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PubMed1998

Salivary defence factor concentrations in relation to oral and general parameters in HIV positive patients.

The objective of this study was to determine the relationships between saliva protein concentrations, oral mucosal lesions, and systemic parameters in HIV positive patients and controls. Twenty-three control volunteers and 58 HIV-antibody positive patients received a complete oral examination and medical evaluation. In saliva and serum samples, protein concentrations were recorded by a nephelometric method. The systemic parameters assessed were CD4+ cell count, CDC stages and antiretroviral therapy. Oral mucosal lesion prevalence was higher among subjects with lower CD4+ counts. Considering the protein profile, correlations were recorded between saliva and serum protein concentration for IgA, haptoglobin and alpha1-proteinase inhibitor. Using assays of immune and non-immune saliva defence factors, we found that the evolution of cellular immuno-suppression during HIV infection was correlated to oral mucosal disease, showing a relationship between local and general systems.

Adult↗
PubMed2001

Intracellular and cell-free (infectious) HIV-1 in rectal mucosa.

The intestinal mucosa contains most of the total lymphocyte pool and plays an important role in viral transmission, but only slight attention has been given to the immunological and virological aspects of human immunodeficiency virus-1 (HIV-1) infection at this site. In this study, before initiating or changing antiretroviral therapy, paired blood samples and rectal biopsies (RB) were obtained from 26 consecutive HIV-infected subjects. HIV-1 isolation and biological characterization, DNA, and HIV-1 RNA titration were assessed, as were in vitro tumor necrosis factor-alpha (TNF-alpha) and interleukin-beta (IL-1beta) spontaneous production. The rate of HIV-1 isolation from peripheral blood mononuclear cells (PBMCs) and RBs was 75% and 58%, respectively. All RB-derived isolates were nonsyncytium inducing (NSI), independent of the phenotype of blood-derived isolates. Proviral DNA and detectable HIV-1 RNA levels were measured in 100% and 77% of RBs, respectively. A statistical correlation was observed between HIV-1 DNA and HIV-1 RNA levels in rectal mucosa (P = 0.0075), whereas no correlation was found between these levels in blood samples (P > 0.05). Antiretroviral treatment did not seem to influence HIV-1 detection in RBs. Higher levels of in vitro proinflammmatory cytokine production were found in the RBs of most infected patients when compared with healthy controls. Therefore, the rectal mucosa is an important HIV-1 reservoir that demonstrates a discordant viral evolution with respect to blood. Both the virus type and the mucosa pathway of immunoactive substances might have important implications for therapeutic decision-making and monitoring and could influence the bidirectional transmission of HIV-1 in mucosal surfaces.

Adult↗
PubMed2006

HIV-1 protease catalytic efficiency effects caused by random single amino acid substitutions.

Protein evolution has occurred by successive fixation of individual mutations. The probability of fixation depends on the fitness of the mutation, and the arising variant can be deleterious, neutral, or beneficial. Despite its relevance, only few studies have estimated the distribution of fitness effects caused by random single mutations on protein function. The human immunodeficiency virus type 1 (HIV-1) protease was chosen as a model protein to quantify protein's tolerability to random single mutations. After determining the enzymatic activity of 107 single random mutants, we found that 86% of single mutations were deleterious for the enzyme catalytic efficiency and 54% lethal. Only 2% of the mutations significantly increased the catalytic efficiency of the enzyme. These data demonstrate the vulnerability of HIV-1 protease to single random mutations. When a second random mutagenesis library was constructed from an HIV-1 protease carrying a highly deleterious single mutation (D30N), a higher proportion of mutations with neutral or beneficial effect were found, 26% and 9%, respectively. Importantly, antagonist epistasis was observed between deleterious mutations. In particular, the mutation N88D, lethal for the wild-type protease, restored the wild-type catalytic efficiency when combined with the highly deleterious mutation D30N. The low tolerability to single random substitutions shown here for the wild-type HIV-1 protease contrasts with its in vivo ability to generate an adaptive variation. Thus, the antagonist epistasis between deleterious or lethal mutations may be responsible for increasing the protein mutational robustness and evolvability.

Amino Acid Substitution↗
PubMed2003

Widespread adaptive evolution in the human immunodeficiency virus type 1 genome.

We investigated variable selective pressures among amino acid sites in HIV-1 genes. Selective pressure at the amino acid level was measured by using the nonsynonymous/synonymous substitution rate ratio (omega = dN/dS). To identify amino acid sites under positive selection with omega > 1, we applied maximum likelihood models that allow variable omega ratios among sites to analyze genomic sequences of 26 HIV-1 lineages including subtypes A, B, and C. Likelihood ratio tests detected sites under positive selection in each of the major genes in the genome: env, gag, pol, vif, and vpr. Positive selection was also detected in nef, tat, and vpu, although those genes are very small. The majority of positive selection sites is located in gp160. Positive selection was not detected if omega was estimated as an average across all sites, indicating the lack of power of the averaging approach. Candidate positive selection sites were mapped onto the available protein tertiary structures and immunogenic epitopes. We measured the physiochemical properties of amino acids and found that those at positive selection sites were more diverse than those at variable sites. Furthermore, amino acid residues at exposed positive selection sites were more physiochemically diverse than at buried positive selection sites. Our results demonstrate genomewide diversifying selection acting on the HIV-1.

Amino Acid Sequence↗
PubMed2001

Dendritic cells and HIV infection; immunity with viral transmission versus compromised cellular immunity?

In this commentary we propose that changes in immune activity in HIV 1 infection are secondary to two aspects of the function of dendritic antigen presenting cells (DC). Firstly DC initiate primary proliferative and cytotoxic T cell responses to HIV but disseminate virus to T cells. Secondly, balanced against the development of protective immunity is progressive inhibition of the capacity of DC to initiate primary T cell responses. With regard to viral transmission via DC, recent studies provide direct evidence that virus has evolved in vivo by passage between DC and T cells and that DC can act as a reservoir for virus. Thus, phylogenetic trees of the sequences of V3 loops of HIV viruses in individual blood samples show evolution via DC and T cells, and plasma virus can be related preferentially to that derived from DC. In functional studies, DC from asymptomatic individuals (lacking lymphadenopathy and without treatment) cause low levels of stimulation of allogeneic lymphocytes in the mixed leukocyte reaction (MLR). By contrast, lymphocytes from these patients respond to normal allogeneic DC. Our recent evidence shows that DC stimulate an MLR by transfer of alloantigens to DC of the responder type with subsequent syngeneic stimulation of T cells. The failure of T cell stimulation by DC in HIV infection therefore shows an incapacity of these DC to transfer antigenic signals to other DC but DC that acquire and present antigen directly to stimulate T cells are still functional. The latter situation provides encouragement that immunotherapy via DC may be feasible. However, DC from HIV infected individuals promote antibody production in B cells suggesting that the initial interaction of HIV with DC produces autocrine effects on DC populations that promote interaction with B cells rather than with T cells. Treatment that pushes the DC back towards stimulating T cells, despite increased viral dissemination, may promote protective immunity.

Animals↗
PubMed1999

[Pulmonary hypertension and HIV infection: report of a case].

Pulmonary hypertension associated to HIV infection has been reported in the literature with increased frequency. Apparently, this condition has a faster clinical evolution and a higher mortality than primary pulmonary hypertension. The pathogenic mechanisms of HIV associated pulmonary hypertension and the influence of its treatment on patient's evolution are not well known. We report a 32 years old homosexual male that developed a severe dyspnea in a period of 2 months. Echocardiogram demonstrated right ventricular dilatation and a systolic pulmonary artery pressure of 86 mm Hg. No other causes for pulmonary hypertension were found. Antiviral therapy and vasodilator treatment with a calcium channel blocker were started and the patient had an important subjective clinical improvement.

Adult↗
PubMed2004

Alternation of antiretroviral drug regimens for HIV infection. Efficacy, safety and tolerability at week 96 of the Swatch Study.

INTRODUCTION: Alternation of antiretroviral drug regimens has been proposed as a novel treatment strategy for HIV infection. However, some concerns persist regarding antiviral efficacy, adherence, toxicity and resistance evolution in the long term. METHODS: A total of 161 antiretroviral-naive HIV-1-infected patients were randomized to receive stavudine/didanosine/efavirenz (group A) or zidovudine/lamivudine/ nelfinavir (group B) or to alternate between the two regimens every 3 months starting with regimen A (group C). Antiviral efficacy, adherence, safety and tolerability were analysed every 12 weeks. RESULTS: After 96 weeks, time to virological failure was significantly delayed in the alternating regimen compared with the standards of care regimens. Virological suppression was seen in 46%, 48% and 58% of patients in groups A, B and C, respectively, in the intention-to-treat analysis and in 75%, 76% and 97% in the on-treatment analysis (A vs C: P=0.014; B vs C: P=0.016; A vs B: P=0.849). At the end of the study, 94% of patients in group A and 92% in groups B and C reported an adherence greater than 95%. Alternating therapy was associated with a similar impact on CD4+ counts in comparison with the standards of care regimens, as well as a lower mitochondrial DNA/nuclear DNA (mtDNA/nDNA) ratio decrease in the mitochondrial substudy performed on 37 patients. The frequency and intensity of adverse events in the alternating group decreased during subsequent cycles. DISCUSSION: Our results favour the hypothesis that proactive therapy switching may delay the accumulation of resistance mutations. Moreover, the alternating regimen was well tolerated and adherence remained comparably high in all treatment groups. The lower mtDNA/nDNA ratio decrease observed in this group may imply a lower impact on mitochondrial toxicity than in standard regimens.

Anti-HIV Agents↗
PubMed2000

Reduced immune activation and T cell apoptosis in human immunodeficiency virus type 2 compared with type 1: correlation of T cell apoptosis with beta2 microglobulin concentration and disease evolution.

This study analyzes the degree of immune activation and characterizes apoptosis in lymphocytes from healthy West African donors or patients infected with human immunodeficiency virus (HIV)-1 or -2. The lower decline of CD4 T cells in HIV-2- compared with HIV-1-infected donors is associated with lower levels of immune activation, evaluated by HLA-DR expression on lymphocytes and sera concentrations of IgG and beta2 microglobulin (beta2m). Ex vivo apoptosis was found in both infections in all lymphocyte subsets, including CD4 and CD8 T cells, as well as B cells, but was lower in HIV-2 than in HIV-1 infection. Interestingly, high correlations were found in HIV-2- and HIV-1-infected donors between the level of CD4 T cell apoptosis and beta2m concentration and progression of the disease. These observations support the hypothesis that long-term activation of the immune system, weaker in HIV-2 infection, significantly contributes to T cell deletion and disease evolution.

Adult↗
PubMed1998

[Characteristics of chronic hepatitis C in patients infected by human immunodeficiency virus].

OBJECTIVES: To know the characteristics of chronic hepatitis C in HIV-infected patients and whether there are differences compared with HIV-negative patients, in order to obtain orientative helpful data for the diagnostic-therapeutic decision making, a usually difficult issue in these patients. PATIENTS AND METHODS: Sixty patients with criteria of chronic hepatitis C virus (HCV) criteria were studied. Thirty-three of these patients were coinfected with HIV. The possible associations between the degree of histologic damage and several variables wee studied: age, estimated time of evolution of HCV infection, transaminases, gammaglobulins, GGT, and alcohol consumption. On the other hand, the possible differences regarding the histologic hepatic aggression were assessed. An attempt was made to know whether HIV could negatively influence the evolution of chronic hepatitis C. RESULTS: A direct relationship was observed between hepatic damage, HAI and levels of GOT, GPT, GGT (p < 0.005), and gammaglobulins (p < 0.01). The degree of hepatic fibrosis was directly correlated with the GGT level (mild fibrosis: 47 +/- 34 U/l; severe fibrosis: 86 +/- 60 U/l) (p < 0.05) and the estimated evolution time of infection (p < 0.05). Alcohol consumption was associated with the fibrosis degree (p < 0.01). The degree of histologic damage was similar in the HIV-positive group (HAI: 8.3 +/- 3.6) and HIV-negative patients (HAI: 7.2 +/- 2.8), although the degree of lobular involvement was higher in HIV-positive patients (p < 0.05). CONCLUSIONS: Patients with chronic hepatitis C and infected with HIV did not have a higher degree of hepatic damage than HIV-negative patients. GOT, GPT, and gamma globulin levels, as well as a longer evolution time of HCV infection were associated with a higher degree of hepatic histologic activity. Alcohol consumption seemed to be associated with a poorer course of the liver disease in these patients.

Adult↗
PubMedDate not supplied

Forecasting the future of HIV epidemics: the impact of antiretroviral therapies & imperfect vaccines.

Mathematical models can be used as health policy tools and predictive tools. Here we review how mathematical models have been used both to predict the consequences of specific epidemic control strategies and to design epidemic control strategies. We review how models have been used to evaluate the potential impact on HIV epidemics of (i) combination antiretroviral therapies (ART) and (ii) imperfect vaccines. In particular, we discuss how models have been used to predict the potential effect of ART on incidence rates, and to predict the evolution of an epidemic of drug-resistant HIV. We also discuss, in detail, how mathematical models have been used to evaluate the potential impact of prophylactic, live-attenuated and therapeutic HIV vaccines. We show how HIV vaccine models can be used to evaluate the epidemic-level impact of vaccine efficacy, waning in vaccine-induced immunity, vaccination coverage level, and changes (increases or decreases) in risky behavior. We also discuss how mathematical models can be used to determine the levels of cross-immunity that vaccines will need to attain if they are to be used to control HIV epidemics in countries where more than one subtype is being transmitted.

AIDS Vaccines↗
PubMed1992

[Candida laryngitis and HIV infection: description of 4 cases].

Candidiasic laryngitis is a very rare Candida spp infection of mucosa, appearing typically in immunosuppressed patients, mainly in patients with neoplasia, and, recently, in patients with Human Immunodeficiency Virus (VIH) infection. We present four cases of candidiasic laryngitis and HIV infection, as well as the clinical description and evolution of said cases after treatment with fluconazole. We review, as well, the cases published on the scientific literature. We maintain that in each HIV infected patient, with or without oral candidiasis, who shows dysphonia, candidiasic laryngitis should be ruled out.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Immune stimulation and HIV-1 viral replication.

A biphasic early and late viremia is characteristic of HIV-1 infection. The first increase in circulating viral burden occurs within weeks after infection, before a host immune response, and the second, later peak emerges during the inevitable HIV-1 devastation of immune function. Recently, intermittent bouts of viremia have also been identified in HIV-1-infected individuals and found to be associated with episodes of immune challenge. Vaccinations, exposure to antigens, and infections often induce reversible increases in circulating viral levels, dependent on CD4+ T lymphocyte numbers. However, even with marked losses in CD4+ T cell counts, opportunistic infections appear to trigger a viremic response. In searching for the source of this virus, macrophages in tissues co-infected with opportunistic pathogens have been identified as prodigious producers of HIV-1. Thus, the fountain from which HIV-1 emerges may shift from CD4+ T lymphocytes in early HIV-1 infection to tissue macrophages later in the natural evolution of the disease, as the CD4+ T cells are depleted. Defining the mechanisms of this transitional event in HIV-1 infection may facilitate regulation and therapeutic control of both opportunistic infections and HIV-1.

AIDS-Related Opportunistic Infections↗
PubMed2003

Phylogenetic relationships between Puerto Rico and continental USA HIV-1 pol sequences: a shared HIV-1 infection.

In order to investigate the existing notion that the human immunodeficiency virus type 1 (HIV-1) infection in Puerto Rico (PR) was imported from the continental United States of America (USA) we sequenced and analyzed 900 bases of the HIV-1 pol sequence from individuals in PR for comparison with pol sequences from the USA mainland. The sequences were derived by direct sequencing of reverse transcription-polymerase chain reaction products generated from plasma virus. The products were sequenced in both directions and the complementary strands were compared prior to analysis. These processed sequences and GenBank sequences from the continental USA were subjected to phylogenetic analyses. The PR and USA sequences did not form independent clusters, indicating a shared HIV-1 infection. This may be due to the continuous human traffic or, less likely, may indicate a similar evolution of a common source virus. Analysis of drug resistance mutations, fairly similar in frequency in the PR and USA sequences analyzed here, supports human traffic as a rationale for the common infection. This work indicates that an efficacious vaccine developed for use in the USA mainland will also be effective in prevention in PR and perhaps the other countries of the Caribbean region.

Drug Resistance, Viral↗
PubMed1997

Brain proton magnetic resonance spectroscopy in HIV-related encephalopathy: identification of evolving metabolic patterns in relation to dementia and therapy.

Proton MRS has proved useful in the early diagnosis of HIV-related encephalopathy. The modifications of brain metabolism in HIV-related encephalopathy can be classified according to different metabolic patterns (Vion-Dury J et al. CR Acad Sci 1994;317:833-840). The present study describes the relative occurrence of these patterns and evaluates their evolution under zidovudine treatment. We have examined 112 HIV patients--35 neuroasymptomatic patients and 77 patients with ADC (AIDS dementia complex)--with localized proton MRS, using the PRESS 135-msec sequence. We have found the same metabolic modifications in N-acetylaspartate and choline-containing compounds as described in the literature. In addition, 14% of HIV patients with normal MRI displayed abnormal MRS, whatever their neurological status. The MRS-added diagnostic value in neuroasymptomatic patients reaches 30 %. The occurrence of undifferentiated (modification of NAA/Cho ratio only) and Cho (mainly an increase in choline signal) patterns is not significantly different in neuroasymptomatic and ADC patients. The NAA pattern (mainly a significant loss of NAA) is more frequent in ADC patients. Only ADC patients display the double pattern (with a significant increase in choline signal and a significant loss of NAA). Quantitated cerebral atrophy (bifrontal ratio) is related to the occurrence of NAA loss (in NAA and double patterns). An MRS follow-up study of 11 HIV patients showed that the clinical outcome was favorable after a 1000-mg/day zidovudine treatment in patients displaying an NAA pattern whereas this treatment had no effect on the patients displaying the Cho pattern. Consequently, MRS appears to be of great interest in predicting responsiveness to antiretroviral drugs and detecting early any resistance to treatment.

AIDS Dementia Complex↗
PubMed1997

Clonal selection of HIV type 1 variants associated with resistance to foscarnet in vitro: confirmation by molecular evolutionary analysis.

Foscarnet (trisodium phosphonoformate, PFA) is an effective inhibitor of retroviral reverse transcriptase (RT) and is known to block the replication of human immunodeficiency virus type 1 (HIV-1). In this article we analyzed the evolutionary process in generating HIV-1 strains related to drug resistance, using PFA as a selective pressure. PFA inhibited virus replication and protected the virus-induced cell killing, but it did not completely eliminate HIV-1 during the course of 7 weeks of treatment. The nucleotide sequence of the 859-bp DNA fragment spanning the core region of the HIV-1 pol gene was determined for 51 clones obtained from genomic DNA of the HIV-1-infected cells at different time points during PFA treatment. The nucleotide sequence analysis documented the presence of a minor HIV-1 variant prior to the PFA treatment. Molecular evolutionary techniques were utilized to analyze how the minor HIV-1 clones became predominant during this evolutionary process under the selective pressure of PFA. A phylogenetic tree analysis divided these 51 HIV-1 clones into 3 groups. One of the groups consisted of the clones associated with the resistance to PFA. The clones belonging to this group became predominant over time during the course of PFA treatment. Thus, the acquisition of PFA resistance by HIV-1 was considered to be due to clonal selection. Furthermore, among the various amino acid substitutions observed, the substitution of arginine at position 172 by lysine (Arg172Lys) clearly distinguished this group from the others. Since the consistent amino acid substitution observed here has not been identified in the HIV-1 strains resistant to other RT inhibitors, PFA in combination with other RT inhibitors is considered to be a feasible candidate for a convergent combined chemotherapy against HIV-1 in the treatment of patients with AIDS and related conditions.

Amino Acid Sequence↗
PubMed1998

[Viremia levels of the chronic hepatitis c virus in HIV infected patients, clinical implications].

BACKGROUND: To know the clinical implications of the viremia level and its evolution in time of the hepatitis C virus (HCV) in patients with chronic hepatitis and infected with the Human Immunodeficiency Virus (HIV). PATIENTS AND METHODS: We have studied the viremia level of the HCV in a a 38 patients group with active chronic hepatitis and infected with the HIV, using a quantitative PCR technic (Amplicor HCV, Roche Diagnostics); we had histological data in 33 of these patients. In 20 patients was analyzed the evolution in time of the viremia level with two or three serialized measurements (20 and 10 patients respectively), throughout 7.5 and 14.8 months on the average. We have analyzed some aspects like the risky behaviors associated with transmission, the estimated time from the contagious, the degree of histological damage and the immunitary impairment. RESULTS: We have observed a tendency to present a higher viremia level (logarithmic expression) with longer evolution time from the infection (p = 0.08). The viral load had an inverse relation with the degree of histological fibrosis (Light fibrosis: 4.5 +/- 0.8 log vs Severe fibrosis: 3.7 +/- 0.8 log) (p < 0.01) and a direct relation with the Knodell histological activity index (HAI), only with those patients with a lower fibrosis degree (p < 0.01). There was no relation between the viremia level of the HCV and the degree of immunosuppression measured by the CD4 lymphocyte count, at least in those patients in which it was higher than 200/mm3. We have not observed relations between the viral load and the age or the transaminases level. The evolution in time of the viremia tended to rise from 3.7 +/- 1.3 to 4.5 +/- 0.9 log in 14.8 months on the average, although there were some cases with tendency to decrease. We have not observed relation between its increase/month and the degree of histological damage or the CD4 lymphocyte count. CONCLUSIONS: The viral load of the HCV in HIV-infected patients seems to have an inverse relation with the degree of liver fibrosis and direct relation with the histological activity when the fibrosis light and so it could indirectly inform us about the liver aggression. The degree of immunosuppression measured by the CD4 lymphocyte count, when these are > 200/mm3, doesn't seem to influence the viremia level of the HCV. The evolution of the viral load in time tend to rise although there could be some cases with intermittent or descending evolution, without these tendencies have any clinical implications.

HIV Infections↗
PubMed2006

The effects of early antiretroviral therapy and its discontinuation on the HIV-specific antibody response.

HIV-specific antibodies become detectable and continue to increase in frequency during primary infection. The effects of early antiretroviral treatment (ART) and its discontinuation on the evolution of this immune response have not been systematically analyzed. To investigate the associations between antibody titer, viral load, and ART, we used a less-sensitive enzyme-linked immunosorbant assay (LS-EIA) to measure changes in HIV-1-specific antibody levels in treated and untreated subjects undergoing primary infection. In this longitudinal study, antibody levels gradually increased in therapy-naive subjects, reaching a plateau approximately 40 weeks postinfection. In contrast, antibody titers remained low among subjects receiving ART. Subjects who discontinued ART exhibited a more rapid rise in antibody titers than therapy-naive subjects, suggesting the presence of an enhanced B cell response. These results demonstrate that early ART prevents the typical evolution of the HIV-1-specific antibody response and can alter the expected kinetics of this response in subjects discontinuing therapy.

Adult↗