Found 16570 matches for
27 December 2017
Heterosexual transmission of HIV is the predominant transmission mode among adults world-wide, while mother-to-child transmission accounts for the majority of HIV infections in children. Factors that affect genital tract shedding of HIV virus or cell-associated provirus in women are probably important determinants of infectiveness, and hence of transmission risk during sexual contact or delivery. This review discusses the genital HIV RNA and DNA loads in relation to those in the blood and outlines some of the parameters influencing genital tract shedding of HIV.
Genotypic and phenotypic changes during culture of a multinucleoside-resistant human immunodeficiency virus type 1 strain in the presence and absence of additional reverse transcriptase inhibitors.
14 March 2018
The observation that human immunodeficiency virus type 1 (HIV-1) mutations conferring resistance to one reverse transcriptase (RT) inhibitor may suppress resistance to other RT inhibitors provides a rationale for treating HIV-1 with certain RT inhibitor combinations. We examined phenotypic and genotypic changes during culture of a multinucleoside (zidovudine, didanosine, zalcitibine, and stavudine)-resistant HIV-1 strain with and without additional RT inhibitors (nevirapine and lamivudine). The development of nevirapine or lamivudine resistance by the multinucleoside-resistant strain was not accompanied by a reduction in zidovudine or didanosine resistance.
Cervical human immunodeficiency virus type 1 shedding is associated with genital beta-chemokine secretion.
3 May 2018
Forty human immunodeficiency virus type 1 (HIV-1)-infected women participated in a cross-sectional study of possible correlations between chemokine receptor (CCR5 and/or CCR2B) genotype, HIV-1 RNA and DNA load, and beta-chemokine levels (RANTES, MIP-1alpha, MIP-1beta) in blood and cervix. HIV-1 nucleic acid and beta-chemokines were found in all patient blood samples and in more than half of the cervical samples regardless of CCR5 or CCR2B genotype. High beta-chemokine concentrations were in general associated with high virus loads in blood and cervix. In the blood, the proviral DNA load was significantly correlated with the MIP-1alpha concentration, whereas the DNA load in cervix was significantly associated with the MIP-1beta concentration. The cervical viral RNA load was significantly associated with levels of all three chemokines. Thus, when HIV-1 shedding was highest in the genital tract, it was associated with other combinations of beta-chemokines than virus load in blood, suggesting that local immune reactions strongly influence virus load in the cervical compartment.
Conserved footprints of APOBEC3G on Hypermutated human immunodeficiency virus type 1 and human endogenous retrovirus HERV-K(HML2) sequences.
18 May 2018
The human polynucleotide cytidine deaminases APOBEC3G (hA3G) and APOBEC3F (hA3F) are antiviral restriction factors capable of inducing extensive plus-strand guanine-to-adenine (G-to-A) hypermutation in a variety of retroviruses and retroelements, including human immunodeficiency virus type 1 (HIV-1). They differ in target specificity, favoring plus-strand 5'GG and 5'GA dinucleotide motifs, respectively. To characterize their mutational preferences in detail, we analyzed single-copy, near-full-length HIV-1 proviruses which had been hypermutated in vitro by hA3G or hA3F. hA3-induced G-to-A mutation rates were significantly influenced by the wider sequence context of the target G. Moreover, hA3G, and to a lesser extent hA3F, displayed clear tetranucleotide preference hierarchies, irrespective of the genomic region examined and overall hypermutation rate. We similarly analyzed patient-derived hypermutated HIV-1 genomes using a new method for estimating reference sequences. The majority of these, regardless of subtype, carried signatures of hypermutation that strongly correlated with those induced in vitro by hA3G. Analysis of genome-wide hA3-induced mutational profiles confirmed that hypermutation levels were reduced downstream of the polypurine tracts. Additionally, while hA3G mutations were found throughout the genome, hA3F often intensely mutated shorter regions, the locations of which varied between proviruses. We extended our analysis to human endogenous retroviruses (HERVs) from the HERV-K(HML2) family, finding two elements that carried clear footprints of hA3G activity. This constitutes the most direct evidence to date for hA3G activity in the context of natural HERV infections, demonstrating the involvement of this restriction factor in defense against retroviral attacks over millions of years of human evolution.
Persistence of attenuated rev genes in a human immunodeficiency virus type 1-infected asymptomatic individual.
16 March 2018
With the goal of examining the functional diversity of human immunodeficiency virus type 1 (HIV-1) env genes within the peripheral blood mononuclear cells of an asymptomatic individual, we substituted four complete env genes into the replication-competent NL4-3 provirus. Despite encoding full-length open reading frames for gp120 and gp41 and the second coding exon of tat and rev, each chimera was replication defective. Site-directed mutagenesis of codon 78 in the Rev activation domain (from a hitherto unique Ile to the subtype B consensus Leu) partially restored infectivity for two of three chimeras tested. Similarly, mutagenesis of rev codon 78 of NL4-3 from Leu to Ile partially attenuated this virus. Ile-78 was found in all 13 clones examined from samples taken from this asymptomatic subject 4.5 years after infection, including 9 from peripheral blood mononuclear cells and 4 from a virus isolate, as well as 4 additional clones each from peripheral blood mononuclear cells sampled 37 and 51 months later. We next examined conservation of the Rev activation domain within and among long-term survivors (LTS) and patients with AIDS, as well as T-cell-line-adapted strains of HIV-1. Putative attenuating mutations were found in a minority of sequences from all five LTS and two of four patients with AIDS. Of the 11 T-cell-line-adapted viruses examined, none had these changes. Among and within LTS virus population had marginally higher levels of diversity in Rev than in Env; patients with AIDS had similar levels of diversity in the two reading frames; and T-cell-line-adapted viruses had higher levels of diversity in Env. These results are consistent with the hypothesis that asymptomatic individuals harbor attenuated variants of HIV-1 which correlate with and contribute to their lack of disease progression.
Drug resistance and heterogeneous long-term virologic responses of human immunodeficiency virus type 1-infected subjects to zidovudine and didanosine combination therapy. The AIDS Clinical Trials Group 143 Virology Team.
16 March 2018
Plasma human immunodeficiency virus (HIV) type 1 RNA levels, CD4 lymphocyte changes, and drug resistance were studied in HIV-infected patients with 200-500 CD4 lymphocytes/microL who received zidovudine and didanosine combination therapy for 2 years. Among 35 patients, 10 had sustained and 16 had transient > 10-fold reductions in HIV RNA: 9 did not have 10-fold HIV RNA reductions. Only patients with sustained HIV suppression maintained increased CD4 cell counts for 2 years (370 to 501 cells/microL; P = .006). Patients with transient HIV suppression were more likely to develop drug-resistant HIV strains (12/16 vs. 5/19, P = .01) and reverse transcriptase (RT) mutations (4.5 vs. 2.5/strain; P = .02) than were patients with sustained or no HIV suppression. Zidovudine resistance occurred with RT mutations at codons 41, 67, 70, 215, and 219. Multidrug resistance occurred with mutations at codons 62, 75, 77, 116, and 151. Mutations occurred at codons 60, 68, 118, 210, and 228 in > or = 4 patients each. Heterogeneity exists among individual virologic responses to zidovudine and didanosine combination therapy. HIV resistance mechanisms during combination therapy appear more complex than reported with monotherapy.
Drug resistance and heterogeneous long-term virologic responses of human immunodeficiency virus type 1-infected subjects to zidovudine and didanosine combination therapy
10 January 2018
Plasma human immunodeficiency virus (HIV) type 1 RNA levels, CD4 lymphocyte changes, and drug resistance were studied in HIV-infected patients with 200-500 CD4 lymphocytes/μL who received zidovudine and didanosine combination therapy for 2 years. Among 35 patients, 10 had sustained and 16 had transient > 10-fold reductions in HIV RNA; 9 did not have 10-fold HIV RNA reductions. Only patients with sustained HIV suppression maintained increased CD4 cell counts for 2 years (370 to 501 cells/μL; P =.006). Patients with transient HIV suppression were more likely to develop drug-resistant HIV strains (12/16 vs. 5/19, P =.01) and reverse transcriptase (RT) mutations (4.5 vs. 2.5/strain; P =.02) than were patients with sustained or no HIV suppression. Zidovudine resistance occurred with RT mutations at codons 41, 67, 70, 215, and 219. Multidrug resistance occurred with mutations at codons 62, 75, 77, 116, and 151. Mutations occurred at codons 60, 68, 118, 210, and 228 in ≤4 patients each. Heterogeneity exists among individual virologic responses to zidovudine and didanosine combination therapy. HIV resistance mechanisms during combination therapy appear more complex than reported with monotherapy. © 1995, by The University of Chicago.
Human papillomavirus type 16 in vulvar carcinoma, vulvar intraepithelial neoplasia, and associated cervical neoplasia.
7 March 2018
Vulvar intraepithelial neoplasia (VIN) is becoming more widespread and the patients are becoming still younger. Although progression to invasive vulvar carcinoma is uncommon, local recurrences are frequent and about one-quarter of the patients have multicentric genital disease. The aim of the present study was to search for a possible significant association of human papillomavirus (HPV) infection with vulvar carcinoma, recurrences, and multicentric disease. We used the polymerase chain reaction to examine vulvar and cervical biopsies from 43 patients with vulvar neoplasia for HPV type 16, which is the subtype most often detected in genital malignant or premalignant lesions. HPV 16 DNA sequences were found in 14 of 24 (58%) vulvar squamous carcinomas and in 15 of 19 (79%) VIN lesions. Nine patients (21%) had associated cervical neoplasia and six of these harbored HPV 16 in both lesions. Patients with recurrent intraepithelial neoplasia had a significantly higher incidence of HPV 16-positive lesions. No association was found with regard to the occurrence of multicentric disease or risk of malignant progression.
23 May 2018
Although cytotoxic T lymphocytes (CTLs) in people infected with human immunodeficiency virus type 1 can potentially target multiple virus epitopes, the same few are recognized repeatedly. We show here that CTL immunodominance in regions of the human immunodeficiency virus type 1 group-associated antigen proteins p17 and p24 correlated with epitope abundance, which was strongly influenced by proteasomal digestion profiles, affinity for the transporter protein TAP, and trimming mediated by the endoplasmatic reticulum aminopeptidase ERAAP, and was moderately influenced by HLA affinity. Structural and functional analyses demonstrated that proteasomal cleavage 'preferences' modulated the number and length of epitope-containing peptides, thereby affecting the response avidity and clonality of T cells. Cleavage patterns were affected by both flanking and intraepitope CTL-escape mutations. Our analyses show that antigen processing shapes CTL response hierarchies and that viral evolution modifies cleavage patterns and suggest strategies for in vitro vaccine optimization.
Detection of human papillomavirus type 16 DNA sequences in archival cervical tissues by the polymerase chain reaction.
8 December 2017
We have evaluated the polymerase chain reaction for the detection of viral DNA sequences in paraffin-embedded archival tissues. In 63 frozen cervical biopsy specimens that were taken from premalignant and invasive lesions, Southern blotting detected human papillomavirus (HPV) type 16 DNA in 28 (44%) of the samples. In the polymerase chain reaction analysis of the formalin-fixed, paraffin-embedded mirror biopsy specimens, 46 (73%) of the tissues were found to be positive for HPV type 16. In three Southern blotting-positive cases, the DNA of the paraffin-embedded sections was too scant or too degraded to allow the detection of HPV DNA by the polymerase chain reaction. In 21 Southern blotting-negative cases, HPV type 16 DNA could be demonstrated in the archival sections by the polymerase chain reaction technique--a sensitivity improvement of more than 80% over the standard method of HPV detection in tissues.