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PubMed2006

Evolutionary dynamics of HIV-1 and the control of AIDS.

Human immunodeficiency viruses (HIV) have exhibited an extraordinary capacity for genetic change, exploring new evolutionary space after each transmission to a new host. This presents a great challenge to the prevention and management of HIV-1 infection. At the same time, the relentless diversification of HIV-1, developing as it does under the constraints imposed by the human immune system and other selective forces, contains within it information useful for understanding HIV epidemiology and pathogenesis. Comparing the sheer mutational potential of HIV with actual data representing viral lineages that can survive selection suggests that HIV does not have unlimited capacity for change. Rather, clinical and bioinformatic data suggest that, even in the most diverse gene of the most highly variable organism, natural selection places severe limits on the portion of amino acid sequence space that ensures viability. This suggests some optimism for those attempting to identify sets of antigens that can generate effective humoral and cellular immune responses against HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Anti-HIV-1/2 Antibody Detection by Dot-ELISA in Oral Fluid of HIV Positive/AIDS Patients and Voluntary Blood Donors.

Serology is the primary means for identifying patients with HIV infection and Acquired Immunodeficiency Syndrome (AIDS). Testing of serum by serologic methods has been extensively used since 1985, not only for clinical diagnosis but also for epidemiological surveillance and donor screening in blood banks. Fast serological diagnostic techniques are now being developed, using urine and oral fluid, as an alternative for anti-HIV antibody screening, and many parallel studies are proving its accuracy. The purpose of this study was to evaluate the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of the ImmunoComb II HIV 1&2 Saliva((R)) test from Orgenics (Dot-ELISA) compared to the routine exams (ELISA and Western Blot) of HIV positive/AIDS patients, undergoing antiretroviral treatment or not, in different stages of the disease's evolution, and compared to serologic testing of known HIV negative patients by the use of serum ELISA (blood donors). To accomplish this, patients of the Immunogenic Deficiencies Control Center (CCDI) and voluntary blood donors of the Blood Bank Center of the Medical School of S&atilde:o Paulo/Federal University of São Paulo (EPM-UN I FESP) were evaluated. Sensitivity of Dot-ELISA in oral fluid was 100%, specificity 97.08%, PPV 96.66% and NPV 100%. The method used in this case study was shown to be highly sensitive and specific, being useful particularly in epidemiological surveillance and screening.

Journal Article↗
PubMed2000

Cervical squamous intraepithelial lesions in HIV-infected women: prevalence, incidence and regression. European Study Group on Natural History of HIV Infection in Women.

OBJECTIVES: To assess the impact of HIV-related immunodeficiency and antiretroviral treatment on the occurrence and evolution of abnormal Papanicolaou tests. STUDY DESIGN: Cohort of 485 HIV-infected women with a known date of infection, enrolled during May 1993-April 1998 in 23 centres (gynaecology, infectious disease or STD clinics, or drug treatment centres) in 12 European countries; in 21 centres, follow-up was performed every 6 months (median follow-up: 2 years). METHODS: Human papillomavirus (HPV) was detected at inclusion by Southern blot and PCR. The prevalence of squamous intraepithelial lesions (SIL), the incidence of SIL and regression from low-grade SIL were studied according to CD4 count after controlling for HPV detection results. RESULTS: Compared with women with CD4 cell counts > 500 x 10(6)/l, women with CD4 cell counts < 200 x 10(6)/l had a twofold increase in both prevalence and incidence of SIL and in non-regression from untreated low-grade SIL; in addition, these women had a lower response rate to treatment of high-grade cervical intraepithelial neoplasia. The increase in SIL incidence associated with a low CD4 cell count was significant in women not receiving antiretroviral treatment (relative risk, CD4 cell count 200-499 x 10(6)/l, 1.9; CD4 cell count < 200 x 10(6)/l, 2.9; CD4 cell count > 500 x 10(6)/l, reference), whereas it was less marked and not statistically significant in treated women. CONCLUSIONS: Severe HIV-related immunodeficiency strongly increases the risk of occurrence of SIL; antiretroviral treatment may reduce this risk, probably by restoring or at least preserving immune function.

Adolescent↗
PubMed2004

Mapping sites of positive selection and amino acid diversification in the HIV genome: an alternative approach to vaccine design?

A safe and effective HIV-1 vaccine is urgently needed to control the worldwide AIDS epidemic. Traditional methods of vaccine development have been frustratingly slow, and it is becoming increasingly apparent that radical new approaches may be required. Computational and mathematical approaches, combined with evolutionary reasoning, may provide new insights for the design of an efficacious AIDS vaccine. Here, we used codon-based substitution models and maximum-likelihood (ML) methods to identify positively selected sites that are likely to be involved in the immune control of HIV-1. Analysis of subtypes B and C revealed widespread adaptive evolution. Positively selected amino acids were detected in all nine HIV-1 proteins, including Env. Of particular interest was the high level of positive selection within the C-terminal regions of the immediate-early regulatory proteins, Tat and Rev. Many of the amino acid replacements were associated with the emergence of novel (or alternative) myristylation and casein kinase II (CKII) phosphorylation sites. The impact of these changes on the conformation and antigenicity of Tat and Rev remains to be established. In rhesus macaques, a single CTL-associated amino substitution in Tat has been linked to escape from acute SIV infection. Understanding the relationship between host-driven positive selection and antigenic variation may lead to the development of novel vaccine strategies that preempt the escape process.

Amino Acid Sequence↗
PubMed1999

Dynamics of immune escape in HIV infection.

The dynamics between pathogens and the immune system involve complicated interactions of many different components and this makes the use of mathematical models necessary to provide a correct interpretation of empirical results as well as to generate new insights and hypotheses. We demonstrate this approach by discussing mathematical models describing the dynamics between HIV and the immune response. Specifically, we show that viral evolution towards increased antigenic diversity may be the driving force underlying HIV disease progression and the reason for the eventual breakdown of the immune system upon development of AIDS. Such insights have important implications for designing efficient treatment regimes for HIV-infected patients.

Acquired Immunodeficiency Syndrome↗
PubMed1994

[Study of 164 episodes of infectious endocarditis in drug addicts: comparison of HIV positive and negative patients].

OBJECTIVE: Intravenous drug-addicts (IVDA) are the most important risk group for acquiring HIV and developing infective endocarditis (IE) in Spain. The clinical and evolutive features of a large series of IE in HIV-infected IVDA are reported and compared with those observed in a smaller group of patients without HIV infection. METHODS: A retrospective analysis was made of 164 episodes of IE from 136 patients diagnosed in a Service of Infectious Diseases in Madrid (1986-1992). IE was defined according to the modified Von Reyn criteria and only the probable and definite IE episodes were evaluated. RESULTS: A total of 143 IE episodes occurred in 117 IVDA infected with HIV (group A) and 21 episodes in 19 HIV-negative patients (group B). Most of seropositive patients were asymptomatic carriers of HIV (54%) and only 22% had AIDS. The IE onset was acute for 97% patients in group A and 81% in group B, with fever and respiratory symptoms as main complaints. Chest X-ray was normal in 19% of cases in group A and in 28% in group B. Septic embolisms were observed in 56% and 41% of patients in group A and B, respectively. The vegetation originated mainly on the tricuspid valve and Staphylococcus aureus was recovered from most blood-cultures. The mortality rate was similar in both groups, 6% and 5% in groups A and B, respectively. CONCLUSIONS: Most IVDA with IE were HIV-positive patients in this series. IE is usually reported in the early stages of HIV infection and apparently its presence has no influence on the clinical course of IE.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Factors related to the chronicity and evolution of hepatitis C infection in patients co-infected by the human immunodeficiency virus.

OBJECTIVES: This work analyses the influence of immune status, serum human immunodeficiency virus (HIV) load and hepatitis C virus (HCV) genotypes on the probability of resolution of HCV infection in HIV-co-infected patients, as well as the evolution of HCV viremia after antiretroviral therapy. PATIENTS AND METHODS: Forty-five patients with anti-HIV and anti-HCV antibodies were classified into two groups as a function of the positivity or persistent negativity of HCV RNA detection (active or recovered HCV infection, respectively). They were treated with highly active antiretroviral therapy (HAART). Serum HCV RNA was quantified by the reverse transcription-polymerase chain reaction. HCV genotypes were detected by line probe assay or by detection of type-specific antibodies. RESULTS: HCV RNA was detectable in 30 (66.6%) out of 45 HIV-infected patients. CD4+ T-cell counts, HIV viremia, or HCV genotypes were similar in patients with active or recovered HCV infection. Patients with active HCV infection had a non-significant decrease of HCV viremia during a follow-up of 12 months (from 6.15 +/- 6.32 to 5.96 +/- 6.05 log copies/mL). This was not influenced by baseline HCV or HIV viral load, HCV genotype, or CD4+ T-cell count. The non-significant decrease was present in patients with or without an immunological response to HAART. CONCLUSION: HCV genotypes, immune status, or serum HIV load did not influence the resolution or chronicity of HCV infection in HIV-co-infected individuals. A non-significant decrease of HCV viremia in these patients treated with combinations including antiproteases could be expected.

Adult↗
PubMed2000

[Influence of highly active antiretroviral therapy on the evolution of AIDS-associated Kaposi's sarcoma].

BACKGROUND: To evaluate the highly active antiretroviral therapy (HAART) in the Kaposi's sarcoma evolution. PATIENTS AND METHOD: Retrospective analysis of a cohort of 126 HIV infected patients suffering from Kaposi's sarcoma with or without HAART. Clinical evolution, immunological status (CD4+ cell count) and response to therapy (HIV-RNA plasma viral load and human herpes-8 virus determination). RESULTS: All patients without HAART died and the cumulate probability survival (SD) among those who received HAART was 2.078 (74) days. The CD4+ count at baseline in the HAART group was 130 (125) * 106/l and the HIV-RNA viral load was 196,818 (244,195) copies/ml while at the moment of the clinical response was 235 (209) * 106/l CD4 + and 2,629 (6.444) copies/ml, respectively. CONCLUSION: HAART prolongs survival in HIV patients suffering from Kaposi's sarcoma. There is a clear relationship among clinical response, HAART and immunological recovery.

Adult↗
PubMed1998

Molecular inhibition of HIV type 1 by HIV type 2: effectiveness in peripheral blood mononuclear cells.

HIV-2 downregulates HIV-1 in human primary peripheral blood mononuclear cells (PBMCs). Although the effect of HIV-2 on HIV-1 in human CD4+ T cell lines was previously reported, the present observations with PBMCs are a necessary demonstration before considering animal model and clinical studies. Notably, the downregulation was observed with at least three phenotypically different HIV-1 proviruses and three different HIV-2 proviruses and was independent of the mode of introduction of the proviruses. HIV-2 inhibited both the production of extracellular HIV-1 p24 antigen and intracellular viral RNA, suggesting the involvement of transcriptional downmodulation. Some of the defective HIV-2 proviruses also inhibited HIV-1. In some cases, these defects were transcomplemented by the corresponding HIV-1 gene products, emphasizing cross-regulation between the two viruses. The phenotype of one of the mutant HIV-2 proviruses suggested that the posttranscriptional effects may also occur. In addition to the possible HIV-2 suppression of HIV-1 in vivo by cross-protective immune mechanisms, intracellular inhibition, noted here, may be another line of defense. We have proposed that the inhibition may be the result of competition between HIV-1 and HIV-2 for cellular factors, possibly involving the long terminal repeats (LTRs). For safety reasons, it may be advantageous to use subunits of HIV-2 for vaccines and gene therapy. HIV-2, specifically noncytopathic HIV-2, could be viewed as an attenuated HIV-1 vaccination model. HIV-2-derived gene transfer vectors may not only be inhibitory themselves but also allow for the insertion of additional protective genes to aim at multiple targets in the HIV-1 life cycle, thus curtailing the evolution of escape mutants.

Antibiosis↗
PubMed1999

Structural similarities between influenza virus matrix protein M1 and human immunodeficiency virus matrix and capsid proteins: an evolutionary link between negative-stranded RNA viruses and retroviruses.

The evolutionary relationship of retroviruses to the negative-stranded RNA virus superfamily was examined by comparing protein structures. Since protein structures are more conserved over time than primary protein sequences, three-dimensional structural comparisons permit the identification of evolutionary relationships that were previously undetected. Human immunodeficiency virus (HIV) and influenza virus were used as representatives of the virus groups, and proteins with similar functions were compared. Since M1 of influenza virus has membrane- and RNA nucleocapsid-binding activities that are functionally analogous to those of the HIV matrix and capsid proteins, the structural similarities between these proteins were determined. Sequence alignments were based on superimposition of the three-dimensional structures. Helices 2, 2', 3 and 4 of the HIV matrix protein aligned and superimposed with the four-helix bundle of the membrane-binding N domain of M1 with a root mean square (RMS) of 3.48 A. Helices A, B and C of the HIV N-terminal capsid protein aligned and superimposed with three helices of the four-helix bundle of the RNA-binding N domain of M1 with an RMS of 2.63 A. The HIV Gag protein and influenza virus matrix protein may have evolved from a common ancestor protein. The similarities between influenza virus M1 and HIV matrix and capsid proteins may indicate an evolutionary link between retroviruses and negative-sense RNA viruses.

Amino Acid Sequence↗
PubMedDate not supplied

[Clinical aspects and complete blood counts in children exposed to HIV-1: comparison between infected patients and seroreverters]

OBJECTIVE: To analyze the evolution of clinical and hematological aspects of children exposed to the vertical transmission of HIV-1, comparing infected patients with uninfected ones or seroreverters. METHODS: Prospective, descriptive, longitudinal study. We analyzed 79 children born from HIV-1 infected mothers, under clinical follow up from March, 1996 until November, 1997, at the Immunodeficiency division of the Hospital de Clínicas da Unicamp (State University Hospital of Campinas). RESULTS: Failure to thrive was observed in both groups, but was greater among seroreverters. Among the infected children, 23 mothers did not use AZT during pregnancy, 16 of them (61.5%) had been breastfed, four were classified into clinical category N, seven into A and fifteen into B. Clinical manifestations in patients younger than one year were seen in 18 infected children (69.2%). Anemia was observed in 73.1% of the infected group and in 41.5% of the seroreverters (P<0.008). The comparison between the groups showed that the most common hematologic alterations in the infected children was microcytosis and hypochromia (P<0.05), lymphopenia between 15 and 18 months (P<0.05), monocytosis between 9 and 12 months (P<0.05) and a tendency towards high ferritin levels, with no statistical significance. CONCLUSIONS: Microcytic and hypochromic anemia were observed in both groups: iron deficiency in the uninfected children, and chronic disease anemia in the infected ones. The infected children presented with monocytosis and lymphopenia at an earlier stage.

Journal Article↗
PubMedDate not supplied

[Bone marrow biopsy in HIV-positive patients with thrombocytopenia. Light and electron microscopy].

Isolated thrombocytopenia (platelets less than 100,000 mmc) may be the first clinical symptom in HIV positive patients or occur in all the evolutive phases up to overt AIDS. In this paper bone marrow lesions are evaluated at light and electron microscopy in 32 HIV positive patients with isolated thrombocytopenia (group II and III CDC 1986). At light microscopy an increase in megakaryocytes with small dysplastic changes, plasmacytosis and hypereosinophilia were the bone marrow lesions detected. Electron microscoy revealed megakaryocytes with focal nuclear alterations (hypolobation and dilatation of the perinuclear cisternae) and abnormalities in the maturation of platelets associated with cytoplasmic micro-macrovacuolation, absence of viral particles or of virus correlated structures. About 9% of HIV positive patients presented with isolated thrombocytopenia as a first clinical symptom: thrombocytopenia is not believed to have unfavourable prognostic significance in the evolution to overt AIDS.

Biopsy↗
PubMed2000

The Evolution of Candida Species and Fluconazole Susceptibility among Oral and Vaginal Isolates Recovered from Human Immunodeficiency Virus (HIV)-Seropositive and At-Risk HIV-Seronegative Women.

Antifungal agents can effectively treat mucosal candidiasis; however, their use can lead to colonization with less susceptible species and to resistance among normally susceptible strains. Oral and vaginal Candida isolates obtained at 3 points over 2 years from human immunodeficiency virus (HIV)-seropositive and at-risk HIV-seronegative women were identified by species and were evaluated for in vitro fluconazole susceptibility. Prevalence of non-C. albicans strains increased over time, and these strains were more likely among women reporting current antifungal use. Among C. albicans isolates, resistance was rare, with no evidence for progressive reduction in susceptibility over time. Among non-C. albicans isolates, reduced susceptibility occurred frequently and increased with time. HIV-seropositive women were more likely to have non-C. albicans isolates with reduced susceptibility as were women reporting current antifungal use. This evolution and selection of mucosa-colonizing Candida species with reduced susceptibility could play a critical early role in the development of antifungal resistance among C. albicans isolates responsible for refractory candidiasis.

Journal Article↗
PubMed2004

Quantitative real-time PCR on Lightcycler for the detection of human immunodeficiency virus type 2 (HIV-2).

Similar to HIV-1, the viral load in HIV-2 is a marker of the evolution of infection and the success of therapy. No approved or commercially distributed assay exists to determine the plasma viral load of HIV-2. We therefore developed a quantitative real-time PCR to determine the plasma RNA viral load of HIV-2, based on the reference strains ROD and EHO, which represent subtypes A and B of HIV-2, respectively. After testing several pairs of primers, a set was chosen that recognised the 5'-LTR region of a subtypes A and B consensus sequence. The quantification of the PCR reaction was done using SYBR-Green I as the fluorescent dye in a Lightcycler system and relying on an external standard curve. The method was then optimised with reference strains, an validated further using patient samples and an inter-laboratory comparison. Good specificity was obtained for both subtypes of HIV-2, and a linear range between 10 and 10(6) copies of viral RNA. The limit of quantitation was 250 copies per millilitre of plasma. The coefficient of variation ranged from 0.7 to 5.6%, depending on the concentration of the target sequences.

Base Sequence↗
PubMed2001

Alterations in T cell phenotype and human immunodeficiency virus type 1-specific cytotoxicity after potent antiretroviral therapy.

Cytotoxic T lymphocytes (CTLs) are an important defense against human immunodeficiency virus (HIV) type 1 but ultimately fail to control infection. To determine whether more efficient sustained immunity is induced by suppressing replication, the evolution of T cell phenotypes and HIV-specific CD8+ lymphocytes was prospectively investigated in 41 patients initiating combination therapy. Suppression of viremia to <200 copies/mL was associated with increases in naive cells (CD45RA+62L+) and declines in activated T cells (CD95+ cell counts and CD38+ HLA-DR+). HIV-specific tetramer-staining CD8+ T cells were detected in 6 of 10 HLA-A*0201-positive persons, which declined in 5 with treatment. CTL precursor frequencies were markedly consistent before and after treatment. Eight (72%) of 11 recognized > or =1 immunodominant epitope, representing either a new or an increased CTL response after treatment. Thus, activated CD8+ T cells, including those recognizing immunodominant epitopes, decline with combination therapy. However, the overall level of antigen-specific cells that are capable of differentiating into effectors remains stable, and the recognition of new epitopes may occur.

Anti-HIV Agents↗
PubMed2002

[Swedish guidelines for antiretroviral treatment of HIV. Good compliance is crucial for a good result].

Antiretroviral combination therapy has markedly decreased the mortality and morbidity in HIV-disease during the last years. An increasing number of new antiretroviral agents has been introduced and there has been a rapid evolution of new information regarding treatment of HIV. Physicians and patients have to deal with medical associated side-effects, problems with adherence, and viral resistance. Recently a national expert group has prepared guidelines for antiretroviral treatment in HIV-infected adults and adolescents which are summarized in this report. The Swedish guidelines recommend initiation of treatment when the CD4-cell-count is in the range between 200 and 350 x 10(6)/l in asymptomatic HIV-infection. They emphasize that the patient should be carefully prepared before treatment initiation to avoid adherence difficulties which regularly leads to viral failure. As first line is suggested a therapy with 2 NRTIs (nucleoside reverse transcriptase inhibitors) in combination with either a NNRTI (non-nucleoside RTI) or a protease inhibitor. When protease inhibitors are chosen, ritonavir-boosted combinations are most often to prefer. The virological treatment goal is to achieve a decrease in HIV-RNA with 1.5-2 log after 4 weeks and to below 50 copies/ml after 3-4 months of therapy. If a therapy fails, the causes should be carefully investigated for adherence difficulties, medicine interactions, and viral resistance. Treatment change should be guided by a thorough drug treatment history and the results of resistance testing. Treatment of HIV is complex and it is recommended that it should be conducted by an expert in the field.

Adolescent↗
PubMed2001

Human immunodeficiency virus type 1 clade A and D neurotropism: molecular evolution, recombination, and coreceptor use.

Human immunodeficiency virus type 1 (HIV-1) non-B clade viral infections of the brain have not been studied to date. Among nine AIDS patients from Nairobi, Kenya, infected with HIV-1 A (N = 5) or D (N = 4) clade strains, brain-derived HIV-1 env sequences displayed greater evolutionary distance than B clade brain-derived viruses (P < 0.001). Similarly, molecular diversity between matched brain and spleen env clones was clade-dependent and concentrated in the hypervariable V4 region (P < 0.001), with phylogenetic clustering of sequences derived from the same organ. Brain-derived A and D clade sequences displayed significantly lower ratios of nonsynonymous/synonymous substitution rates (d(N)/d(S)) compared to matched spleen-derived clones and brain-derived B clade viruses. Interclade recombination events were infrequently observed among the present env sequences. A chimeric virus containing the C2V3 region from an A clade brain-derived sequence preferentially used CD4 and CCR5 for infection. These findings demonstrate that differences in molecular diversity in brain-derived sequences were dependent on the individual clade and domain within the env gene, but both B and non-B clade brain-derived viruses exhibit a preference for CCR5 as a coreceptor.

AIDS Dementia Complex↗