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PubMed1998

Evolution of envelope sequences from the genital tract and peripheral blood of women infected with clade A human immunodeficiency virus type 1.

The development of viral diversity during the course of human immunodeficiency virus type 1 (HIV-1) infection may significantly influence viral pathogenesis. The paradigm for HIV-1 evolution is based primarily on studies of male cohorts in which individuals were presumably infected with a single virus variant of subtype B HIV-1. In this study, we evaluated virus evolution based on sequence information of the V1, V2, and V3 portions of HIV-1 clade A envelope genes obtained from peripheral blood and cervical secretions of three women with genetically heterogeneous viral populations near seroconversion. At the first sample following seroconversion, the number of nonsynonymous substitutions per potential nonsynonymous site (dn) significantly exceeded substitutions at potential synonymous sites (ds) in plasma viral sequences from all individuals. Generally, values of dn remained higher than values of ds as sequences from blood or mucosa evolved. Mutations affected each of the three variable regions of the envelope gene differently; insertions and deletions dominated changes in V1, substitutions involving charged amino acids occurred in V2, and sequential replacement of amino acids over time at a small subset of positions distinguished V3. The relationship among envelope nucleotide sequences obtained from peripheral blood mononuclear cells, plasma, and cervical secretions was evaluated for each individual by both phylogenetic and phenetic analyses. In all subjects, sequences from within each tissue compartment were more closely related to each other than to sequences from other tissues (phylogenetic tissue compartmentalization). At time points after seroconversion in two individuals, there was also greater genetic identity among sequences from the same tissue compartment than among sequences from different tissue compartments (phenetic tissue compartmentalization). Over time, temporal phylogenetic and phenetic structure was detectable in mucosal and plasma viral samples from all three women, suggesting a continual process of migration of one or a few infected cells into each compartment followed by localized expansion and evolution of that population.

Amino Acid Sequence↗

PubMed2005

HIV testing technologies after two decades of evolution.

Over the past two decades, HIV diagnostics have been essential in detecting and monitoring infection, and continue to play a major role in saving lives throughout the world. As technology evolved, screening, confirmatory, and HIV monitoring assays have been improved and offer better alternatives to address blood screening, surveillance, diagnosis, and patient management. Molecular methods are critical in detecting early infection and for managing patients on anti retroviral therapy whose viral infection may become resistant to therapy. In addition, modifications to conventional methods have introduced new assays, such as sensitive/less sensitive (detuned) assays that can estimate when someone was infected, thereby providing a useful tool for epidemiologic incidence estimates and enrollment into specific intervention programmes for recently infected persons. Many of the newly evolving technologies are essential for use in resource-limited countries because they can address cost issues, limited infrastructure, and a lack of formally trained personnel. Newer rapid HIV kits can be stored in a wide range of temperatures (2-30 degrees C) to address cold-chain issues, can use easily-collected fingerstick blood and oral fluids, and have one-step procedures that are relatively foolproof. Manual CD4 lymphocyte count assays that require only a light microscope and haemacytometer and more simple assays to estimate viral load are appropriate for developing countries where sophisticated instrumentation cannot be supported. Technologic advances with HIV diagnostics continue to address outstanding and new issues associated with diagnosis and the monitoring of infection by providing more simplified, cost-effective, and accurate testing throughout the world.

AIDS Serodiagnosis↗

PubMed1992

[HIV-1 infection in patients with hemophilia. The Argentinian experience from 1983 to 1990].

We present studies on the evolution of HIV-1 infection in 638 hemophilic patients receiving commercial antihemophilic concentrates (CAH) at the Institute of Hematological Research and the Argentine Foundation of Hemophilia between 1983 and 1990. Positive serology for HIV-1 was detected in 30% of the patients studied. Prevalence of HIV-1 infection was higher (about 70%) in the group with severe hemophilia requiring more CAH, but there were no differences between patients with hemophilia A or B. Sexual transmission was demonstrated in 8/64 women (13%) with stable sexual relationship with HIV-1 + hemophilic patients. Three of them became pregnant, and HIV-1 infection was demonstrated in two of the three children. In general, the clinical evolution, as well as the hematologic and immunologic parameters of infected patients were similar to those described for the hemophilic population in other occidental countries. Opportunistic infections were also those observed elsewhere (with predominance of P. carinii pneumonia and disseminated Candida infections). However, the presence of fatal chagasic encephalitis in two of the patients with AIDS is unusual. Thus, central nervous system localization of T. cruzi (which can be observed during the acute period of T. cruzi infection or in immunosuppressed patients), must be considered as a possible severe complication of HIV-1 disease in T. cruzi infected patients.

AIDS-Related Opportunistic Infections↗

PubMed2004

Immunology of AIDS virus and mycobacterial co-infection.

While detrimental consequences of biological interaction between HIV and M. tuberculosis are well described, immune mechanisms underlying the evolution of HIV and mycobacterial coinfection remain poorly characterized. Recent studies in HIV-infected humans and SIV-infected monkeys have enhanced our understanding of complex issues of HIV and M. tuberculosis coinfection. Importantly, an anti-viral immune response and an associated control of AIDS virus infection can be induced during coinfection with mycobacterium or other pathogens in HIV-infected humans or SIV-infected monkeys. Restoration of anti-mycobacterial immunity during antiretroviral treatment can contribute to prevention and treatment of AIDS-related mycobacterial diseases. This article discusses recent progress in immune aspects of HIV and mycobacterial coinfection.

Animals↗

PubMed2005

Genetic diversification and recombination of HIV type 1 group M in Kinshasa, Democratic Republic of Congo.

As the HIV-1 pandemic becomes increasingly complex, the genetic characterization of HIV strains bears important implications for vaccine research. To better understand the molecular evolution of HIV-1 viral diversity, we performed a comparative molecular analysis of HIV strains collected from high-risk persons in Kinshasa, Democratic Republic of Congo (DRC). Analysis of the gag-p24, env-C2V3 and -gp41 regions from 83 specimens collected in 1999-2000 revealed that 44 (53%) had concordant subtypes in the three regions (14 subsubtype A1, 10 subtype G, 8 subtype D, 5 subtype C, 2 each subsubtype F1 and CRF01_AE, and one each of subtypes H and J, and subsubtype A2, while the remaining 39 (47%) had mosaic genomes comprising multiple subtype combinations. Similar multisubtype patterns were also observed in 24 specimens collected in 1985. Sequence analysis of the gag-pol region (2.1 kb) from 21 discordant specimens in the gag-p24, env-C2V3 and -gp41 regions in 1985 and 1999-2000 further confirmed the complex recombinant patterns. Despite the remarkable similarity in overall subtype distribution, the intra- and intersubtype distances of major subtypes A1 and G increased significantly from 1985 to 1999-2000 (p=0.018 and p=0.0016, respectively). Given the complexity of HIV-1 viruses circulating in DRC, efforts should focus on the development of vaccines that result in cross-clade immunity.

Democratic Republic of the Congo↗

PubMed2002

Cellular tropisms and co-receptor usage of HIV-1 isolates from vertically infected children with neurological abnormalities and rapid disease progression.

The longitudinal evolution of HIV-1 phenotypes was studied in a cohort of six vertically infected children with early onset and rapid progression of clinical disease. Among 30 viral isolates obtained from peripheral blood, tropisms for both human blood-derived cells (macrophages, T-lymphocytes), and for human neural (brain-derived) cells (microglia, astrocytes) were determined, as was chemokine co-receptor usage. All children harbored from birth macrophage-tropic isolates using the CCR5 co-receptor. Two children later developed T-cell tropic isolates with CXCR4 and CCR3 usage. While all six patients developed neurological abnormalities, only three produced neural cell tropic isolates, which used CCR5. However, early and persistent finding of both astrocyte- and microglia-tropic isolates in one patient did associate with the most rapid progression to brain atrophy among the six patients. Viral phenotypic properties determined in cell culture did not specifically predict clinical features or course, and the development of AIDS did not coincide with, or depend on, the appearance T-tropic, syncytia-inducing viruses.

Astrocytes↗

PubMed2006

HIV-1 GP120 V3 conformational and informational entropies.

In an attempt to analyze structure, function and evolution of HIV-1 GP120 V3, interactions among the Hartree-Fock energy, the conformational entropy and the Shannon entropy were determined for the 1NJ0 set of antibody-bound V3 loop conformers. The Hartree-Fock energy of each conformer was determined at the MINI level with GAMESS. The conformational entropy was determined per conformer and per residue from the mass-weighted covariance matrices. The Shannon entropy per residue was determined from sequence-substitution frequencies. Correlations were determined by linear regression analysis. There was a negative correlation between the Hartree-Fock energy and the conformational entropy (R=-0.4840, p=0.0078, df =28) that enhanced the negative Helmholtz-free-energy change for the binding of the GP120 ligand to target CD4. The Shannon entropy of V3 was a function of the conformational entropy variance (R=0.7225, p=0.00157, df=15) and of the V3 Hartree-Fock energy. Biological implications of this work are that (1) conformational entropy interacts with V3 Hartree-Fock energy to enhance GP120 binding to CD4 cell receptors and that (2) the Hartree-Fock energy of V3 interacts with the evolutionary system to participate in the regulation of V3 diversity.

Entropy↗

PubMed1990

Immunological and serological markers predictive of progression to AIDS in a cohort of HIV-infected drug users.

We have performed a prospective 33-month follow-up of the evolution of HIV infection in a cohort of 76 HIV-positive intravenous drug users (IVDUs). We report on immunological and serological variables that proved to be highly predictive of development to AIDS. In a stepwise multivariate analysis of the actuarial progression rate we found the number of CD4+ lymphocytes to be the most powerful predictor of progression to AIDS. We found no independent predictive effects associated with any other variable with predictive power: loss of antibody to p24 antigen, anergy, HIV p24 antigenaemia, loss of antibody to p53 (reverse transcriptase), decreased number of CD8+ T cells, loss of antibody to p31, loss of antibody to p17, beta 2-microglobulin level, loss of antibodies to gp41 and p64, or immunoglobulin A level. We have found that our data differ from those obtained in studies in homosexual men in the different prognostic value of those predictive markers. Our findings should help to identify high risk of progression to clinical AIDS among IVDUs, thereby assisting in the selection of patients for prophylaxis and therapy.

Acquired Immunodeficiency Syndrome↗

PubMed2000

[Trend of HIV seroprevalence among mothers of new-born infants from 1996 to 1999].

BACKGROUND: To analyze the evolution of HIV prevalence in mothers of Spanish new-borns. SUBJECTS AND METHOD: Unlinked anonymous testing of HIV in blood spots for detection of metabolic diseases of all new-borns in 1996-1999 in seven regions: Baleares, Canarias, Castilla-La Mancha, Castilla y León, Galicia, Melilla and Murcia. HIV antibody detection was done with ELISA and confirmation with a immunoblot. RESULTS: The prevalence of HIV antibodies was 0.99 per 1,000 in 1996, 1.29 in 1997, 1.42 in 1998 and 1.54 in 1999. There was an upward trend both in the global sample (p = 0.0015) and in those from Canarias (p < 0.0001) and Castilla y León (p = 0.0389). The prevalence of HIV-1 for the whole period was 1.31 per 1.000 and of 1.13 per 100.000 for HIV-2. CONCLUSIONS: There is a need to offer systematic counselling and HIV testing to all pregnant women.

HIV Antibodies↗

PubMedDate not supplied

[Importance of measurement of plasma viral load for the therapeutic follow-up of children infected with HIV-1. Study of its evolution according to modifications of treatment in 55 children].

Since 1987 we started to treat all vertically HIV-1 infected newborns by an antiretroviral therapy as soon as the diagnosis was confirmed. From the study of 55 HIV-1 infected children followed at Armand Trousseau Hospital (Paris, France) we retrospectively evaluated the use of the plasma viral load as a marker of the treatment efficiency. This parameter and CD4 counts were measured the day of any modification in antiviral therapy (Day 0), 1 and 3 months later (M1 and M3) and every 3 months as long as possible. In the 3 groups of treatment modifications a decrease in plasma viral load was observed. A statistically significant increase in CD4 counts was only observed in the group treated with the association of 2 nucleoside analogues and 1 proteinase inhibitor. This group demonstrated the most important decrease in plasma viral load (> 0.7 log 10 Eq Cop/ml). This leads us to propose to the "ANRS" a protocol study for the treatment of all vertically HIV-1 infected children by the association of 3 nucleoside analogues and 1 proteinase inhibitor as early as 8 weeks post natal when the HIV infection is confirmed.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Human immunodeficiency virus type 1 genotypic and pharmacokinetic determinants of the virological response to lopinavir-ritonavir-containing therapy in protease inhibitor-experienced patients.

The response to regimens including lopinavir-ritonavir (LPV/r) in patients who have received multiple protease (PR) inhibitors (PI) can be analyzed in terms of human immunodeficiency virus type 1 (HIV-1) genotypic and pharmacokinetic (pK) determinants. We studied these factors and the evolution of HIV-1 resistance in response to LPV/r in a prospective study of patients receiving LPV/r under a temporary authorization in Bordeaux, France. HIV-1 PR and reverse transcriptase sequences were determined at baseline LPV/r for all the patients and at month 3 (M3) and M6 in the absence of response to treatment. pK measurements were determined at M1 and M3. Virological failure (VF) was defined as a plasma viral load >or=400 copies/ml at M3. A multivariate analysis of the predictors of VF, including clinical and biological characteristics and the treatment history of the patients, was performed. The PR gene sequence at M0, including individual mutations or a previously defined LPV mutation score (D. J. Kempf, J. D. Isaacson, M. S. King, S. C. Brun, Y. Xu, K. Real, B. M. Bernstein, A. J. Japour, E. Sun, and R. A. Rode, J. Virol. 75:7262-7269, 2001), and the individual exposure to LPV were also included covariates. Sixty-eight patients were enrolled. Thirty-four percent had a virological response at M3. An LPV mutation score of >5 mutations, the presence of the PR I54V mutation at baseline, a high number of previous PIs, prior therapy with ritonavir or indinavir, absence of coprescription of efavirenz, and a lower exposure to LPV or lower LPV trough concentrations were independently associated with VF on LPV/r. Additional PI resistance mutations, including primary mutation I50V, could be selected in patients failing on LPV/r. Genotypic and pK parameters should be used to optimize the virological response to LPV/r in PI-experienced patients and to avoid further viral evolution.

Adult↗

PubMed2000

Evolution in the body of HIV nursing knowledge.

The role nurses occupy in the care of the HIV/AIDS affected has evolved over time. This evolution is exhibited in the body of nursing knowledge and is recorded in the published literature. The purpose of this study was to describe landmarks in the evolution of nursing's involvement in the provision of care to HIV/AIDS patients and to examine the body of nursing knowledge relative to HIV/AIDS, employing bibliometric analytic techniques. It was expected that the literature would grow in both breadth and depth concurrent with nursing's increased role in caring for those infected, or at risk for infection, with HIV.

Bibliometrics↗

PubMed1998

The effect of different immune responses on the evolution of virulent CXCR4-tropic HIV.

We use mathematical models to determine possible mechanisms contributing to the evolution and rise of virulent CXCR4-tropic HIV in vivo. The models predict that the ability of the virus to specialize on a given target cell type depends on the exact fitness landscape of the viral mutants. Because this fitness landscape varies between people, this may explain why the evolution of fully CXCR4-tropic strains only occurs in about 50% of infected patients. Assuming that CXCR4-tropic HIV may evolve, we investigate the effect of different immune responses on the rise of such virulent strains. If we assume that CXCR4-tropic HIV is more cytopathic than CCR5-tropic virus, virulent CXCR4-tropic mutants remain suppressed at low levels both in the absence of an immune response, and in the presence of responses that act on the virus before integration into the host genome. On the other hand, this difference in cytopathogenicity is reduced by the presence of immune responses acting on infected cells, allowing CXCR4-tropic HIV to coexist with the CCR5-tropic virus. These results may help to interpret experimental data and are discussed with reference to the literature.

HIV↗

PubMed2004

Independent evolution of human immunodeficiency virus (HIV) drug resistance mutations in diverse areas of the brain in HIV-infected patients, with and without dementia, on antiretroviral treatment.

AIDS dementia complex (ADC) in human immunodeficiency virus (HIV)-infected patients continues to be a problem in the era of highly active antiretroviral therapy (HAART). A better understanding of the drug resistance mutation patterns that emerge in the central nervous system (CNS) during HAART is of paramount importance as these differences in drug resistance mutations may explain underlying reasons for poor penetration of antiretroviral drugs into the CNS and suboptimal concentrations of the drugs that may reside in the brains of HIV-infected individuals during therapy. Thus, we provide a detailed analysis of HIV type 1 (HIV-1) protease and reverse transcriptase (RT) genes derived from different regions of the brains of 20 HIV-1-infected patients (5 without ADC, 2 with probable ADC, and 13 with various stages of ADC) on antiretroviral therapy. We show the compartmentalization and independent evolution of both primary and secondary drug resistance mutations to both RT and protease inhibitors in diverse regions of the CNS of HIV-infected patients, with and without dementia, on antiretroviral therapy. Our results suggest that the independent evolution of drug resistance mutations in diverse areas of the CNS may emerge as a consequence of incomplete suppression of HIV, probably related to suboptimal drug levels in the CNS and drug selection pressure. The emergence of resistant virus in the CNS may have considerable influence on the outcome of neurologic disease and also the reseeding of HIV in the systemic circulation upon failure of therapy.

AIDS Dementia Complex↗

PubMed1998

Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients.

We have studied the phenotypic impact of adaptative Gag cleavage site mutations in patient-derived human immunodeficiency virus type 1 (HIV-1) variants having developed resistance to the protease inhibitor ritonavir or saquinavir. We found that Gag mutations occurred in a minority of resistant viruses, regardless of the duration of the treatment and of the protease mutation profile. Gag mutations exerted only a partial corrective effect on resistance-associated loss of viral fitness. Reconstructed viruses with resistant proteases displayed multiple Gag cleavage defects, and in spite of Gag adaptation, several of these defects remained, explaining the limited corrective effect of cleavage site mutations on fitness. Our data provide clear evidence of the interplay between resistance and fitness in HIV-1 evolution in patients treated with protease inhibitors.

Amino Acid Sequence↗

PubMed2003

Comparing the ex vivo fitness of CCR5-tropic human immunodeficiency virus type 1 isolates of subtypes B and C.

Continual human immunodeficiency virus type 1 (HIV-1) evolution and expansion within the human population have led to unequal distribution of HIV-1 group M subtypes. In particular, recent outgrowth of subtype C in southern Africa, India, and China has fueled speculation that subtype C isolates may be more fit in vivo. In this study, nine subtype B and six subtype C HIV-1 isolates were added to peripheral blood mononuclear cell cultures for a complete pairwise competition experiment. All subtype C HIV-1 isolates were less fit than subtype B isolates (P < 0.0001), but intrasubtype variations in HIV-1 fitness were not significant. Increased fitness of subtype B over subtype C was also observed in primary CD4(+) T cells and macrophages from different human donors but not in skin-derived human Langerhans cells. Detailed analysis of the retroviral life cycle during several B and C virus competitions indicated that the efficiency of host cell entry may have a significant impact on relative fitness. Furthermore, phyletic analyses of fitness differences suggested that, for a recombined subtype B/C HIV-1 isolate, higher fitness mapped to the subtype B env gene rather than the subtype C gag and pol genes. These results suggest that subtype B and C HIV-1 may be transmitted with equal efficiency (Langerhans cell data) but that subtype C isolates may be less fit following initial infection (T-cell and macrophage data) and may lead to slower disease progression.

Cells, Cultured↗

PubMed2005

Impact of genetic diversity of HIV-1 on diagnosis, antiretroviral therapy & vaccine development.

HIV-1 strains have diversified extensively through mutation and recombination since their initial transmission to human beings many decades ago in central Africa. The high error rate of HIV reverse transcriptase combined with the estimated in vivo HIV-1 replication rate of ten billion new virions each day leads to extraordinary genetic diversity of HIV. Twenty seven circulating genetic forms of the HIV-1 group M are presently recognized, including 11 subtypes and sub-subtypes, and 16 circulating recombinant forms (CRF). Genotypic analyses have provided a better understanding of the molecular diversity of HIV-1, enabling the detection of emerging HIV-1 variants and improving the tracking of the epidemic worldwide. The rapid evolution of HIV within infected hosts contributes significantly to the elusiveness of this pathogen from host antiviral responses. The complex nature of HIV envelope glycoprotein that is inherently resistant to neutralization, the selective infection, progressive destruction and impaired regeneration of CD4+ T helper cells, generation of cytotoxic T lymphocyte (CTL) escape mutants, together with high genetic diversity with continually evolving HIV variants worldwide, makes design of an effective vaccine a formidable task. Given the rapidity and unpredictability with which HIV-1 genetic forms may propagate in future, a vaccine protective against all major HIV-1 circulating genetic forms is desirable, which could require multivalent formulations. Understanding the kinetics and directions of this continuing adaptation and its impact on viral fitness, immunogenicity and pathogenicity are crucial to the successful design of effective HIV vaccines. In this review, we focus on extensive diversity of HIV-1, emergence of recombinant forms and their impact on diagnosis, antiretroviral therapy, disease progression, transmission, and vaccine development.

AIDS Vaccines↗

PubMed1991

[Spanish Pediatric Association. Madrid. Human immunodeficiency virus infection. Spanish multicenter study].

The results of an epidemiological survey in Spain organized by the "Spanish Pediatric Association" of children born to HIV+ mothers from 1981-1989 are presented. The objectives were, a) to document in the different parts of Spain the number of HIV+ children born to HIV+ mothers, and b) to identify the risk factors involved in the HIV infection. Only in public hospitals, a total of 1938 HIV+ children born to HIV+ mothers were identified. A systematic yearly increase of HIV+ newborns was evident since 1985. Madrid, Catalonia, Valencia, Basq and Andalucia communities incorporated 85% of all cases. 93% of mothers were IVDU and 51% of them were married. Prematurity occurred in 27% of cases and low birth weight in 33% of NB's. The rate of transmission in children over 18 months of age was 25.6% Breast feeding could be a risk factor in the transmission of HIV infection observed in children over 18 months of age. No other maternal risk factors responsible for the HIV transmission were identified. 12% of children died with AIDS. Clinical classification and evolution of HIV infection did not significantly differ from similar studies in other parts of the world. In spite of only public hospitals being involved, Spain has more identified HIV+ children than Italy, Switzerland, Federal Republic of Germany, United Kingdom, Sweden and Belgium combined. The pediatric centres with large number of cases require interdisciplinary pediatric specialized units to cope with the increase demand of medical services, now inadequate and insufficient. To fight drug use and HIV infection in Spain, health education and family support, are indispensable in trying to arrest the continuous spread the HIV infection.

Acquired Immunodeficiency Syndrome↗