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PubMed1992

Neuropathology and pathogenesis of HIV encephalopathies.

The nervous system is frequently affected in patients with the acquired immune deficiency syndrome (AIDS). In addition to opportunistic CNS infections and cerebral lymphomas, approx. 20% of the patients develop HIV-associated encephalopathies. Two major histopathological manifestations are observed. HIV leukoencephalopathy (progressive diffuse leukoencephalopathy) is characterized by a diffuse loss of myelin in the deep white matter of the cerebral and cerebellar hemispheres, with scattered multinucleated giant cells and microglia but scarce or absent inflammatory reaction. HIV encephalitis (multinucleated giant cell encephalitis) is associated with accumulations of multinucleated giant cells, inflammatory reaction and often focal necroses. In some patients, both patterns may overlap. In order to identify the HIV genome in the CNS, brain tissue from 27 patients was analyzed for the presence of HIV gag sequences using the polymerase chain reaction (PCR) and primers encoding a 109 base pair segment of the gag gene. Amplification of HIV gag succeeded in all 5 patients with clinical and histopathological evidence for HIV encephalopathy but was negative in the 20 AIDS patients with opportunistic bacterial, parasitic and/or viral infections or with cerebral lymphomas. These results strongly suggest that the evolution of histopathologically recognizable HIV-encephalopathies closely correlates with the presence and/or tissue concentration of HIV. Since there were no cases with amplified HIV DNA in the absence of HIV-associated tissue lesions, we conclude that harboring and replication of HIV in the CNS rapidly causes corresponding clinical and morphological changes of HIV-associated encephalopathies. In two children with severe HIV encephalomyelitis, large amounts of HIV gag and env transcripts were detected in affected areas of the brain and spinal cord by in situ hybridization.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS Dementia Complex↗
PubMed2004

[Studies on virulence of HIV and development of non-virulent live AIDS vaccine using monkeys].

A great effort for developing AIDS vaccine has been carried out in the world, designed by various new ideas based on basic research information obtained in recent virology and immunology. Withall it, to obtain effective AIDS vaccine is considered skeptical. One of the reasons of its difficulty is a lack of experimental animals susceptible to HIV-1. In our laboratory, we have succeeded in developing chimeric SIV having 3' half of HIV-1 genome including env (SHIV), which is infectious to macaque monkeys. One of SHIVs has been proved nonpathogenic in monkeys from various aspects and it afforded protective immunity to monkeys against pathogenic SHIV challenge infection. Now, we are trying to develop anti-HIV live attenuated vaccines using the nonpathogenic SHIV as a starting material. In the history of virus vaccine, live attenuated vaccines have been proved most effective in measles and polio-myelitis. However, it is not clear whether nonpathogenic HIV exists or not. Futhermore, even if nonpathogenic HIV could be obtained, there is possibility that it will easily mutate to pathogenic one. Therefore, to develop live attenuated AIDS vaccine is considered dangerous. In this article, We will introduce our research on SHIV pathogenicity using monkeys and hypothesize possibility to obtain nonpathogenic HIV which is speculated from the origin and evolution of HIV/SIV. To clarify virulence and nonvirulence of HIV and to obtain nonpathogenic virus are not only applied research but also basic science to dissolve the fundemental question why HIV can induce the disease.

AIDS Vaccines↗
PubMed2005

Estimating HIV evolutionary pathways and the genetic barrier to drug resistance.

BACKGROUND: The evolution of drug-resistant viruses challenges the management of human immunodeficiency virus (HIV) infections. Understanding this evolutionary process is important for the design of effective therapeutic strategies. METHODS: We used mutagenetic trees, a family of probabilistic graphical models, to describe the accumulation of resistance-associated mutations in the viral genome. On the basis of these models, we defined the genetic barrier, a quantity that summarizes the difficulty for the virus to escape from the selective pressure of the drug by developing escape mutations. RESULTS: From HIV reverse-transcriptase sequences that had been obtained from treated patients, we derived evolutionary models for zidovudine, zidovudine plus lamivudine, and zidovudine plus didanosine. The genetic barriers to resistance to zidovudine, stavudine, lamivudine, and didanosine, for the above 3 regimens, were computed and analyzed. We found both the mode and the rate of development of resistance to be heterogeneous. The genetic barrier to zidovudine resistance was increased if lamivudine was added to zidovudine but was decreased for didanosine. The barrier to lamivudine resistance was maintained with zidovudine plus didanosine, whereas the barrier to didanosine resistance was reduced most with zidovudine plus lamivudine. CONCLUSION: Mutagenetic trees provide a quantitative picture of the evolution of drug resistance. The genetic barrier is a useful tool for design of effective treatment strategies.

Anti-HIV Agents↗
PubMed2001

Selecting models of nucleotide substitution: an application to human immunodeficiency virus 1 (HIV-1).

The blind use of models of nucleotide substitution in evolutionary analyses is a common practice in the viral community. Typically, a simple model of evolution like the Kimura two-parameter model is used for estimating genetic distances and phylogenies, either because other authors have used it or because it is the default in various phylogenetic packages. Using two statistical approaches to model fitting, hierarchical likelihood ratio tests and the Akaike information criterion, we show that different viral data sets are better explained by different models of evolution. We demonstrate our results with the analysis of HIV-1 sequences from a hierarchy of samples; sequences within individuals, individuals within subtypes, and subtypes within groups. We also examine results for three different gene regions: gag, pol, and env. The Kimura two-parameter model was not selected as the best-fit model for any of these data sets, despite its widespread use in phylogenetic analyses of HIV-1 sequences. Furthermore, the model complexity increased with increasing sequence divergence. Finally, the molecular-clock hypothesis was rejected in most of the data sets analyzed, throwing into question clock-based estimates of divergence times for HIV-1. The importance of models in evolutionary analyses and their repercussions on the derived conclusions are discussed.

Databases, Factual↗
PubMedDate not supplied

[Protease and reverse transcriptase genetic polymorphism in HIV type 1 subtype A variants predominating in cis countries].

To define frequencies of drug resistance mutations among HIV-1 variants circulating within the territory of Russia, subtype A HIV-1 nucleotide sequences encoding protease and reverse transcriptase were analyzed. The analysis was carried out in 141 antiretroviral-naive individuals. Low frequency (less than 1%) of primary drug resistance mutations was shown. However, high frequencies of secondary mutations V77I in protease and A62V in RT (67% H 63%, respectively) linked to each other in most cases were observed. The HIV-1 isolates bearing both substitutions (MutV77I/A62V) were also characterized by the presence of several synonymous mutations, suggesting common origin for these viruses. HIV Biochip Hybridization microarray and/or Restriction fragment-length polymorphism analyses were performed to characterize gene pol polymorphism in additional 178 subtype A HIV-1 isolates. Among total 319 samples studied, Mutv77IA62V variant accounted for 56%, and was found to predominate in Russia in terms of both its geographical distribution and number of cases caused. Moreover, these viruses were prevalent in the regions known to have highest incidence of HIV-1 infection (Irkutsk, Samara, and Moscow regions). In addition, three other variants were found: viruses not containing the substitutions V77I or A62V, and variants bearing only one of them. Evolutional relationships between all four HIV-1 variants, as well as potential impact of the gene pol polymorphism on HIV-1 replicative fitness and drug resistance development are discussed.

Amino Acid Substitution↗
PubMed1999

Human immunodeficiency virus type 1 genetic evolution in patients with prolonged suppression of plasma viremia.

Treatment of human immunodeficiency virus type 1 (HIV-1)-infected patients with combination drug regimens results in a reduction of plasma viral load to levels below the limit of detection. To investigate the genomic fluctuations in HIV-1 populations from long-term responders to antiviral therapies we analyzed the viral sequence evolution of env and pol genes from sequential peripheral blood mononuclear cell (PBMC) DNA samples of three infected patients. Analyses of sequences covering the V3 and flanking env regions obtained from blood samples at the beginning of the therapy and at 14 or 24 months from baseline revealed that HIV-1 quasispecies continue to evolve in the three patients following combination antiretroviral therapy. Minor drug-resistant mutant subpopulations were also searched for and found in one patient. Interestingly, no minor resistant subpopulations were found in the other two patients despite the fact that they showed evidence of ongoing viral replication. Finally, the genetic analysis of the env gene shows a reduction in PBMC env viral population diversity after long-term response to the therapy in all the patients analyzed.

Anti-HIV Agents↗
PubMed2005

Prevalence of, evolution of, and risk factors for fat atrophy and fat deposition in a cohort of HIV-infected men and women.

BACKGROUND: At present, no uniform definition of human immunodeficiency virus (HIV)-associated lipoatrophy exists. The risk factors for fat atrophy (FA) and central fat deposition (FD) are multifactorial. We assessed the evolution and predictors of FA and FD in HIV-infected men and women. METHODS: Participants (n = 452) were evaluated at baseline (starting in November 1998) and 1 year later. FA was defined as triceps skin-fold measurement less than the 10th percentile on the National Health and Nutrition Examination Survey for sex and age. FD was defined as a waist-to-hip ratio of > 0.95 for men and of > 0.85 for women. Predictors of the baseline prevalence of FA and FD and new cases of each syndrome after 1 year were determined. RESULTS: The baseline prevalences of FA, FD, and combined FA and FD were 35%, 44%, and 14%, respectively. Twenty-two percent of subjects had newly developed FA at 1 year, and 16% of subjects with FA at baseline did not have it at 1 year. Also, 23% of subjects had newly developed FD at 1 year, and 15% of those with FD at baseline did not have it at 1 year. The risk of developing new FA was increased among participants with low triceps skin-fold values (P < .001), smaller hips (P < .001), higher nadir HIV load (P = .006), abacavir use (P < .001), stavudine use (P < .001), and use of highly active antiretroviral therapy (P = .002). The risk of developing new FD was higher among women (P < .001) and among participants with greater body fat levels (P = .005) and higher triglyceride levels (P < .001), and it was lower among those with a high school education (P = .003) and higher triceps skin-fold values (P = .026). CONCLUSIONS: FA and FD are common in HIV-infected patients, but may change over time in the individual. FA and FD appear to be different syndromes, because risk factors for the development differ, and the prevalence of the combined syndrome differs from the prevalences of the 2 independent syndromes.

Adult↗
PubMed1994

Semiparametric models for longitudinal data with application to CD4 cell numbers in HIV seroconverters.

The paper describes a semiparametric model for longitudinal data which is illustrated by its application to data on the time evolution of CD4 cell numbers in HIV seroconverters. The essential ingredients of the model are a parametric linear model for covariate adjustment, a nonparametric estimation of a smooth time trend, serial correlation between measurements on an individual subject, and random measurement error. A back-fitting algorithm is used in conjunction with a cross-validation prescription to fit the model. A notable feature in the application is that the onset of HIV infection is associated with a sudden drop in CD4 cells followed by a longer-term slower decay. The model is also used to estimate an individual's curve by combining his data with the population curve. Shrinkage toward the population mean trajectory is controlled in a natural way by the estimated covariance structure of the data.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Coreceptor change appears after immune deficiency is established in children infected with different HIV-1 subtypes.

Change of HIV-1 coreceptor use has been connected to progression of disease in children infected with HIV-1, presumably subtype B. It has not been possible to discern whether the appearance of new viral phenotypes precedes disease development or comes as a consequence of it. We studied the evolution of coreceptor use in HIV-1 isolates from 24 vertically infected children. Their clinical, virological, and immunological status was recorded and the env V3 subtype was determined by DNA sequencing. Coreceptor use was tested on human cell lines, expressing CD4 together with CCR5, CXCR4, and other chemokine receptors. The children carried five different env subtypes (nine A, five B, four C, three D, and one G) and one circulating recombinant form, CRF01_AE (n = 2). Of the 143 isolates, 86 originated from peripheral blood mononuclear cells (PBMCs) and 57 originated from plasma, received at 90 time points. In 52 of 54 paired plasma and PBMC isolates the coreceptor use was concordant. All 74 isolates obtained at 41 time points during the first year of life used CCR5. A change from use of CCR5 to use of CXCR4 occurred in four children infected with subtype A, D, or CRF01_AE after they had reached 1.5 to 5.8 years of age. There was a significant association with decreased CD4+ cell levels and severity of disease but, interestingly, the coreceptor change appeared months or even years after the beginning of the immunological deterioration. Thus CXCR4-using virus may emerge as a possible consequence of immune deficiency. The results provide new insights into AIDS development in children.

Acquired Immunodeficiency Syndrome↗
PubMed2000

HIV-1 strains from a cohort of American subjects reveal the presence of a V2 region extension unique to slow progressors and non-progressors.

OBJECTIVES: To determine the molecular nature of HIV-1 quasispecies and their evolution, in vivo over time, in an American cohort of 22 homosexual men [four rapid progressors (RP), 15 slow progressors (SP) and three long-term non-progressors (LTNP)], infected with HIV-1 between 1982 and 1983, and to assess the possible role of the HIV-1 V2 region extension in HIV disease progression. DESIGN: Genetic and phylogenetic analyses of the V3 region and the nef gene clones over time from uncultured peripheral blood mononuclear cells (PBMC) of American patients with varying HIV disease progression rates. METHODS: Proviral DNA from longitudinally collected uncultured PBMC were subjected to PCR amplification in the nef gene and env V2 and V3 regions, followed by cloning, sequencing and phylogenetic analysis to establish evolutionary relationships between HIV-1 strains over time. RESULTS: Analysis of multiple viral clones showed nef gene deletions/insertions in 10 out of 15 SP, along with the coexistence of intact and defective nef gene lineages in the same individual over time, whereas these nefgene abnormalities were absent from HIV-1 strains from LTNP. Increasing quasispecies diversity in HIV-1 strains, over time, abrogation of a V3 region N-linked glycosylation site in > 60% of the clones, and, importantly, an extended V2 region were unique features of HIV-1 strains from SP and LTNP. CONCLUSIONS: The V2 region extension was unique to only SP and LTNP, and so may have a role in slow progression or non-progression of HIV disease. Increasing genetic diversity in HIV-1 strains in SP and LTNP correlated with the immunocompetent status of the host.

Amino Acid Sequence↗
PubMed1993

[Epidemiologic and clinical characteristics and clinical course of the HIV positive patient infected by heterosexual transmission].

We reviewed the features of patients with human immunodeficiency virus (HIV) infection, whose only way of acquisition was heterosexual contacts, analyzing differences with others risk groups. Epidemiological features (age, gender, family situation, socioeconomic status and sexual behavior), clinical manifestations immunological status, and evolution of 40 patients with HIV infection through heterosexual contact are studied, and compared with others risk groups. All were attended in our center from 1985 to October 1991; 15 were in stage IV. Along the study period, the proportion of heterosexual patients has steadily increased to represent 40% on total number of acquired immunodeficiency syndrome (AIDS) cases diagnosed in 1991. This study allow to establish two groups of patients depending on the gender. All men had had occasional sexual contacts with prostitutes, most had no stable partner, they mainly were between their fourth and sixth decade of life, and they were stable partners of seropositive patients or prostitutes, they had an averaged age significantly lower than men, and they were diagnosed in earlier stages. Two groups with different features can be established among the patients infected through heterosexual contacts. Men are adults, and acquired HIV infection through contacts with prostitute; they are diagnosed in late phases of the disease. On the contrary, women are younger, with no homogeneous patterns of behavior and they are diagnosed in earlier stages. Complications throughout the evaluation were similar in the heterosexual and in the other groups.

Adult↗
PubMed2001

Trends in causes of death in the Aquitaine cohort of HIV-infected patients, 1995-1997.

OBJECTIVE: To describe trends in the evolution of causes of death in a cohort of HIV-infected patients before and after the introduction of highly active antiretroviral treatment (HAART). METHODS: This descriptive study concerned all the patients of the Aquitaine cohort who died between 1995 and 1997. Causes of deaths were grouped into 13 'deaths due to an AIDS-defining underlying cause', and eight 'non AIDS' categories. Comparisons were performed between two comparable periods of 18 months, January 1995-June 1996 and July 1996-December 1997 to focus on changes introduced by the prescription of HAART in June 1996. RESULTS: Five hundred and thirty-two deaths were notified in 36 months for a total of 3687 patients. The comparison between causes of deaths before and after June 1996 showed a significant difference between the two periods with a decreasing proportion of AIDS causes of death, from 82.7% to 72.2% (p = 0.007). CONCLUSION: HAART treatment has reduced the number and percentage of deaths due to AIDS-related causes among persons who died with HIV infection in South-western France.

Antiretroviral Therapy, Highly Active↗
PubMed2005

Differential evolution of cell-associated virus in blood and genital tract of HIV-infected females undergoing HAART.

PBMC and vaginal cell (VC) viruses were studied from 5 HIV-infected females for the presence of drug-resistance and non-drug resistance associated mutations. A 1318-bp fragment of polymerase gene was amplified from PBMC and VC proviral DNA. Four of the 5 PBMC viruses exhibited drug resistance-associated mutations in reverse transcriptase and protease genes, whereas only 2 VC viruses contained drug resistance-associated mutations. However, all 5 females showed non-drug resistance-associated mutations both in PBMC and VC virus suggesting continuous evolution of the virus in these compartments. The emergence of drug resistance was slower in PBMC and VC viruses than that observed in the cell-free plasma (P) and vaginal secretion (VS) viruses. Phylogenetic analysis revealed that VC virus was closer to PBMC virus than either cell-free viruses (P and VS) suggesting comparable evolution among cell-associated viruses.

Adult↗
PubMed2001

Timing of the HIV-1 subtype C epidemic in Ethiopia based on early virus strains and subsequent virus diversification.

OBJECTIVE: To trace the introduction of HIV-1 subtype C into Ethiopia based on virus diversification during the epidemic. DESIGN: A set of 474 serum samples obtained in Ethiopia in 1982-1985 was tested for HIV-1. HIV-1 env gp120 V3 and gag or pol regions were sequenced and analysed together with sequences from later stages of the epidemic. RESULTS: None of 98 samples from 1982-1983, one of 193 samples from 1984, and one of 183 samples from 1985 were HIV-1 positive. Phylogenetic analysis of virus sequences from positive samples revealed that they belong to the Ethiopian C, and not the C', cluster. Analysis of 81 Ethiopian C V3 sequences from 1984-1997 revealed that the consensus sequence of the Ethiopian epidemic has been stable over time. Both the 1984 and 1985 V3 sequences, in contrast with three out of 27 (11%) of the 1988 and none out of 51 of the 1992-1997 sequences, had no synonymous substitutions compared to the reconstructed common ancestor of the Ethiopian C viruses. A highly significant correlation between sampling years of the V3 sequences and their synonymous distances to the common ancestor was demonstrated. CONCLUSIONS: The increasing genetic heterogeneity together with stable consensus sequence of the Ethiopian HIV-1 C population demonstrates that evolution of the virus population is characterized by an unbiased expansion around a stationary consensus. Based on the rate of synonymous diversification of HIV-1 strains within the Ethiopian population, we were able to estimate 1983 (95% confidence interval, 1980-1984) as the year of HIV-1 C introduction into Ethiopia.

Adult↗
PubMed1992

Towards a new predictor of AIDS progression through the quantitation of HIV-1 DNA copies by PCR in HIV-infected individuals.

The proviral copy (PVC) number in peripheral blood mononuclear cells (PBMCs) of human immunodeficiency virus (HIV)-infected individuals was measured by a quantitative polymerase chain reaction (PCR) assay to determine over time the relation between the viral load and the evolution towards the disease in HIV-infected people: 67 anti-HIV-1 positive individuals (60 stage II/III, 7 stage IV) were studied. The mean PVC number per 1.5 x 10(5) PBMCs in stage II/III individuals (14.4 +/- 14.2) and in stage IV individuals (32.2 +/- 22.9) was significantly different (P < 0.02). PVC number was inversely correlated to the CD4 lymphocyte count (P < 0.01). In the logistic regression, the PVC number was a better marker of evolution towards the disease than the CD4 lymphocyte count. The mean proportion of HIV-infected PBMCs in stage IV individuals and in stage II/III individuals was 1/4606 and 1/10714, respectively.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Disseminated, lethal prostate cancer during human immunodeficiency virus infection presenting with non-specific features. Open questions for urologists, oncologists, and infectious disease specialists.

INTRODUCTION: Prostate cancer is a very infrequent occurrence in persons aged 55 years or less, and it has been rarely reported in HIV-infected patients (10 overall cases so far); therefore, an increased incidence compared with the general population has not been established, although a younger age seems more frequent among population with HIV disease. CASE REPORT: We report a case of metastatic prostate cancer occurred in a 53-year-old HIV-infected man, admitted due to non-specific signs, and symptoms: impaired general conditions, fever, weight loss, fatigue, and exertional dyspnea. A remarkable anemia and an aortic systolic murmur were the prominent initial findings, while AIDS-related conditions were not suspected due to a sustained CD4+ count and a contained viremia, which never required antiretroviral therapy. Repeated red blood cell transfusions and an empiric, combined antimicrobial therapy were promptly carried out, under the suspicion of infectious endocarditis, but no appreciable improvement of clinical conditions was achieved. Subsequently, our patient complained not only of an increasingly severe pain at the root of his left thigh, together with overcoming dysuria and urgency, but also urinary tract infection that was rapidly ruled out. During the diagnostic workup for an HIV-associated fever of undetermined origin, a bone marrow biopsy disclosed a metastatic prostatic cancer, with elevated prostate specific antigen (PSA) and acid phosphate levels. An abdominal-pelvic ultrasonography and computerized tomographic scan allowed to detect a dyshomogeneous endopelvic expansive mass with extrinsic compression of the urinary bladder, and involvement of the last lumbar vertebra, large portions of pelvis, and the proximal epiphysis of the right femur. A skeleton scintigraphy pointed out multiple hypercaptation (areas of concentrated traces of radioactivity) areas with involvement of cranial, cervical, dorsal, lumbar, and sacral vertebrae, as well as the pelvis and upper portions of both femurs. Despite therapeutic attempts, our patient deceased after seven weeks due to an overwhelming disseminated intravascular coagulation (DIC). CONCLUSIONS: The non-specific clinical presentation of our case (mimicking other generalized or focal illnesses), and the final, lethal complication (DIC) pose striking problems related to the differential diagnosis during HIV disease, while the rapid evolution into an advanced, complicated, and widely metastatic disease with extensive bone marrow invasion which preceded the appearance of local signs-symptoms, and the lethal overwhelming DIC, deserves attention by specialists who care for HIV-infected subjects.

Biopsy↗
PubMed1996

[Colony-stimulating factors and HIV-related neoplasms].

OBJECTIVE: it is analyzed a group of patients with HIV related malignancy treated with myelosuppressive therapy with granulocyte colony stimulating factor (G-CSF) to study the efficacy of hematopoietic growth factors in these subjects. PATIENTS AND METHODS: it was studied the clinical and hematological evolution of 20 patients with HIV related malignancy treated with standard dose of chemotherapy and 5 micrograms/Kg/day of G-CSF starting 24 hours after the completion of chemotherapy administration. It was done an epidemiological study and was determined haemoglobin level, and the number of leukocytes, monocytes, neutrophils, lymphocytes, CD4+ lymphocytes and platelets before and after the chemotherapy administration. RESULTS: all of the patients were men with mean age of 37 +/- 2 years. The mean of lymphocyte CD4+ count was 17 x 10(6)/l and the tumor was the first aids manifestation in 50% of the subjects. The mean days of hospitalization was 14 +/- 3 days. As the result of the G-CSF administration, the leucocyte and the neutrophil count was statistically elevated (p < 0.01) and the platelets, the lymphocytes and the monocytes were not statistically elevated. Only one patient had a severe adverse reaction. Seventeen patients (85%) are dead, but only in 3 the cause was an infectious disease. CONCLUSION: the use of G-CSF prophylactically can elevate the neutrophil count and avoid the apparition of febrile neutropenia in patients with HIV related malignancies.

Adult↗