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[Strongyloides stercoralis and HIV: a case report of an indigenous disseminated infection from non-endemic area].

Strongyloides stercoralis affects people who live in the tropics, but it also extends to temperate regions where its low incidence rate may lead to misdiagnose it. Inside the host this nematode may remain silent for many years, nevertheless, in patients infected with HIV its reactivation leads to a disseminated infection in ectopic sites. This report presents the case of a 34 years-old man infected with HIV who lived in a highland area in the province of Córdoba, Argentina. He was admitted to the hospital because of a complicated Pneumocystis jiroveci pneumonia, receiving trimethoprim-sulfamethoxazole and prednisone treatment. A few days after admission his conditions deteriorated badly, a sputum examination revealed filariform larvae of S. stercoralis, he was then given oral ivermectin medication (200 microg/kg/d). Malabsorption and ileus were installed and he died from multiorganic failure. The evolution of HIV infection to AIDS, a steroids treatment and therapy failure despite oral ivermectin triggered larvae proliferation and lead to disseminated hyperinfection until he died. This report presents not only the first case of disseminated strongyloidiasis detected in our Hospital but also an indigenous infection acquired in a non-endemic area. An awareness of an increased predisposition to this infection, especially in immunocompromised patients with malabsorption and ileus is of paramount importance, since failure to initiate appropriate therapy can lead to catastrophic outcomes, as illustrated in this case report.

Adult↗

Response to treatment and disease progression linked to CD4+ T cell surface CC chemokine receptor 5 density in human immunodeficiency virus type 1 vertical infection.

The factors governing interindividual variability in disease progression among children vertically infected with human immunodeficiency virus type 1 (HIV-1) remain unclear. Because it has recently been shown in infected adults that the density of CC chemokine receptor 5 (CCR5) molecules at the surface of nonactivated (human leukocyte antigen [HLA]-DR(-)) CD4+ T cells correlates with disease progression, the same correlation was sought in children. HLA-DR(-)CD4+ T cell surface CCR5 density was constant over time and correlated with the bioclinical stage and with the CD4 cell slope observed before antiretroviral treatment. In addition, CCR5 density was negatively correlated with the intensity of the decrease in viremia during antiretroviral therapy and was positively correlated with CD4 cell slope since birth. These results are compatible with the hypothesis that CCR5 density is a key factor governing disease progression in pediatric HIV-1 infection and, thereby, an indicator of prognosis. Moreover, they suggest that therapies aimed at reducing CCR5 accessibility should slow down HIV disease evolution in children.

Acquired Immunodeficiency Syndrome↗

Quantification of human immunodeficiency virus type 1-infected mononuclear cells in peripheral blood of seropositive subjects by newly developed flow cytometry analysis of the product of an in situ PCR assay.

The presence of human immunodeficiency virus type 1 (HIV-1) proviral DNA in peripheral blood mononuclear cells (PBMC) of three groups (group 1, more than 500 CD4+ T cells per microliter; group 2, between 200 and 499 CD4+ T cells per microliter; group 3, fewer than 200 CD4+ T cells per microliter) of HIV-1-infected patients, in different stages of the disease, was determined by using a newly developed flow cytometry analysis of the product of in situ PCR assay and compared with other markers of viral replication (HIV-1 p24 antigenemia and viral isolation). Results showed varied percentages of HIV-1-infected PBMC, ranging from 0.6 to 20%. Patients with more than 500 CD4+ T cells per microliter showed the lowest percentage of HIV-1-infected PBMC (2.1 +/- 1.7), compared with patients with CD4+ T-cell counts of between 200 and 499 per microliter (6.5% +/- 4.1%; P < 0.001) and patients with fewer than 200 CD4+ T cells per microliter (4.9% +/- 4.7%; P < 0.05). The difference in the percentage of HIV-1-infected PBMC between group 2 and group 3 patients may in part reflect the loss of CD4+ T lymphocytes in more advanced stages of the disease. However, the results clearly indicate a striking coincidence between the fall of the CD4+ T-cell count below 400/microliter and the sharp increase in PBMC virus loading and p24 antigenemia. Since the procedure is relatively easy to perform, it could be used to monitor the evolution of HIV-1 infection and may prove a useful adjunct in tailoring therapeutic strategies.

AIDS-Related Complex↗

Mutual functional destruction of HIV-1 Vpu and host TASK-1 channel.

Sequence analysis predicted significant structural homology between the HIV-1 accessory protein Vpu and the N-terminal region of TASK-1, a mammalian background K(+) channel. If the homology resulted from molecular piracy during HIV-1 evolution, these two proteins may have important functional interactions. Here we demonstrate that TASK and Vpu physically interact in cultured cells and in AIDS lymphoid tissues. The functional consequences were potentially destructive for both components: Vpu abolished TASK-1 current, while overexpressing TASK led to a marked impairment of Vpu's ability to enhance viral particle release. Further, the first 40 amino acids of TASK-1 (part of the homology to Vpu) were capable of enhancing HIV-1 particle release. This virus-host interaction may influence HIV-1/AIDS progression, as well as electrical signaling in infected host tissues.

Amino Acid Sequence↗

[Antiretroviral therapy in HIV infection. Effects of the introduction of new drugs on health care expenditures, 1994-1999].

The administration of antiretroviral compounds to our cohort of HIV-infected patients was assessed since 1994, on the ground of some epidemiological, clinical, and therapeutic variables. During the six-year study period, a significant increase of mean prescription rate of overall anti-HIV agents was observed, with a nearly 10-fold rise of mean prescribed daily doses per 1,000 patients-year. In particular, lamivudine and indinavir represented the most frequently administered drugs, among nucleoside analogues and protease inhibitors, respectively. A significant increase of the percentage of HIV-infected patients undergoing combined antiretroviral therapy (79.3% in 1999), and the mean number of drugs prescribed per patient (3.02 in 1999), was concurrently detected. The progressive changes of antiretroviral therapy guidelines were responsible for a nearly 16-fold increase of expenditures directly related to antiretroviral drug administration in 1999 compared with 1994 (with over 41% of costs related to protease inhibitors). On the other hand, a substantial modification of HIV disease evolution occurred in our patient cohort in terms of absolute morbidity and mortality figures, as expressed by a drop of notified AIDS cases and AIDS-related deaths ranging from 2.5 to 5 times, during the considered period.

Acquired Immunodeficiency Syndrome↗

Clinical manifestations of allergy and their relation to HIV infection.

In this retrospective study 141 HIV positive subjects were included. Allergy was studied by a specific questionnaire and the Phadia Top Test, an in vitro screening test for specific IgE. Both were related to the patients' history, clinical symptoms and the treatment used. Allergy was studied in reference to HIV negative controls and in relation to the clinical and biological subgroups of HIV patients. The statistical analysis (x 2 test) demonstrated a relationship between allergy and HIV infection and the clinical stage of AIDS-IKEL among patients with CD4 > 300 microliters, which may suggest that allergy contributes to the functional deficiency of these cells. We also demonstrated a high frequency of hypersensitivity reactions (75%) in HIV asymptomatic patients with CD4 < 300 microliters, which indicates that allergy could contribute to the early destruction of these cells. The allergic patients declared to be hypersensitive before contamination. Both mechanisms, functional deficiency and destruction of CD4 T-lymphocytes could be the result of the mediators, cytokines and enzymes released from the mast cells during IgE allergic reaction. Thus this study demonstrated that allergy could be a predisposing factor for the contamination and a polyvalent co-factor for the clinical and biologic evolution of HIV infection.

Acquired Immunodeficiency Syndrome↗

True gynecomastia in congenitally HIV-infected children treated with antiretroviral agents.

Gynecomastia is an emerging untoward effect of HIV-infected patients treated with antiretroviral agents, but frequency, pathogenesis, relationship to single anti-HIV compounds, evolution, and outcome are still under investigation. We report the first two cases of true gynecomastia observed in prepubertal congenitally-infected boys, and clinical, antiretroviral, metabolic, hormonal, virological, and immunological aspects.

Antiretroviral Therapy, Highly Active↗

Tracking changes in HIV-1 envelope quasispecies using DNA heteroduplex analysis.

A DNA heteroduplex tracking assay (HTA) using single-stranded probes is described. This assay provides a rapid means of resolving genetic variants coamplified by PCR and of measuring the level of particular variants in complex populations. To confidently detect minor quasispecies changes, the importance of maximizing template input into nested PCR (nPCR) and of duplicating nPCR and HTA to ensure correct population sampling is highlighted. The sensitivity of detection of rare variants within a genetically mixed population using single-stranded DNA probes is shown to be 1:500. The effects of nucleotide substitution at different locations on heteroduplex electrophoretic mobility are used to illustrate the limits of HTA for mutation detection. This simple assay may be used to track the evolution of HIV as well as to address issues of contamination and transmission.

DNA, Single-Stranded↗

Anti-nef antibodies and other predictors of disease progression in HIV-1 seropositive injecting drug users.

A cross-sectional and retrospective longitudinal study has been conducted in three Italian infectious disease centres to evaluate the role of anti-nef antibodies and other markers (HIV-1 p24 antigen, p24 Ag; Beta 2-microglobulin, B2-M; and number of CD4+ lymphocytes) as predictors of disease progression in HIV seropositive injecting drug users (IDUs). The selected patients were: 1) HIV-seropositive IDUs in different stages of HIV infection; 2) HIV-seropositive IDUs who had developed AIDS, from whom serial serum samples were available during the asymptomatic stage, and 3) HIV seropositive IDUs who remained asymptomatic through a follow-up period of the same duration as the patients who developed AIDS. Absence of anti-nef antibodies was associated with symptomatic HIV infection. A significant association between the absence of anti-nef antibodies, the presence of p24 Ag, high levels of B2-M, a number of CD4+ lymphocytes less than 500/ml at first visit and disease progression was found. Subjects who were persistently positive for antibody to nef were less likely to develop AIDS than those who were transiently or persistently negative. This difference was statistically significant (p = 0.03). The results of this study show that absence or disappearance of anti-nef antibodies may be used as predictor of disease evolution in HIV seropositive IDUs. This study also confirms the usefulness of other markers, such as p24 Ag, B2-M and number of CD4+ lymphocytes previously shown to be predictive of rapid disease progression for predicting the course of HIV seropositive IDUs.

AIDS-Related Complex↗

[Bacteremia caused by non-typhoid Salmonellas during an infection by the human immunodeficiency virus (HIV) in the African adult].

Infection caused by non-typhous Salmonellae during the course of HIV infection is known since 1983. The authors report on 103 bacteremiae of this type found in one year. Diagnosis has been based on hemocultures. 86 patients out of 103 were HIV+. All of them were febrile. 67 suffered from digestive disorders, 33 with diarrhoea. Splenomegalia was noted in 16 cases and consciousness troubles in 13 cases. At the admission, 8 complications were observed. Other infections were associated in 86 cases particularly in HIV+ patients evolutive tuberculosis (38 cases), candidosis of oropharynx (32 cases), neuromeningeal crytococcosis (13 cases), pneumocystosis (3 cases), Kaposi's sarcoma was discovered in 3 cases. The salmonellae isolated were in the 54 cases where characterization was made: Salmonella typhi murium in 44 cases and Salmonella enteridis in 10 cases. Classical cure (chloramphénicol) was effective in 85% of the treated patients. 28 positive hemocultures out of 103 isolated non-typhous Salmonellae were sampled later than the 72th hour after admission. This fact poses the problem of nosocomial infections in hospital departments in Black Africa, where HIV+ patients represent 52% of the admissions. Non-typhous Salmonellae would be part of the definition of African AIDS concerning patients with HIV test positive.

AIDS-Related Opportunistic Infections↗

Mutational patterns of paired blood and rectal biopsies in HIV-infected patients on HAART.

Blood and concurrent rectal biopsy samples of human immunodeficiency virus type 1 (HIV-1)-positive highly active antiretroviral therapy (HAART)-treated patients were tested for genotypic resistance by direct sequencing of reverse transcriptase (RT) and protease (PR) regions to compare the patterns of resistance in these compartments. Fourteen subjects (five with undetectable plasma viral load (pVL) and nine persistently viremic) were studied. Four of five patients with undetectable pVL also had undetectable mucosal HIV RNA; sequence analyses from proviral DNA (PBMCs and rectal biopsy) were obtained with none or few resistance-associated mutations and no alteration of susceptibility profile. All viremic patients, and one with negative pVL, had detectable levels of mucosal HIV RNA (1.93-4.21 log(10) copies/mg); sequences of HIV RNA (plasma and/or rectal biopsy) were also obtained, and multiple mutations generally compatible with current/past medications were detected. Overall, 40 HIV-1 PR and 42 RT sequences were analyzed, yielding a total of 42 PR and 47 RT sequence pairs (plasma/tissue-RNA; plasma-RNA/tissue-DNA; PBMC/tissue-DNA; tissue-DNA/RNA; tissue-RNA/PBMC-DNA; PBMC-DNA/plasma-RNA), which almost always differed at the total amino acid level (median percentage discordance 8.08% in the PR, 4.8% in RT). The median percentage of resistance position discordance equaled 88.8% (IQR = 20-100) in the PR and 74.55% (IQR = 31.75-100%) in the RT pairs, respectively. Different resistance levels were detected by means of a computer-assisted interpretation of mutational profiles. The results support the multiform evolution of HIV genotype in various body compartments and emphasize the participation of intestinal mucosa in HIV genotype selection. Samples from diverse tissues should be used for resistance evaluation to obtain a complete picture of drug resistance for antiretroviral-treated patients.

Adult↗

Ugandan HIV-1 V3 loop sequences closely related to the U.S./European consensus.

The third variable (V3) loop of the human immunodeficiency virus type 1 (HIV-1) envelope protein is an important determinant for virus neutralization and cell tropism. V3 loop sequences from uncultured lymphocytes obtained in 1990 from 22 Ugandan HIV-1-infected patients could, with the exception of two patients' sequences, be divided into two groups (A and B) on the basis the V3 loop size and sequence. The V3 loop consensus sequences from both groups showed a high degree of homology to a U.S./European consensus, a characteristic also reflected by the results of peptide serology. In the case of group B the difference in sequence was only five amino acids. In contrast, the V3-flanking regions for both groups showed greater homology to an earlier (1986/1987) Ugandan consensus. The discovery of these two new Ugandan V3 loop genotypes, which are closely related to the U.S./European consensus, has implications for the understanding of the evolution of HIV-1 and for the future design of a vaccine for use in Africa.

Amino Acid Sequence↗

[Long-term follow-up study of 35 children with ADS treated with zidovudine (AZT)].

Thirty-five children diagnosed of AIDS were studied in order to evaluate toxicity and efficacy of oral Zidovudine treatment (AZT), as well as to analyze the clinical, biochemical, immunological and virological evolution of HIV infection throughout the treatment. Patients (19 males and 16 females) were studied from April 1988 to May 1990 with a mean follow-up time of 13.5 months (SD = 6.7 months). The mean age of the group was 4.68 years. The means of acquisition of this disease was 71.45 vertical and 28.6% via hemo-derivatives. Tolerance has been good with the main toxicity being hematological (28.5% anemia and/or neutropenia), 23% of which required blood supplements. The presence of neurological involvement and thrombopenia were observed in the incidence of greater toxicity. No influence on weight during AXT treatment was observed and hepatosplenomegalia and adenopathies were not modified. Bacterial and opportunistic infections were observed in 97.1% and 20% of patients, respectively. Neurological evolution was irregular and the improvement observed in some patients was mild and transitory. Three patients died during the follow-up from intercurrent infectious process. A progressive increase in MCV and a tendency towards leucopenia and lymphopenia (mainly in hemo-derivative infected patients) was observed. Neither significant immunological nor virological changes were observed during the treatment (except the tendency to diminish basal hypergammaglobulinemia). The results of this study were compared to other pediatric series treated with AZT.

Acquired Immunodeficiency Syndrome↗

Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study.

OBJECTIVE: In a prospective randomized study, the impact of plasma protease inhibitor (PI) trough levels on changes in HIV RNA were assessed in patients treated with genotypic-guided therapy. METHODS: Patients failing combination therapy (HIV-1 RNA > 10,000 copies/ml, and at least 6 months of therapy with nucleoside analogues and 3 months with PI) were randomly assigned into two arms: control group (C) in which the treatment was modified according to the standard of care; genotypic group (G) in which the treatment was modified according to resistance mutation profiles. Serial PI plasma levels were performed in patients throughout the 12 month study. PI levels were determined by high performance liquid chromatography. 'Suboptimal' concentration (SOC) was defined as at least two PI plasma levels below 2 x IC95. Others were defined as 'optimal' concentration (OC). Patients were categorized into four groups: G1 (SOC/control); G2 (OC/control); G3 (SOC/genotype); G4 (OC/genotype). An intent-to-treat analysis was performed with viral load as the primary endpoint. RESULTS: A total of 81 patients [mean age 39.7 +/- 8 years, 59 men, 52.7% Centers for Disease Control and Prevention (CDC) stage C] were included in the pharmacological substudy. The two groups according to randomization arms were comparable in terms of risk factor, age, sex, previous treatments, baseline CD4 cell count, HIV-1 RNA and mean PI plasma concentrations. Linear regression analysis showed a significant relationship between PI concentration and HIV RNA in the plasma. OC and SOC were found in 67.9% (55/81) and 32.1% (26/81) of patients, respectively. Mean changes in HIV RNA from baseline at month 6 were: -0.23 +/- 0.29 log10 copies/ml (G1); -0.97 +/- 0.28 (G2); -0.68 +/- 0.37 (G3); -1.38 +/- 0.20 (G4). Multivariate analysis showed PI plasma concentrations to be an independent predictor of HIV-RNA evolution (P = 0.017). CONCLUSION: Multiple parameters determine the response to antiretroviral therapy and causes other than the development of drug resistance should be considered in the setting of therapeutic failure. Suboptimal concentrations of PI limit the response to antiretroviral therapy. Therapeutic drug monitoring of the PI plasma concentration may therefore prove useful in optimizing antiretroviral therapy.

Adult↗

HCV and HIV co-infection in pregnant women attending St. Camille Medical Centre in Ouagadougou (Burkina Faso).

Five hundred and forty-seven pregnant women with less than 32 weeks of amenorrhoea, attending an antenatal clinic of St. Camille Medical Centre (SCMC) of Ouagadougou were enrolled for a hepatitis C virus (HCV) and HIV co-infection study. Fifty-eight (10.6%) were HIV positive and 18 (3.3%) were anti-HCV positive. Only seven pregnant women (i.e., 1.3%) had a documented HIV and HCV co-infection. HCV-RNA was found in 5 out of 18 (27.8%) patients, who had anti-HCV antibodies. The genotype analysis of these five patients showed that two were of 1b whereas three were of 2a genotype. Mother-to-infant transmission of the same HCV genotype (2a) was documented in only one case. High 1b prevalence has been reported in other parts of Africa, while 2a is the prevalent genotype (60%) in Burkina Faso. This genotype has a higher response rate to treatment. Serum transaminases were normal, also in presence of HCV-RNA. The higher than expected rate of co-infection in Burkina Faso seems to demonstrate a correlation between these two infections, which could influence the evolution of HIV and HCV diseases.

Adolescent↗

Long polymerase chain reaction amplification of heterogeneous HIV type 1 templates produces recombination at a relatively high frequency.

Studies of HIV molecular evolution and pathogenesis have relied on the polymerase chain reaction (PCR) to provide sequence information from infected tissues. Until recently, studies have been constrained by the limited length of fragments that can be reliably amplified. The addition of a thermostable 3'-exonuclease activity and altered cycling profiles has increased the length of target sequences that can be amplified by more than 10-fold. We have evaluated the fidelity of long PCR (LPCR). We determined that LPCR amplification maintains the distribution of sequences found in a heterogeneous sample and introduces nucleotide misincorporations at a rate comparable to that found with routine PCR. However, a significant proportion of the LPCR-amplified DNA fragments resulted from recombination events. This result suggests that LPCR amplification may have limited utility in the production and analysis of full-length HIV clones.

Base Sequence↗

Functional consequences of mutations in HIV-1 Gag p55 selected by CTL pressure.

Amino acid changes in the CA domain of the p55 Gag protein of HIV-1 have been observed during the course of an infection that appear to correlate with escape from cytotoxic T cell surveillance (Phillips et al., Nature 354, 453-459, 1991). A corollary of this observation is that all such changes should be functionally silent but, as the changes were observed in populations of virus, this has not been formally demonstrated. We have introduced the amino acid changes representative of those observed to occur in vivo into the Gag p55 gene cloned in the baculovirus expression system where the wild-type gene product produces virus-like particles (VLP). We show that none of these mutations affect particle formation as judged by VLP morphology and density despite their location within a sequence of the Gag open reading frame known to be important for assembly. These data add tacit support to the hypothesis that CTL pressure can drive virus evolution in HIV and add to the fine mapping of sequences involved in Gag subunit interactions.

Amino Acid Sequence↗

Constitutive cell surface association between CD4 and CCR5.

HIV-1 entry into cells involves formation of a complex between gp120 of the viral envelope glycoprotein (Env), a receptor (CD4), and a coreceptor. For most strains of HIV, this coreceptor is CCR5. Here, we provide evidence that CD4 is specifically associated with CCR5 in the absence of gp120 or any other receptor-specific ligand. The amount of CD4 coimmunoprecipitated with CCR5 was significantly higher than that with the other major HIV coreceptor, CXCR4, and in contrast to CXCR4 the CD4-CCR5 coimmunoprecipitation was not significantly increased by gp120. The CD4-CCR5 interaction probably takes place via the second extracellular loop of CCR5 and the first two domains of CD4. It can be inhibited by CCR5- and CD4-specific antibodies that interfere with HIV-1 infection, indicating a possible role in virus entry. These findings suggest a possible pathway of HIV-1 evolution and development of immunopathogenicity, a potential new target for antiretroviral drugs and a tool for development of vaccines based on Env-CD4-CCR5 complexes. The constitutive association of a seven-transmembrane-domain G protein-coupled receptor with another receptor also indicates new possibilities for cross-talk between cell surface receptors.

3T3 Cells↗