of AIDS; 4) evolution is unlikely to increase the virulence of HIV; and 5) if HIV chemotherapy reduces the transmissibility of the virus, treating individual patients can reduce the frequency of HIV infections and AIDS deaths in the general population.

Acquired Immunodeficiency Syndrome↗
PubMed2003

CD4T lymphocyte subsets and disease manifestation in children with and without HIV born to HIV-1 infected mothers.

OBJECTIVE: To understand the natural history of HIV-1 infection in children in terms of evolution of childhood clinical manifestations versus the immune status, we prospectively studied children with and without maternally transmitted HIV-1 infection born to mothers infected with HIV-1 for two years between March 1998 and March 2000. DESIGN: A prospective cohort study. SETTING: An institutional children's home. SUBJECTS: Fifty nine children (26 males and 33 females) with and without maternally transmitted HIV-1 infection born to mothers infected with HIV-1 and adopted in institutional children home. METHODS: HIV-1 status of children under nine months was confirmed by polymerase chain reaction(PCR). ELISA for HIV-1 antibody in serum/plasma was used to confirm HIV-infection status for children aged < or = 18 months. Children were visited every three months between March and June 2000. At every visit blood was collected for total white cell count, haemoglobin and CD4+ and CD8+ T cell counts. The institutional doctor routinely examined children and treated all ailments. Clinical data were recorded. MEASURES: HIV-DNA, anti-HIV antibodies, total white blood count, total T cell counts, CD4 and CD8 T cell subset counts, frequency of childhood manifestations of infection. RESULTS: The children were aged between 4.5 and 13 years. The baseline haematological and immunological profiles (mean, mode) were: HIV-1 sero-converters (WBC 7151,7150; HB 11.6, 12.0; CD4+ 686, 795; CD8+ 2168, 1507) and HIV-1 de-seroconverters (mean, mode) were: (WBC 8386, 7150; HB 11.7, 12.8; CD4+ 735, 795; CD8+ 2168, 1507). The commonest causes of illnesses among the HIV-1 children were URTI (85.3%), TB(56.1 %), pneumonia (56.2%), tonsillitis (34.1%), parotiditis (28%) and acute otitis media (25%). The distribution of clinical manifestations was similar between the two categories of children, except URTI, whose prevalence was significantly increased among HIV-1 infected children (p-value=0.006). Among the HIV-1 infected children, only TB, parotiditis, and acute otitis media (AOM) were significantly associated with decreased CD4+ T cell count (p<0.05) resulting from HIV infection. CONCLUSIONS: HIV infection in children predisposes them to common childhood infections that can be used as markers of immune decline. TB, AOM, URTI may be early indicators of suspicion that would enable selective screening for HIV infection in children.

Biomarkers↗
PubMed1994

Temporal analysis of the antibody response to HIV envelope protein in HIV-infected laboratory workers.

Three laboratory workers have been infected with the IIIB strain of HIV; their antibody response to HIV has been studied in serial serum specimens. Because the infecting virus is known, the fine specificity of the antibody response was studied on the homologous strain of HIV. Anti-p17, anti-p24, anti-gp160, CD4/gp120 blocking and neutralizing antibodies developed in parallel. Epitope mapping of the anti-gp160 response indicated several regions that consistently induced an antibody response. Serum contained antibody which reacted with V3-specific peptides corresponding to the very tip of the loop and crossreactivity was seen with V3 loop peptides from other sequence divergent strains of HIV. Antibody to the V1 loop was produced at levels comparable with that seen for the V3-loop. Anti-V1 neutralized HIV with a titration curve equivalent to an anti-V3 monoclonal antibody. Because the infecting virus is known and serial reisolates have been obtained, we explored the relationship between production of antibody to a given epitope and mutation in the virus. The data suggest that an association exists, but do not clearly indicate that antibody drives the selection for mutant viruses. The findings presented here provide a fine specificity analysis of the evolution of the antibody response to HIV in greater detail than has previously been performed.

Amino Acid Sequence↗
PubMed1996

Human immunodeficiency virus type 1 molecular evolution and the measure of selection.

Human immunodeficiency virus (HIV) envelope genes are highly variable between and often within individuals. Part of this variability is thought to be the result of immune-mediated positive selection for sequence diversity. To measure positive selection it has become customary in HIV research to calculate the ratio of the proportions of synonymous (ds) and nonsynonymous (dn) substitutions per potential synonymous or nonsynonymous site, respectively. However, another measure that can be used is the difference between ds and dn, delta d. We show, by example, that using the ratio, ds/dn, or the difference, delta d, may lead us to different conclusions regarding the existence of positive selection pressure. We conclude by noting that until we understand the processes that mediate nucleotide variation in a host selective environment, inferences based on summary statistics characterizing types of nucleotide substitutions should be made with caution.

Base Sequence↗
PubMed1992

On the early emergence of reverse transcription: theoretical basis and experimental evidence.

Reverse transcriptase (RT) was first discovered as an essential catalyst in the biological cycle of retroviruses. However, in the past years evidence has accumulated showing that RTs are involved in a surprisingly large number of RNA-mediated transpositional events that include both viral and nonviral genetic entities. Although it is probable that some RT-bearing genetic elements like the different types of AIDS viruses and the mammalian LINE family have arisen in recent geological times, the possibility that reverse transcription first took place in the early Archean is supported by (1) the hypothesis that RNA preceded DNA as cellular genetic material; (2) the existence of homologous regions of the subunit tau of the E. coli DNA polymerase III with the simian immunodeficiency virus RT, the hepatitis B virus RT, and the beta' subunit of the E. coli RNA polymerase (McHenry et al. 1988); (3) the presence of several conserved motifs, including a 14-amino-acid segment that consists of an Asp-Asp pair flanked by hydrophobic amino acids, which are found in all RTs and in most cellular and viral RNA polymerases. However, whether extant RTs descend from the primitive polymerase involved in the RNA-to-DNA transition remains unproven. Substrate specificity of the AMV and HIV-1 RTs can be modified in the presence of Mn2+, a cation which allows them to add ribonucleotides to an oligo (dG) primer in a template-dependent reaction. This change in specificity is comparable to that observed under similar conditions in other nucleic acid polymerases. This experimentally induced change in RT substrate specificity may explain previous observations on the misincorporation of ribonucleotides by the Maloney murine sarcoma virus RT in the minus and plus DNA of this retrovirus (Chen and Temin 1980). Our results also suggest that HIV-infected macrophages and T-cell cells may contain mixed polynucleotides containing both ribo- and deoxyribonucleotides. The evolutionary significance of these changes in substrate specificities of nucleic acid polymerases is also discussed.

Amino Acid Sequence↗
PubMed2005

Sensitive phenotypic detection of minor drug-resistant human immunodeficiency virus type 1 reverse transcriptase variants.

Detection of drug-resistant variants is important for the clinical management of human immunodeficiency virus type 1 (HIV-1) infection and for studies on the evolution of drug resistance. Here we show that hybrid elements composed of the Saccharomyces cerevisiae retrotransposon Ty1 and the reverse transcriptase (RT) of HIV-1 are useful tools for detecting, monitoring, and isolating drug-resistant reverse transcriptases. This sensitive phenotypic assay is able to detect nonnucleoside reverse transcriptase inhibitor-resistant RT domains derived from mixtures of infectious molecular clones of HIV-1 in plasma and from clinical samples when the variants comprise as little as 0.3 to 1% of the virus population. Our assay can characterize the activities and drug susceptibilities of both known and novel reverse transcriptase variants and should prove useful in studies of the evolution and clinical significance of minor drug-resistant viral variants.

Drug Resistance, Viral↗
PubMed2001

Effects of human T-lymphotropic virus type II on human immunodeficiency virus type 1 phenotypic evolution.

Phenotypic change and broader coreceptor usage by HIV-1 have been associated with disease progression. HIV-1 coreceptor usage by primary isolates obtained from HIV-1-infected and HIV-1/HTLV-II-coinfected individuals was determined. HIV-1 was isolated from 15 of 20 HIV-1-infected and 17 of 24 HIV-1/HTLV-II-coinfected individuals. None of the isolates from either the HIV-1-infected or the coinfected group infected CCR5delta32 PBMCs, suggesting that they all were R5-tropic. Further, both spontaneous and PHA-stimulated production of MIP-1beta and RANTES were similar in HIV-1-infected and coinfected individuals. These data indicate that coinfection with HTLV-II has no effect on HIV-1 coreceptor usage or ex vivo beta-chemokine production.

CD4-Positive T-Lymphocytes↗
PubMed1991

[Monoclonal immunoglobulins in kidney transplantation. Characterisation, evolution and risk factors].

Sera from 192 consecutive HIV negative renal transplant patients with more than 6 months follow-up were investigated for monoclonal or oligoclonal immunoglobulins (mIg) by immunoelectrophoresis or immunofixation. Gammapathy was present in 25 patients (13 percent). Eleven patients had only one monoclonal band, whereas 14 had two or more bands. Sixty percent were IgG K, 29 percent IgG lambda and 11 percent IgM lambda or K. Ninety percent of these mIg did not exceed 2 g/l; mIg appeared within 2-27 months following the transplantation (mean time-lag 8 +/- 6.4 months). The mIg were often transient: 20 disappeared within 1-33 months, most of them (14) being absent after 1 year of follow-up. Some risk factors for mIg could be identified: the patient's age (a risk factor only in women); the duration of dialysis; the occurrence of prior CMV infection; treatment with cyclosporine. The persistence of mIg was characterised by one or more of the followings: high titer of mIg, EBV infection or reactivation, inability to switch from IgM to IgG CMV antibodies. No significant association was found with the hepatitis B surface antigenemia, previous infection with hepatitis C or the number of rejection episodes. In 6 patients, the clinical course was characterised by severe infection or tumours. Although long-term follow ups are not yet available, patients in whom one or more mIg have been demonstrated should be carefully followed.

Adult↗
PubMed1990

[Human immunodeficiency virus infection associated with tuberculosis].

In order to detect an association between HIV infection and tuberculosis (TB), 130 TB inpatients were studied one of whom presented a pulmonary disease due to Mycobacterium avium intracellulare. All had advanced TB, 95.4%, with pulmonary localization. Serum anti-HIV antibodies were detected by ELISA and their presence confirmed by immunoblotting in 4 (3.1%) individuals, three males and one female, with different degrees of pulmonary TB. Of the males, 1 was bisexual, 2 were promiscuous, and the female was the sexual partner of a non symptomatic HIV-infected man. No immunological disturbances or other AIDS related alterations were observed. There was one case of miliary TB, but neither atypical X-ray abnormalities nor extrapulmonary involvement were found. Tuberculin reaction was positive in three of the four HIV infected patients. Clinical, radiological and bacteriological evolution were favorable. Adverse drug reaction occurred in two cases, one of them presenting serious toxidermia caused by isoniazid. Of the 130 individuals, 12 presented risk factors for HIV infection so that the prevalence of anti-HIV antibodies presented here, 4 cases out of 12, is consistent with data from previous reports for high risk populations.

AIDS Serodiagnosis↗
PubMed1999

Highly specific recognition of primer RNA structures for 2'-OH priming reaction by bacterial reverse transcriptases.

A minor population of Escherichia coli contains retro-elements called retrons, which encode reverse transcriptases (RT) to synthesize peculiar satellite DNAs called multicopy single-stranded DNA (msDNA). These RTs recognize specific RNA structures in their individual primer-template RNAs to initiate cDNA synthesis from the 2'-OH group of a specific internal G residue (branching G residue). The resulting products (msDNA) consist of RNA and single-stranded DNA, sharing hardly any sequence homology. Here, we investigated how RT-Ec86 recognizes the specific RNA structure in its primer-template RNA. On the basis of structural comparison with HIV-1 RT, domain exchanges were carried out between two E. coli RTs, RT-Ec86 and RT-Ec73. RT-Ec86 (320 residues) and RT-Ec73 (316 residues) share only 71 identical residues (22%). From the analysis of 10 such constructs, the C-terminal 91-residue sequence of RT-Ec86 was found to be essential for the recognition of the unique stem-loop structure and the branching G residue in the primer-template RNA for retron-Ec86. Using the SELEX (systematic evolution of ligands by exponential enrichment) method with RT-Ec86 and primer RNAs containing random sequences, the identical stem-loop structure (including the 3-U loop) to that found in the retron-Ec86 primer-template RNA was enriched. In addition, the highly conserved 4-base sequence (UAGC), including the branching G residue, was also enriched. These results indicate that the highly diverse C-terminal region recognizes specific stem-loop structures and the branching G residue located upstream of the stem-loop structure. The present results with seemingly primitive RNA-dependent DNA polymerases provide insight into the mechanisms for specific protein RNA recognition.

Amino Acid Sequence↗
PubMed1998

Peripheral facial paralysis (PFP) and HIV infection in Togo.

OBJECTIVES: The purpose of this study was to determine the seroprevalence of HIV in a group of 150 patients with PFP and to study the semiological and evolutive aspect of PFP in patients with or without HIV. MATERIAL AND METHODS: This semilongitudinal study was conducted during 6 years (1990-1995) at the Lomé teaching hospital. Patients consulting for PFP had the HIV test and regular controls. RESULTS: The HIV seroprevalence was 52%. The average age was 31.4+/-8.81 years There was no difference on clinical features between patients with or without HIV infection. Cerebrospinal fluid was normal in patients without HIV infection, but it showed pleiocytosis in patients with HIV infection (87.88%). Of the HIV carriers 14% presented a recurrence. A total of 26.32% of the patients screened in 1990 developed AIDS when followed up. CONCLUSION: Peripheral facial paralysis is frequently associated to HIV infection. An HIV test must be proposed to all patients with PFP in Africa.

AIDS Dementia Complex↗
PubMed2003

Different subtype distributions in two cities in Myanmar: evidence for independent clusters of HIV-1 transmission.

A molecular epidemiological investigation was conducted in two major cities in Myanmar (Yangon and Mandalay). The study revealed a unique predominance of HIV-1 subtype B' (Thailand variant of subtype B) among injecting drug users in Yangon, indicating the strong founder effect of this variant. In contrast, multiple lineages of HIV-1 strains were found in Mandalay, leading to the evolution of various forms of intersubtype recombinants. The results showed independent clusters of HIV-1 transmission in Myanmar.

Female↗
PubMed1991

Structural and evolutionary relationships between retroviral and eucaryotic aspartic proteinases.

Three-dimensional crystal structures of the homologous retroviral proteinases from Rous sarcoma virus (RSV PR) and from human immunodeficiency virus (HIV-1 PR) are to a large extent similar and bear close resemblance to the six known structures of the bilobal fungal and mammalian aspartic proteinases. Systematic three-dimensional structural superpositions were carried out between the retroviral and the eucaryotic aspartic proteinases. Both retroviral enzymes were found to be similarly related to their fungal and mammalian counterparts. The most strongly conserved parts correspond to those regions in the N- and C-domains of the eucaryotic enzymes that are related by the interdomain dyad and consist of a combination of secondary structural elements that form the psi loop-alpha helix motif at the active sites of the aspartic proteinases. The retroviral proteinase monomer exhibits nearly the same degree of structural equivalence to the N- and C-domains of the eucaryotic enzymes. In light of the deduced structural relationships between HIV-1 PR and RSV PR, sequence alignments were performed for a number of retroviral proteinases from different subfamilies. There are three highly conserved amino acid sequence stretches, of which two belong to the psi loop-alpha helix motif, that bear moderate sequence similarity with the eucaryotic enzymes. The third conserved sequence stretch among the retroviral proteinases belongs to the flap and bears no resemblance to the flap sequences in the eucaryotic enzymes. The interdomain antiparallel beta sheet in the cellular enzymes differs from the intersubunit beta sheet in the number, arrangement, and directionality of strands, suggesting the possibility of convergent evolution.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2001

Population genetic analysis of the protease locus of human immunodeficiency virus type 1 quasispecies undergoing drug selection, using a denaturing gradient-heteroduplex tracking assay.

Monitoring the evolution of human immunodeficiency virus type 1 (HIV-1) drug resistance requires measuring the frequency of closely related genetic variants making up the complex viral quasispecies found in vivo. In order to resolve both major and minor (>/=2%) protease gene variants differing by one or more nucleotide substitutions, we analyzed PCR products derived from plasma viral quasispecies by using a combination of denaturing gradient gel electrophoresis and DNA heteroduplex tracking assays. Correct population sampling of the high level of genetic diversity present within viral quasispecies could be documented by parallel analysis of duplicate, independently generated PCR products. The composition of genetically complex protease gene quasispecies remained constant over short periods of time in the absence of treatment and while plasma viremia fell >100-fold following the initiation of protease inhibitor ritonavir monotherapy. Within a month of initiating therapy, a strong reduction in the genetic diversity of plasma viral populations at the selected protease locus was associated with rising plasma viremia and the emergence of drug resistance. The high levels of protease genetic diversity seen before treatment reemerged only months later. In one patient, reduction in genetic diversity at the protease gene was observed concomitantly with an increase in diversity at the envelope gene (E. L. Delwart, P. Heng, A. Neumann, and M. Markowitz, J. Virol. 72:2416-2421, 1998), indicating that opposite population genetic changes can take place in different HIV-1 loci. The rapid emergence of drug-resistant HIV-1 was therefore associated with a strong, although only transient, reduction in genetic diversity at the selected locus. The denaturing gradient-heteroduplex tracking assay is a simple method for the separation and quantitation of very closely related, low-frequency, genetic variants within complex viral populations.

Biological Evolution↗
PubMed2001

DNA aptamers selected against the HIV-1 RNase H display in vitro antiviral activity.

The DNA polymerase of the human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a target widely used to inhibit HIV-1 replication. In contrast, very few inhibitors of the RNase H activity associated with RT have been described, despite the crucial role played by this activity in viral proliferation. DNA ligands with a high affinity for the RNase H domain of HIV-1 RT were isolated by systematic evolution of ligands by an exponential enrichment strategy (SELEX), using recombinant RTs with or without the RNase H domain. The selected oligonucleotides (ODNs) were able to inhibit in vitro the HIV-1 RNase H activity, while no effect was observed on cellular RNase H. We focused our interest on two G-rich inhibitory oligonucleotides. Model studies of the secondary structure of these ODNs strongly suggested that they were able to form G-quartets. In addition to the inhibition of HIV-1 RNase H observed in a cell free system, these ODNs were able to strongly diminish the infectivity of HIV-1 in human infected cells. Oligonucleotides described here may serve as leading compounds for the development of specific inhibitors of this key retroviral enzyme activity.

Anti-HIV Agents↗
PubMedDate not supplied

[Comparative study of the Candida albicans genotypes isolated from immunocompromised patients and health carriers].

The aim of this study is to compare Candida albicans strain genotype isolates from oral cavity of immunocompromised patients due to different immunologic impairments with apparently normal carriers. Four populations were studied: 1) HIV positive hospitalized patients, 2) HIV negative immunocompromised patients (leukemia, lymphoma, organ transplant recipients), 3) drug addicts prior to AIDS pandemia in Argentina, 4) apparently normal carriers. DNA extracted was digested with the enzyme Eco RI, electrophoresed, transferred to nitrocellulose membrane and hybridized with the 27A probe labelled with 32P. The comparison between the profiles obtained permitted the differentiation of 16 genotypes. The distribution of the strains led to the conclusion that: a) all the isolated strains from AIDS patients were closely related and distributed in only three genotypes (1, 3, 11); b) a major genetic relationship between the isolates from AIDS patients and HIV negative immunocompromised patients was observed; c) strains from carriers showed a minor genetic similarity with those obtained from AIDS patients; d) characteristic profiles belonging to any of the studied groups were not found; e) significant genomic changes have not been observed during the last twenty years.

Argentina↗
PubMed2001

[Epidemiological features and incidence trends of primary cerebral lymphomas observed in 80 HIV-infected patients from 1983 to 1999].

OBJECTIVE: To describe the epidemiological characteristics of primary central nervous system lymphoma (PCNSL) and the evolution of the incidence of this lymphoma in HIV-infected patients with a more than 17-year follow-up. RESULTS: Eighty cases of PCNSL were analyzed from a data base of 2,263 AIDS subjects followed from 1983 to 1999 (3.5% of the patients with AIDS). At the time of diagnosis, PCNSL was the first AIDS defining event in 36% of the cases, median CD4 count was 9/mm3 (0-134); 82% of the patients were given antiretroviral therapy (HAART = 0). Only eight cases of PCNSL were observed after 1996 (median HIV RNA level: 250,000 copies/mL (24,000-1,500,000)). The incidence was 39 per 100 patients-year in 1991 and decreased to 1.9 in 1999. At the end of the study, 78 patients had died (98%). The median survival was one month before 1996 ([0-27], n = 72), and was ten months after ([0-44], n = 8). Two patients were still alive 38 and 44 months after diagnosis. After 1996, survival was increased in patients with good response to antiretroviral treatment and in patients with high CD4 count at the moment of diagnosis. CONCLUSION: After the introduction of HAART (1996), the incidence of PCNSL has decreased drastically and survival was increased.

Adult↗