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PubMed1989

[Hospital epidemiology of HIV infection in the Parisian public hospitals].

The evolution of hospitalization for patients with HIV infections in Parisian public hospitals (Assistance Publique de Paris) can be analyzed from the data base containing discharge diagnoses and from the results of a cross-sectional survey "on a given day". At present, the activity associated with HIV infection represents more than 2% of the total activity of this institution. From 1982 to 1987, HIV-associated activity increased extremely rapidly, treating patients in acute care hospitals and clinical departments and concomitantly developing home care and day hospitalizations. The latter were responsible for the substantial decrease in the average length of hospitalization. Home care and day care hospitalizations for HIV infection continued to increase during 1988, while longer-term hospitalizations decreased.

France↗
PubMed1997

Causes of death of HIV-infected persons in Ottawa, Ontario, 1984-1995.

BACKGROUND: Acquired immunodeficiency syndrome (AIDS) has become a leading cause of death of young men in the United States. With the introduction of prophylaxes and antiretrovirals for opportunistic infection, there have been significant changes in the clinical history of human immunodeficiency virus (HIV) infection. OBJECTIVE: To determine the cause of death of the patients followed up by our clinic from 1984 to 1995. METHODS: A critical chart review was performed on the records of all patients affiliated with the Ottawa General Hospital HIV/AIDS Clinic, Ottawa, Ontario, who died between 1984 and July 15, 1995. Data regarding the cause of death, last CD4 T-lymphocyte cell count before death, medication use at time of death, and location and year of death were collected. Data were analyzed for 1984 through 1988, 1989 through 1991, and 1992 through 1995, corresponding to the evolution of HIV-related medical care. RESULTS: The median CD4 T-lymphocyte cell count at death had declined. Pneumocystis carinii pneumonia has decreased significantly as cause of death (28.6%-3.8%, P < .001). No other specific attributable terminal illness has decreased in frequency during 11 years. The wasting illnesses, particularly HIV wasting syndrome (3.6%-13.7%, P = .04), and untreatable illnesses have increased in frequency as causes of death. Patients are increasingly likely to die at home (0%-25%, P < .001) and less likely to die in hospital (54%-35%, P < .001). CONCLUSIONS: The HIV-infected persons are dying with more advanced HIV immunosuppression. Advances in P carinii pneumonia prophylaxis and treatment have had a dramatic effect on the cause of death of HIV-infected persons. Improved prophylaxis and treatment for non-P carinii pneumonia opportunistic infections and malignancies and HIV wasting syndrome are required.

AIDS-Related Opportunistic Infections↗
PubMed1989

Cell-mediated suppression of HIV-specific cytotoxic T lymphocytes.

CTL specific for HIV have been described in lungs of infected patients at early stages of HIV disease. In order to characterize the evolution over time of HIV-specific CTL, we have analyzed the cytotoxic function and the cell surface phenotype of the alveolar lymphocytes from 41 patients at various stages of HIV disease. We demonstrated a progressive decline of alveolar anti-HIV CTL activity and detected Ts cells from the lungs of patients with advanced HIV disease. These alveolar T cells strongly suppressed the effector phase of anti-HIV CTL lysis. They lacked a marked specificity of function because they also block anti-HLA CTL response and were not restricted by the HLA-class-I transplantation Ag. They displayed the CD3, CD8, and HNK1 markers, were CD4 and CD16 negative, and lacked NK activity. The presence of Ts cells at late stages of HIV disease could thus partly explain the inefficiency of host defenses against HIV.

AIDS-Related Complex↗
PubMed1994

[Tricuspid endocarditis caused by penicillin-resistant Staphylococcus aureus: 2 cases in parenteral drug addicts].

BACKGROUND: Staphylococcus aureus is the main causal agent of infectious endocarditis (IE) in intravenous drug addicts (IVDA) with most of the strains, isolated in Spain being resistant to penicillin and sensitive to methycillin, although the latter condition varied in recent years. Two cases of IE caused by S. aureus strains sensitive to penicillin in IVDA are presented. METHODS: All bacteremia episodes diagnosed in the Hospital General Penitenciario (Madrid) over a 33-month period (March 1991 to December 1993) were prospectively studied. Special attention was given to patients diagnosed of IE. Blood cultures were processed according to the usual technique by a non radiometric system. RESULTS: One hundred and four bacteremias were detected with 14 being produced by S. aureus. Ten episodes of the total number of bacteremias fulfilled criteria for IE with 2 being produced by strains of S. aureus sensitive to penicillin (CMI < 0.06 mu/ml). Both patients had coinfection by HIV. The clinical evolution prior to diagnosis was prolonged although clinical and microbiologic cure were achieved with intravenous beta-lactam antibiotics treatment, without complications. CONCLUSIONS: Despite the low incidence of the isolation of Staphylococcus aureus sensitive to penicillin (< 3%) recently observed in Spain, strains producing severe infections, showing patterns of sensitivity such as those found during the preantibiotic era, may still be isolated.

Adult↗
PubMed2005

Identification of a major restriction in HIV-1 intersubtype recombination.

Genetic recombination increases diversity in HIV-1 populations, thereby allowing variants to escape from host immunity or antiviral therapies. In addition to the currently described nine subtypes of HIV-1, many of the circulating strains are intersubtype recombinants. In this study, we determined the recombination rate between two HIV-1 subtype C viruses and between a subtype B virus and a subtype C virus during a single round of virus replication. Although HIV-1 subtype C recombines at a high rate, similar to that of HIV-1 subtype B, the recombination rate between a subtype B virus and a subtype C virus is much lower than the intrasubtype recombination rate. A 3-nt sequence difference in the dimerization initiation signal (DIS) region between HIV-1 subtypes B and C accounts for most of the reduction of intersubtype recombination. By matching the DIS sequences, the B/C intersub-type recombination rate was elevated 4-fold; by introducing mismatches in the 3-nt sequences, the B/B intrasubtype recombination rate was reduced 4-fold. Further analyses showed that the intermolecular template-switching frequency was unaffected by the sequence identity of the DIS region. These results support the hypothesis that mismatched sequences in the DIS region alter the formation of heterozygous virions, thereby lowering the observable recombination rate. Here, we present the discovery of a major restriction in HIV-1 intersubtype recombination. These results have important implications for virus evolution, the mechanism of HIV-1 RNA packaging, high negative interference in recombination, and the generation of circulating intersubtype recombinants within the infected population.

Base Sequence↗
PubMed2006

Impact of highly active antiretroviral therapy on the maturation of anti-HIV-1 antibodies during primary HIV-1 infection.

OBJECTIVES: To study the impact of highly active antiretroviral therapy (HAART) on isotype switching and avidity maturation of HIV-1-specific immunoglobulin G (IgG) in patients with primary HIV-1 infection (PHI). METHODS: We studied the emergence and the evolution of anti-HIV IgG antibodies by quantitative immunoblotting to analyse IgG subclasses and IgG avidity. Serum samples were obtained from 16 PHI patients from the French PRIMO Cohort Study at various points in the first year of infection: eight patients received no treatment (group I), and eight patients received efficient HAART (group II) during the study period. RESULTS: Early initiation of HAART in PHI patients partially prevented an increase in anti-HIV-1 IgG levels. Within IgG subclasses, the amount of anti-HIV-1 IgG1 gradually increased with time in both groups, although levels remained lower in treated patients. The anti-p24 IgG2 level was always lower in group II. We observed a decrease in anti-p24 IgG3 over time in both groups. Treatment did not affect the maturation of HIV-1 IgG avidity, which increased in both groups until month 3 and then remained high until the end of the 12-month follow-up period. CONCLUSIONS: HAART in PHI partially prevents the emergence of HIV-1 IgG antibodies, but does not affect the quality of these antibodies, as reflected in their isotype and avidity.

Adolescent↗
PubMed1999

[Genetic diversity of HIV infection worldwide and its consequences].

Phylogenetic study of HIV-1 strains from different geographical locations has revealed the existence of three separate groups that have been named M, N, and O. Most strains involved in the pandemia belong to group M which contains several subtypes. Nearly 20 p. 100 of isolates in group M are recombinant with genomic components from different subtypes. Some mosaic virus are one-of-a-kind or limited to small transmission groups while others are major players in the worldwide AIDS epidemic. They are currently called circulating recombinant forms (CRFs). Since subtypes or CRFs must be similar over the whole genome, only 9 subtypes are possible within group M (A, B, C, D, F, G, H, J and K). Viruses E and I in the envelope are recombinant. Subtyping is a powerful molecular tool for monitoring the evolution of the HIV-1 epidemic. Overall the predominant viral forms in the world are subtypes A and C followed by recombinant CRF01-AE (formerly subtype E) and CRF02-AG (identical to the IBNG prototype strain in Nigeria) and subtype B. The highest degree of genetic diversity in HIV-1 is observed in Africa where all subtypes and groups can be observed. The geographic distribution of subtypes is subject to constant change. Recombinant forms of the virus will continue to appear as long as the different subtypes of HIV-1 continue to circulate between continents and recombination continues to occur.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Molecular epidemiology of HIV-1 in Rio Grande, RS, Brazil.

We conducted a molecular epidemiological study to investigate HIV-1 strains in Rio Grande, southern Brazil, searching for an association with transmission mode and risk behavior. Patients (185) identified at an AIDS treatment reference Hospital, from 1994 to 1997, were included; from which 107 blood samples were obtained. Nested PCR was realized once for each sample; for amplified samples (69) HIV subtypes were classified using the heteroduplex mobility assay. Subtypes identified were B (75%), C (22%) and F (3%). All infections with C were diagnosed after 1994. Comparing patients with B and C, no differences were detected regarding demographic, clinical and laboratory characteristics; survival analysis did not reveal differences in HIV to AIDS evolution. A higher proportion of injecting drug users, IDU (not significant, p < .07) was found among those with C. This suggests that C may have been introduced in this area through IDU, and is being spread, probably by their sexual partners, to persons with other risk practices.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Long-term methadone treatment: effect on CD4+ lymphocyte counts and HIV-1 plasma RNA level in patients with HIV infection.

The objective was to examine the effect of methadone on CD4+ lymphocyte counts and viral load and to expect to document the safety of methadone maintenance in patients with human immune deficiency syndrome. This is a retrospective chart analysis comparing the trends in CD4+ count and viral load in two populations of 21 human immunodeficiency virus (HIV) infected patients, one on methadone maintenance and a methadone non-using group. Each methadone user was matched with a control methadone non-user that had a similar CD4+ at the beginning of the study. For the CD4+ count we compared the slope of regression for each couple of patients. In 15 patients we also collected the viral load, which was measured at 4-6 monthly intervals. The mean length of follow-up was 811 days for the methadone group and 797 days in the control group. There was no statistical difference in the treatment received by the two groups of patients during the study. The slope of regression of CD4+ count showed a significantly steeper decline in the methadone-using patients compared with the methadone non-users (r= 0.487; p< 0.05). The evolution of the HIV-1 RNA levels was the same during the follow-up of mean 186 months in a few of the patients in each of the two groups. Long-term methadone use was associated with a significantly faster decrease of CD4+ count in HIV-1 affected patients compared with methadone non-users. HIV-1 RNA data were found in too few patients to enable any conclusions about the development of viral load in the two groups.

Adult↗
PubMed2004

Evolution of human immunodeficiency virus type 1 coreceptor usage during antiretroviral Therapy: a Bayesian approach.

There is substantial evidence for ongoing replication and evolution of human immunodeficiency virus type 1 (HIV-1), even in individuals receiving highly active antiretroviral therapy. Viral evolution in the presence of antiviral therapy needs to be considered when developing new therapeutic strategies. Phylogenetic analyses of HIV-1 sequences can be used for this purpose but may give rise to misleading results if rates of intrapatient evolution differ significantly. To improve analyses of HIV-1 evolution relevant to studies of pathogenesis and treatment, we developed a Bayesian hierarchical model that incorporates all available sequence data while simultaneously allowing the phylogenetic parameters of each patient to vary. We used this method to examine evolutionary changes in HIV-1 coreceptor usage in response to treatment. We examined patients whose viral populations exhibited a shift in coreceptor utilization in response to therapy. CXCR4 (X4) strains emerged in each patient but were suppressed following initiation of new antiretroviral regimens, so that CCR5-utilizing (R5) strains predominated. By phylogenetically reconstructing the evolutionary relationship of HIV-1 obtained longitudinally from each patient, it was possible to examine the origin of the reemergent R5 virus. Using our Bayesian hierarchical approach, we found that the reemergent R5 virus detectable after therapy was more closely related to the predecessor R5 virus than to the X4 strains. The Bayesian hierarchical approach, unlike more traditional methods, makes it possible to evaluate competing hypotheses across patients. This model is not limited to analyses of HIV-1 but can be used to elucidate evolutionary processes for other organisms as well.

Antiretroviral Therapy, Highly Active↗
PubMed1998

Rare mutations in a domain crucial for V3-loop structure prevail in replicating HIV from long-term non-progressors.

OBJECTIVE: To evaluate the role of the selective forces exerted by the host on the HIV-1 structures involved in viral entry. DESIGN AND METHODS: The V3 region of the env gene was analysed in cell-free HIV-1 RNA from 17 infected subjects: 11 long-term non-progressors (LTNP) and six symptomless, typical progressor patients. To evaluate the potential biological significance of one of the rare variants detected in the LTNP, it was reproduced by recombinant PCR into a HIV-1 molecular clone. RESULTS: The intrapatient divergence of the V3-loop sequences averaged 8.62% in LTNP and 5.29% in progressors, although LTNP displayed lower divergence from the clade B consensus than progressors (16.65 and 19.76%, respectively). The analysis of non-synonymous and synonymous substitutions indicated that selective pressure was exerted in this region in both LTNP and progressors. Individual peculiarities (unique and rare V3-loop variants) emerged, however, in most sequences from LTNP, and variants bearing mutations in a domain crucial for the V3-loop structure were more prevalent in LTNP (P = 0.0012). The pNL4-3-derived mutant reproducing a V3-loop variant detected in a LTNP was efficiently expressed upon transfection, but the mutant virus was nearly completely unable to infect CD4+ cell lines, activated primary peripheral blood lymphocytes, or monocyte-derived macrophages, suggesting that a defect impaired the entry phase of the replication cycle. CONCLUSIONS: The results indicate that host factors impose selective constraints on the evolution of the HIV-1 structures involved in viral entry. In LTNP, these factors are likely to force the virus into attenuated variants.

Amino Acid Sequence↗
PubMed2005

The antiretroviral rollout and drug-resistant HIV in Africa: insights from empirical data and theoretical models.

The U.S. Government has pledged to spend $15 billion in Africa and the Caribbean on AIDS. A central focus of this plan is to provide antiretroviral treatment (ART) to millions. Here, we evaluate whether the plan to rollout ART in Africa is likely to generate an epidemic of drug-resistant strains of HIV. We review what has occurred as a result of high usage of ART in developed countries in terms of changes in risky behavior, and the emergence and transmission of drug-resistant HIV. We also review how mathematical models have been used to predict the evolution of drug-resistant HIV epidemics. We then show how models can be used to predict the likely impact of the ART rollout on the evolution of drug-resistant HIV in Africa. At currently planned levels of treatment coverage, we predict that (over the next decade) in Africa: (i) the impact of ART on reducing HIV transmission (and prevalence) is likely to be undetectable (unless accompanied by substantial changes in behavior), (ii) the transmission rate of drug-resistant HIV will be below the WHO surveillance threshold of 5%, and (ii) the majority of cases of drug-resistant HIV that will occur will be due to acquired (and not transmitted) resistance. For the next decade, large-scale surveillance for detecting transmitted resistance in Africa is unnecessary. Instead, we recommend that patients should be closely monitored for acquired resistance, and sentinel surveillance (in a few urban centers) should be used to monitor transmitted resistance.

Africa↗
PubMed2004

Selection in context: patterns of natural selection in the glycoprotein 120 region of human immunodeficiency virus 1 within infected individuals.

Evolution of the HIV-1 V3 loop was monitored in 15 subjects over a period of 5 years at approximately 6-month intervals. Putative recombination was detected in many of the sequences. Evolutionary trees were estimated from the nonrecombinant viral sequences found in each individual. Selection and altered demographic regimes were detected with logit and other contingency analyses in a highly context-dependent fashion. Mutations leading to amino acid substitutions are subject to positive selection over a broad range of clinical conditions in the nonsyncytium-inducing (NSI) form, and the growth rates of the NSI strains and their level of genetic subdivision change little in going from a healthy immune system to a severely compromised immune system. In contrast, the SI form has a significant increase in growth rate as the immune system goes from healthy to compromised, particularly in those subjects who did not receive any antiviral drug therapy. This increase in SI growth rate results in a significant growth advantage of SI over NSI when the immune system is compromised. The SI strains also show more demographic subdivision when the immune system is healthy than when the immune system is compromised, and the SI form has greater demographic subdivision than NSI in subjects with healthy immune systems who also are not receiving antiviral drug therapy. Positive selection on amino-acid-changing mutations weakens and then intensifies again in the SI strains in going from healthy to compromised immune systems. These patterns are consistent with other studies that suggest that NSI strains inhibit replication of SI strains, that the V3 loop is more hidden from the immune system in the NSI form, that evolution in the V3 loop influences cell tropism and coreceptor usage, that substrate for replication of SI forms increases as the disease progresses, and that death of CD8 cells is influenced by the type of coreceptor usage typically found in SI but not in NSI strains. Finally, the transition between NSI and SI forms is associated with a burst of evolutionary change due to strong positive selection at sites other than those that define the NSI/SI phenotypes.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Fitness variations and their impact on the evolution of antiretroviral drug resistance.

The human immunodeficiency virus (HIV) exhibits extensive heterogeneity due to its rapid turnover, high mutation rate, and high frequency of recombination. Its remarkable genetic diversity plays a key role in virus adaptation, including development of drug resistance. The increasing complexity of antiretroviral regimens has favored selection of HIV variants harboring multiple drug resistance mutations. Evolution of drug resistance is characterized by severe fitness losses, which can be partially overcome by compensatory mutations or other adaptive changes that restore virus replication capacity. Recent reports have addressed the impact of drug-resistance mutations on viral fitness. Methods include in vitro estimates based on the determination of viral replication kinetics, viral infectivity in single-cycle assays and growth competition experiments; as well as estimates of the relative fitness of viral populations in vivo calculated from standard population genetics theory. This review focuses on the effects in viral fitness of mutations arising during treatment with reverse transcriptase and protease inhibitors, and the molecular mechanisms (including compensatory mutations) that improve the viral fitness of drug-resistant variants.

Anti-HIV Agents↗
PubMed2004

The lymphocyte HIV reservoir in patients on long-term HAART is a memory of virus evolution.

OBJECTIVE: To investigate the dynamics of the lymphocyte HIV reservoir in patients on prolonged and effective highly active antiretroviral therapy (HAART). DESIGN: Nine HAART-treated patients were selected on the basis of long-term infection and long-term undetectable plasma viral RNA. Five patients had received antiretroviral therapy before HAART. We compared a polymorphic region of the env gene (C2V4), and the part of the pol gene encoding the reverse transcriptase in pre-HAART plasma and in the reservoir lymphocytes during HAART; the first plasma sample taken after structured treatment interruption was also studied in three patients. METHODS: Both regions of interest were amplified from plasma HIV RNA and cellular proviral DNA, then cloned, sequenced and subjected to phylogenetic analysis. RESULTS: Diversity of the lymphocyte reservoir was found in six of nine patients. Archiving of pre-HAART plasma clones was observed in six of nine patients. 'Wild-type' and zidovudine-resistant strains co-existed in reservoir T cells of two pre-HAART treated patients. In three patients, no resistant virus was found in the T-cell reservoir despite the detection of resistant virus in pre-HAART plasmas. However, virus archiving was documented in two of these three patients on the basis of C2V4 analysis. Latently infected T cells only partly accounted for the plasma viral load rebound after structured treatment interruption. CONCLUSIONS: The HIV lymphocyte reservoir is dynamic. Its diversity results mainly from successive archiving of circulating plasma viruses during the course of HIV infection. Archiving of resistant virus must be taken into account in therapeutic decisions.

Antiretroviral Therapy, Highly Active↗
PubMed1999

A second-site mutation that restores replication of a Tat-defective human immunodeficiency virus.

We previously constructed a large set of mutants of the human immunodeficiency virus type 1 (HIV-1) regulatory protein Tat with conservative amino acid substitutions in the activation domain. These Tat variants were analyzed in the context of the infectious virus, and several mutants were found to be defective for replication. In an attempt to obtain second-site suppressor mutations that could provide information on the Tat protein structure, some of the replication-impaired viruses were used as a parent for the isolation of revertant viruses with improved replication capacity. Sequence analysis of revertant viruses frequently revealed changes within the tat gene, most often first-site reversions either to the wild-type amino acid or to related amino acids that restore, at least partially, the Tat function and virus replication. Of 30 revertant cultures, we identified only one second-site suppressor mutation. The inactive Y26A mutant yielded the second-site suppressor mutation Y47N that partially restored trans-activation activity and virus replication. Surprisingly, when the suppressor mutation was introduced in the wild-type Tat background, it also improved the trans-activation function of this protein about twofold. We conclude that the gain of function measured for the Y47N change is not specific for the Y26A mutant, arguing against a direct interaction of Tat amino acids 26 and 47 in the three-dimensional fold of this protein. Other revertant viruses did not contain any additional Tat changes, and some viruses revealed putative second-site Tat mutations that did not significantly improve Tat function and virus replication. We reason that these mutations were introduced by chance through founder effects or by linkage to suppressor mutations elsewhere in the virus genome. In conclusion, the forced evolution of mutant HIV-1 genomes, which is an efficient approach for the analysis of RNA regulatory motifs, seems less suited for the analysis of the structure of this small transcription factor, although protein variants with interesting properties can be generated.

Cells, Cultured↗
PubMed2005

R5 to X4 switch of the predominant HIV-1 population in cellular reservoirs during effective highly active antiretroviral therapy.

HIV-1 coreceptor usage plays a critical role for virus tropism and pathogenesis. A switch from CCR5 to CXCR4-using viruses can occur in the natural course of infection and correlates with subsequent disease progression. To investigate whether HIV-1 genetic evolution might lead to changes in virus coreceptor usage during highly active antiretroviral therapy (HAART), a longitudinal genotypic analysis of the virus found in cellular reservoirs was conducted in 32 patients with undetectable viral loads on HAART for 5 years. The genotype of the 3rd variable region of the env gene predicting coreceptor usage was retrospectively determined in the plasma or in peripheral blood mononuclear cells (PBMC) at baseline and then in PBMCs at months 30 and 60 of HAART. There was a switch from R5 to X4 variants in 11 of the 23 patients who harbored a majority virus population of R5 variants at baseline. X4 variants remained predominant in the 9 patients who harbored mainly X4 variants at baseline. The patients harboring predominantly X4 variants during HAART, either from baseline or after an R5 to X4 switch, tended to have lower CD4+ T-cell counts on HAART than did patients harboring continuously a majority population of R5 variants. These results suggest that potent antiretroviral therapy produces the conditions necessary for the gradual emergence of X4 variants in cellular reservoirs.

Acquired Immunodeficiency Syndrome↗