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PubMed1996

[Current clinical manifestations of tuberculosis].

Tuberculosis is an enormously serious and growing global disease that is becoming increasingly concentrated in the so-called "developing" nations of the world, where the epidemic is fuelled by the rapid expansion of the population, the presence of extreme poverty, and the coexistence of HIV infection. Most persons who become infected with M. tuberculosis do not develop the disease tuberculosis. In those who do, two types are recognised: 1) early progression of the primary pulmonary lesion or its lymph node component, or a complication from hematogenous dissemination, and 2) late reactivation of one or more previously latent sites, of which upper lobe pulmonary disease is the most common; extrapulmonary disease may also occur. Progressive immunosuppression from HIV infection exaggerates and accelerates the evolution of virtually all aspects of tuberculosis.

AIDS-Related Opportunistic Infections↗

PubMed1998

Nonparametric estimation of covariance structure in longitudinal data.

In longitudinal studies, the effect of various treatments over time is usually of prime interest. However, observations on the same subject are usually correlated and any analysis should account for the underlying covariance structure. A nonparametric estimate of the covariance structure is useful, either as a guide to the formulation of a parametric model or as the basis for formal inference without imposing parametric assumptions. The sample covariance matrix provides such an estimate when the data consist of a short sequence of measurements at a common set of time points on each of many subjects but is impractical when the data are severely unbalanced or when the sequences of measurements on individual subjects are long relative to the number of subjects. The variogram of residuals from a saturated model for the mean response has previously been suggested as a nonparametric estimator for covariance structure assuming stationarity. In this paper, we consider kernel weighted local linear regression smoothing of sample variogram ordinates and of squared residuals to provide a nonparametric estimator for the covariance structure without assuming stationarity. The value of the estimator as a diagnostic tool is demonstrated in two applications, one to a set of data concerning the blood pressure of newborn babies in an intensive care unit and the other to data on the time evolution of CD4 cell numbers in HIV seroconverters. The use of the estimator in more formal statistical inferences concerning the mean profiles requires further study.

Anti-HIV Agents↗

PubMed1998

Models of natural mutations including site heterogeneity.

New computational models of natural site mutations are developed that account for the different selective pressures acting on different locations in the protein. The number of adjustable parameters is greatly reduced by basing the models on the underlying physical-chemical properties of the amino acids. This allows us to use our method on small data sets built of specific protein types. We demonstrate that with this approach we can represent the evolutionary patterns in HIV envelope proteins far better than with more traditional methods.

Evolution, Molecular↗

PubMed2005

Increased multinucleoside drug resistance and decreased replicative capacity of a human immunodeficiency virus type 1 variant with an 8-amino-Acid insert in the reverse transcriptase.

Resistance to antiretroviral drugs is generally conferred by specific amino acid substitutions, rather than insertions or deletions, in reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1). The exception to these findings is the amino acid insertions found in the beta3-beta4 loop of the RT enzyme in response to treatment with nucleoside reverse transcriptase inhibitors. This insert consists most commonly of two amino acids, but we describe in detail the evolution of a variant with an 8-amino-acid (aa) insert in a patient treated with zidovudine (ZDV) and 2'-3'-dideoxycytidine (ddC). The 24-nucleotide insert is a partial duplication of local sequences but also contains a sequence segment of unknown origin. Extensive sequence analysis of longitudinal patient samples indicated that the HIV-1 population prior to the start of therapy contained not the wild-type amino acid 215T in RT but a mixture with 215D and 215C. Treatment with ZDV and subsequent ZDV-ddC combination therapy resulted in the evolution of an HIV-1 variant with a typical ZDV resistance genotype (41L, 44D, 67N, 69D, 210W, 215Y), which was slowly replaced by the insert-containing variant (41L, 44D, insert at position 69, 70R, 210W, 215Y). The latter variant demonstrated increased resistance to a wide range of drugs, indicating that the 8-aa insert augments nucleoside analogue resistance. The gain in drug resistance of the insert variant came at the expense of a reduction in replication capacity when assayed in the absence of drugs. We compared these data with the resistance and replication properties of 133 insert-containing sequences of different individuals present in the ViroLogic database and found that the size and actual sequence of the insert at position 69 influence the level of resistance to nucleoside analogues.

Adult↗

PubMed2004

Persistent HIV type 1 infection in semen and blood compartments in patients after long-term potent antiretroviral therapy.

HIV-1 RNA levels in semen and blood compartments decrease below detection limits during highly active antiretroviral therapy. Despite these therapeutic effects, it is clear that persistent, latent HIV-1 reservoirs are capable of rebounding in the absence of drug treatment or by evolution of escape mutants remain. The current study was designed to examine the presence of latent virus in semen and blood compartments and its evolution following potent combination therapy with indinavir (protease inhibitor) and efavirenz [nonnucleoside reverse transcriptase (RT) inhibitor]. Using an ultrasensitive in situ hybridization assay HIV-1 mRNA was detected in cultured seminal and blood mononuclear cells in all patients up to 1789 days posttherapy. Higher levels of HIV-1 mRNA were consistently detected in seminal mononuclear cells as compared to peripheral blood mononuclear cells (PBMC) in all time points analyzed posttherapy. Analysis of viral RNA from cultured PBMC before and after therapy displayed no evidence of therapy-induced drug resistance in the viral polymerase gene in the majority of patients. However, distinct envelope populations were detected in these viral RNA populations following therapy, indicating possible selection of quasispecies. The observed ongoing replication and evolution in the PBMC viral envelope sequences likely occurred in the seminal compartment HIV populations, given that the seminal cells showed the ability to express HIV-1 mRNA following cultivation. This together with our previous studies (Gupta P, et al.: J Infect Dis 2000;182:79-87) suggest that the genital and blood compartments likely serve as distinct reservoirs harboring latent HIV-1 during prolonged drug therapy.

Alkynes↗

PubMed2002

Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Recommendations of the Panel on Clinical Practices for Treatment of HIV.

The availability of an increasing number of antiretroviral agents and the rapid evolution of new information has introduced substantial complexity into treatment regimens for persons infected with human immunodeficiency virus (HIV). In 1996, the Department of Health and Human Services and the Henry J. Kaiser Family Foundation convened the Panel on Clinical Practices for the Treatment of HIV to develop guidelines for clinical management of HIV-infected adults and adolescents (CDC. Report of the NIH Panel To Define Principles of Therapy of HIV Infection and Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR 1998;47[RR-5]:1-41). This report, which updates the 1998 guidelines, addresses 1) using testing for plasma HIV ribonucleic acid levels (i.e., viral load) and CD4+ T cell count; 2) using testing for antiretroviral drug resistance; 3) considerations for when to initiate therapy; 4) adherence to antiretroviral therapy; 5) considerations for therapy among patients with advanced disease; 6) therapy-related adverse events; 7) interruption of therapy; 8) considerations for changing therapy and available therapeutic options; 9) treatment for acute HIV infection; 10) considerations for antiretroviral therapy among adolescents; 11) considerations for antiretroviral therapy among pregnant women; and 12) concerns related to transmission of HIV to others. Antiretroviral regimens are complex, have serious side effects, pose difficulty with adherence, and carry serious potential consequences from the development of viral resistance because of nonadherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic decisions is critical. Treatment should usually be offered to all patients with symptoms ascribed to HIV infection. Recommendations for offering antiretroviral therapy among asymptomatic patients require analysis of real and potential risks and benefits. Treatment should be offered to persons who have <350 CD4+ T cells/mm3 or plasma HIV ribonucleic acid (RNA) levels of >55,000 copies/mL (by b-deoxyribonucleic acid [bDNA] or reverse transcriptase-polymerase chain reaction [RT-PCR] assays). The recommendation to treat asymptomatic patients should be based on the willingness and readiness of the person to begin therapy; the degree of existing immunodeficiency as determined by the CD4+ T cell count; the risk for disease progression as determined by the CD4+ T cell count and level of plasma HIV RNA; the potential benefits and risks of initiating therapy in an asymptomatic person; and the likelihood, after counseling and education, of adherence to the prescribed treatment regimen. Treatment goals should be maximal and durable suppression of viral load, restoration and preservation of immunologic function, improvement of quality of life, and reduction of HIV-related morbidity and mortality. Results of therapy are evaluated through plasma HIV RNA levels, which are expected to indicate a 1.0 log10 decrease at 2-8 weeks and no detectable virus (<50 copies/mL) at 4-6 months after treatment initiation. Failure of therapy at 4-6 months might be ascribed to nonadherence, inadequate potency of drugs or suboptimal levels of antiretroviral agents, viral resistance, and other factors that are poorly understood. Patients whose therapy fails in spite of a high level of adherence to the regimen should have their regimen changed; this change should be guided by a thorough drug treatment history and the results of drug-resistance testing. Because of limitations in the available alternative antiretroviral regimens that have documented efficacy, optimal changes in therapy might be difficult to achieve for patients in whom the preferred regimen has failed. These decisions are further confounded by problems with adherence, toxicity, and resistance. For certain patients, participating in a clinical trial with or without access to new drugs or using a regimen that might not achieve complete suppression of viral replication might be preferable. Because concepts regarding HIV management are evolving rapidly, readers should check regularly for additional information and updates at the HIV/AIDS Treatment Information Service website (http://www.hivatis.org).

Adolescent↗

PubMed2002

Endogenous expression of a high-affinity pseudoknot RNA aptamer suppresses replication of HIV-1.

Aptamers, small oligonucleotides derived from an in vitro evolution process called SELEX, are promising therapeutic and diagnostic agents. Although very effective in vitro, only a few examples are available showing their potential in vivo. We have analyzed the effect of a well characterized pseudoknot RNA aptamer selected for tight binding to human immunodeficiency virus (HIV) type 1 reverse transcriptase on HIV replication. Transient intracellular expression of a chimeric RNA consisting of the human initiator tRNA(Met) (tRNA(Meti))/aptamer sequence in human 293T cells showed inhibition of HIV particle release by >75% when the cells were co-transfected with proviral HIV-1 DNA. Subsequent virus production of human T-lymphoid C8166 cells, infected with viral particles derived from co-transfected 293T cells, was again reduced by >75% as compared with the control. As the observed effects are additive, in this model for virus spread, the total reduction of HIV particle formation by transient intracellular expression of the pseudoknot RNA aptamer amounts to >95%. Low-dose HIV infection of human T cells stably expressing the aptamer did not show any virus replication over a period of 35 days. This is the first example of an RNA aptamer selected against a viral enzyme target to show powerful antiviral activity in HIV-1-permissive human T-lymphoid cell lines.

Base Sequence↗

PubMed2000

Baseline HIV type 1 genotypic resistance to a newly added nucleoside analog is predictive of virologic failure of the new therapy.

We evaluated the predictive value of baseline HIV-1 genotypic resistance mutations for failure of a nucleoside reverse transcriptase inhibitor (NRTI) containing therapy. The change in therapy of 88 HIV-1-infected patients was analyzed retrospectively, relating the genotypic resistance profile at baseline to the evolution of viral load and CD4+ T cell counts. Genotypic resistance at baseline and at 6 months was evaluated with the LiPA HIV-1 RT, which detects mutations at codons 41, 69, 70, 74, 184, and 215. At 1 to 3 months after change in therapy, patients without preexisting resistance mutations to the new drug (group S) had a significantly better evolution in viral load (reduction of 0.37 log(10)) compared with patients with known preexisting resistance mutation(s) (group R) (increase of 0.08 log(10)). This difference was particularly striking for patients with the baseline M184V mutation and whose treatment was modified by the addition of lamivudine. After 6 months the median difference in viral load evolution between the two groups increased to 0.61 log(10): the viral load of patients of group S was still 0.18 log(10) below baseline while patients of group R had an increase of 0.43 log(10) in viral load above baseline. Changes in CD4+ T cell counts were not significantly different. The evolution in viral load in HIV-1-infected patients with and without baseline resistance mutation(s) toward a newly added NRTI is significantly different at 1-3 months and at 6 months after changing or adding one NRTI.

CD4 Lymphocyte Count↗

PubMed2005

Genetic analysis reveals the complex structure of HIV-1 transmission within defined risk groups.

We explored the epidemic history of HIV-1 subtype B in the United Kingdom by using statistical methods that infer the population history of pathogens from sampled gene sequence data. Phylogenetic analysis of HIV-1 pol gene sequences from Britain showed at least six large transmission chains, indicating a genetically variable, but epidemiologically homogeneous, epidemic among men having sex with men. Through coalescent-based analysis, we showed that these chains arose through separate introductions of subtype B strains into the United Kingdom in the early to mid-1980s. After an initial period of exponential growth, the rate of spread generally slowed in the early 1990s, which is more likely to correlate with behavior change than with reduced infectiousness resulting from highly active antiretroviral therapy. Our results provide insights into the complexity of HIV-1 epidemics that must be considered when developing HIV monitoring and prevention initiatives.

Disease Outbreaks↗

PubMed1999

["Buffalo hump" related to indinavir treatment].

BACKGROUND: Since 1997, new side effects like lipodystrophia have been described in HIV-1-infected patients treated with protease inhibitors. The evolution is not specified in the most reported cases. CASE REPORT: A 44-year-old man treated for HIV 1 infection developed a Buffalo hump 12 months after initiating a new treatment including indinavir-protease inhibitor (Crixivan). Ten months later, we observe neither other fat accumulation nor fat loss and significant metabolic disorders. DISCUSSION: Many publications emphasized the relationship that would exist between protease inhibitors therapy and the occurrence of lipodystrophia. Clinical features of this syndrome appear like an accumulation of fatty tissue anywhere on the trunk, or a fat loss on the limbs, the buttocks and the face. It is sometimes associated with metabolic disorders. The pathogenesis of these lipodystrophia is unclear. Larger studies have to be led to highlight the incidence of these lipodystrophia and their subsequent effects on the HIV-1 infection.

Adipose Tissue↗

PubMed2001

Using HIV-1 sequence variability to explore virus biology.

Human immunodeficiency virus type 1 (HIV-1) only recently established an epidemic world-wide infection in the human population. The virus persists in the human host through active replication and is able to avoid clearance by the immune system. Active replication is an important component of the rapid evolutionary potential of HIV-1, a potential which manifests itself in the evolution of immune escape variants, drug resistant variants, and variants with the ability to use different cell surface coreceptors in conjunction with CD4. Multiple zoonotic introductions, compartmentalization of virus replication in the body, and genetic bottlenecks associated with sampling during transmission, antiretroviral therapy, and geographic and/or host population isolation further contribute to the range of sequences present in extant viruses. The sum of the history of all of these phenomena is reflected in HIV-1 sequence variability, and most of these phenomena are ongoing today. Here we review the use of HIV-1 sequence variability to explore its underlying biology.

Animals↗

PubMed2003

Clinical implications of HIV-1 drug resistance in the neurological compartment.

The tropism of human immunodeficiency virus type 1 (HIV-1) for the central nervous system (CNS) develops early during the course of the infection. Potent antiretroviral therapy has been demonstrated to be effective in controlling the replication of HIV-1 in cerebrospinal fluid (CSF), even though a variable response in this compartment compared with that in plasma has been observed. Different concentrations of antiretroviral drugs are found in CSF and the use of antiretroviral drugs penetrating across the blood-brain barrier is considered to be required for controlling CNS infection in advanced patients, particularly in those with neurological disorders. The compartmentalization of HIV-1 infection in the CNS may affect the treatment response, which may cause a different evolution of viral drug resistance in the 2 compartments. Although HIV-1 resistance testing in CSF is not recommended for the routine management of patients with virological failure, treatment decisions in patients with neurological disorders may require knowledge of the resistance profile of the virus in the CSF.

AIDS Dementia Complex↗

PubMed2026

Emergence of two novel HIV-1 Circulating Recombinant Forms (CRF190_0708 and CRF191_0708): molecular characterization and clinical insights from a five-year study in Yunnan, China.

BACKGROUND: To characterize HIV-1 molecular epidemiology and identify novel circulating recombinant forms (CRFs) among antiretroviral therapy (ART)-naïve heterosexuals in Yunnan, China, and evaluate their clinical impact. METHODS: This study examined 636 HIV-1 pol sequences to analyze genetic diversity, pretreatment drug resistance (PDR), and transmission networks. Near full-length genomes were obtained to identify and characterize novel recombinants, with their evolutionary history inferred by Bayesian analysis. Co-receptor tropism was predicted, and the five-year clinical outcomes (including immune reconstitution and virologic response) of patients infected with the novel CRFs were compared. RESULTS: The most prevalent type identified was CRF08_BC, accounting for 50.16% of cases. The prevalence of drug resistance was 5.97% (38/636), with the K103N mutation being the most common. An analysis of transmission networks revealed that 52.2% (272/521) of clusters were associated with CRF07_BC and CRF08_BC. Two novel second-generation CRFs were identified: CRF190_0708, with an estimated time to the most recent common ancestor (tMRCA) of 1998.9, and CRF191_0708, with a more recent tMRCA ranging from 2009.5 to 2011.6. During the five-year follow-up period, viral rebound was observed in 7 patients in the CRF190_0708 group and in 1 patient in the CRF191_0708 group. Drug-resistance mutations (M184V and K103N) were detected in a subset of rebound cases in the CRF190_0708 group. CONCLUSIONS: This study identifies two novel HIV-1 recombinants, CRF190_0708 and CRF191_0708, highlighting ongoing viral evolution in Yunnan. Preliminary findings suggest possible clinical differences, warranting further investigation. Continued molecular surveillance is needed. TRIAL REGISTRATION: The clinical study was registered at ClinicalTrials.gov under the identifier NCT03852849. The date of registration was March 22, 2019.

Adult↗

PubMed1997

[Historical cohort study on bacterial pneumonias as predictors of the progression of the human immunodeficiency virus disease].

BACKGROUND: Recognition of the importance of bacterial pneumonias in the context of HIV infection has continuously grown throughout the pandemia. It has recently been suggested that these may be predictors of progression of the disease. PATIENTS AND METHODS: The evolution of an historic cohort of patients with HIV infection who were studied in 1989 with pneumonia regarding the presentation of AIDS or death was investigated. A control cohort was established, being age matched for sex, CD4 lymphocyte count, previous HIV disease and the use of zidovudine. Kaplan-Meier curves of survival without AIDS were made and compared by the logarythmic range test. Other predictors of progression were studied by the Cox models. RESULTS: Forty-nine patients were studied in each group, with a total of 121 and 153 patients/year of follow up. Final events were counted in 33 and 27 cases, respectively (p = 0.11). The relative risk of progression was 1.55 (confidence interval of 95%, 0.93 to 2.56) for the group of pneumonias. The estimated relative risk (hazard) performed by a Cox model of proportional risks was however 1.85 (confidence interval of 95%: 1.05 to 3.25, p < 0.05) when the lymphocyte count adjustment was carried out according to the real values rather than by categories. CONCLUSIONS: The results of this historic cohort study support the existence of an association between history of bacterial pneumonia and the risk of HIV disease progression.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Longitudinal assessment of immune response and viral characteristics in HIV-infected patients with prolonged CD4(+)/viral load discordance.

Although suppression of HIV-1 RNA below the limit of detection is associated with optimal outcomes, many patients can maintain or increase their CD4(+) count for prolonged time periods in the presence of persistent low-level viremia. We followed seven patients with prolonged (>5 years) discordant CD4(+)/viral load (VL) responses on protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) prospectively for 1 year to assess evolution of immune function, viral phenotype, replication capacity (RC), and resistance profile. Immune function was assessed by qualitative and quantitative measurement of cellular activation (CD38(+)HLA-DR(+) and CD38 antibodies bound per cell), and the interferon (IFN)-() ELISpot assay. Presence of syncytium-inducing (SI) or nonsyncytium-inducing (NSI) viral strains was determined by MT-2 cell culture. RC was measured by a modified rapid recombinant virus assay. The resistance profile was characterized by both genotypic and phenotypic analysis. Over the year of follow-up, IFN-() production to gag persisted, responses to other HIV antigens increased, and markers of cellular activation did not change. NSI virus predominated. The genotypic (GSS) and phenotypic (PSS) susceptibility scores remained stable. Evolution of RC was variable over the year of follow-up, but the RC of viruses remained well below that of wild-type clinical isolates. Thus, CD4(+)/VL discordance can be maintained for periods exceeding 5 years in some patients receiving PI-based HAART without significant evolution of HIV resistance.

Adolescent↗

PubMed2001

Relapsing visceral leishmaniasis in HIV-infected patients undergoing successful protease inhibitor therapy.

The aim of this study was to establish the evolution of visceral leishmaniasis (VL) in 10 consecutive patients coinfected with VL and HIV, taking into account the decline in the incidence of opportunistic infections after the introduction of protease inhibitor therapy. During a median follow-up of 31 months, 7 (70%) of 10 patients relapsed. The incidence of relapse was slightly lower than before institution of protease inhibitor therapy (20 vs. 13 patient-months), with a 31% probability that relapse would not have taken place within 2 years. VL relapses occurred even though increases in the CD4+ cell counts were observed and HIV loads were undetectable, suggesting that successful antiretroviral therapy is not sufficient to control the disease. Relapsing patients also had a lower increase in the CD4+ cell count.

AIDS-Related Opportunistic Infections↗

PubMed1998

Drug concentration heterogeneity facilitates the evolution of drug resistance.

Pathogenic microorganisms use Darwinian processes to circumvent attempts at their control through chemotherapy. In the case of HIV-1 infection, in which drug resistance is a continuing problem, we show that in one-compartment systems, there is a relatively narrow window of drug concentrations that allows evolution of resistant variants. When the system is enlarged to two spatially distinct compartments held at different drug concentrations with transport of virus between them, the range of average drug concentrations that allow evolution of resistance is significantly increased. For high average drug concentrations, resistance is very unlikely to arise without spatial heterogeneity. We argue that a quantitative understanding of the role played by heterogeneity in drug levels and pathogen transport is crucial for attempts to control re-emergent infectious disease.

Anti-HIV Agents↗

PubMed2005

A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction.

Retroviral restriction factors are cellular proteins that interfere with retrovirus replication at a postpenetration, preintegration stage in the viral life cycle. The first restriction activity described was the mouse Fv1 gene. Three different alleles of Fv1, capable of restricting different murine leukaemia viruses (MLV), have been characterized at the molecular level. Two further activities, Ref1, which acts on MLV, and Lv1, which acts on lentiviruses, have been identified in other mammalian species. Recently, it has become clear that Ref1 and Lv1 are encoded by the same gene, Trim5alpha, which inhibits retrovirus replication in a species-specific manner. A series of chimeras between the human and rhesus monkey Trim5 genes were created to map and identify these specificity determinants. The Trim5alpha SPRY domain was found to be responsible for targeting HIV-1 restriction. By contrast, N-MLV restriction appears dependent on both the coiled-coil domain and the SPRY domain. A single amino acid substitution (R332P) in the human Trim5alpha can confer the ability to restrict HIV-1, suggesting that small changes during evolution may have profound effects on our susceptibility to cross-species infection.

Amino Acid Sequence↗