HIV infects white blood cells in the body's immune system called T-helper cells ( or CD4 cells). The virus attaches itself to the T-helper cell;. For HIV, this relationship is particularly complex and intimate because HIV targets , infects, and incapacitates cells central to antimicrobial defenses. Thus, host. People living with HIV who have a CD4 cell count below are at high risk of But these factors don't seem to make any difference to how well your immune.
Detailed information about the date of HIV diagnosis, HIV status, HIV treatment, previous episodes of venous and arterial thrombosis, exposure to risk factors for thrombosis, and anticoagulant treatment was retrospectively collected by physicians at the outpatient clinic via a questionnaire and review of medical records. In women, the use of oral contraceptives and their obstetric histories were also documented, considering that oral contraceptives and pregnancy are risk factors for venous thrombosis and may be associated with thrombophilic abnormalities.
Clinical data were collected before laboratory testing to avoid bias in assessing clinical outcome events. To determine whether HIV status was correlated with thrombophilic abnormalities, we simultaneously collected blood samples for measurements of CD4 cell counts and HIV RNA, and for thrombophilia testing.
Thrombophilia tests included those for the following: We also measured anticardiolipin antibodies and measured C-reactive protein CRP 1 to assess the effects of acute-phase inflammatory reactions. We repeated all tests with a second blood sample collected after an interval of at least 3 months median, 3 months; range, 3—12 months to confirm the concentrations of proteins and CD4 cell counts obtained in the first set of measurements.
We considered a factor VIII: Reference intervals were determined from measurements in healthy volunteers who had no personal or family history of venous thrombosis, were not pregnant, and had not used oral contraceptives during the preceding 3 months.
We used 3 different phospholipid-dependent coagulation tests to screen for lupus anticoagulant: Tests that produced abnormal results were repeated with a 1: If the test result remained abnormal, we confirmed phospholipid dependence with a phospholipid-neutralization test. We used Gradipore reagents LA-screen and LA-confirm for the dilute Russell viper venom time test, Actin FSL Dade Behring to measure the activated partial thromboplastin time, and Thromboplastin IS Dade Behring in 2 dilutions 1 part reagent plus 49 parts diluent and 1 part reagent plus parts diluent to measure tissue thromboplastin inhibition.
Blood samples were taken from patients undergoing long-term anticoagulant treatment with vitamin K antagonists after treatment had been interrupted; nadroparin was administered subcutaneously in the meantime. Venous thrombosis was considered established if deep vein thrombosis was confirmed by compression ultrasound or venography, and pulmonary embolism was confirmed by ventilation and perfusion lung scanning, spiral computed tomography scanning, or pulmonary angiography.
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Coronary and peripheral arterial disease had to be symptomatic and angiographically proven, and myocardial infarction was diagnosed according to clinical, enzymatic, and electrocardiographic criteria. Ischemic stroke was defined as the onset of rapidly developing symptoms and signs of loss of cerebral function that lasted at least 24 h and had an apparent vascular cause, as demonstrated by computed tomography scanning or magnetic resonance imaging.
If a cerebral event completely resolved within 24 h without the demonstration of cerebral lesions at scanning, it was classified as a transient ischemic attack. Risk factors for atherosclerosis included known diabetes mellitus, hyperlipidemia, hypertension, and active smoking. Differences between groups were evaluated with the Student t-test or the Mann—Whitney U-test, depending on whether the data were normally distributed, for continuous data and with the Fisher exact test for categorical data.
Medians and interquartile ranges for protein concentrations were calculated by group. The interquartile range included the 25th and 75th percentile values, which represented the variation in the data without undue emphasis on extreme values, which can occur when the data are highly skewed.
In box plots, whiskers extended to 1. Annual incidences of venous and arterial thrombosis were calculated by dividing the number of events by the number of observation years. Observation time was defined as the period from the age of HIV diagnosis until the first thrombotic episode or until the end of the observation period. We ignored the occurrence of arterial thrombosis when calculating the annual incidence of venous thrombosis, and vice versa.
Statistical analyses were performed with SAS software version 9. The follicular dendritic cell is related to the other dendritic cells discussed above only in terms of its dendritic morphology; the origin of this cell is not well understood. Natural Killer Cells Natural killer cells are large granular lymphocytes with cytolytic capabilities.
Lytic activity is greatest against tumor cells and virus-infected cells that have diminished expression of major histocompatibility complex MHC class I antigens. Because MHC class I expression is required for peptide presentation to T-cell receptors, natural killer cells comprise a cellular component of the innate host defense system with activity against cells that may escape adaptive host defenses because of failure of MHC class I expression.
Lysis by natural killer cells also can be directed against cells recognized by host antibodies through binding of immunoglobulin to fragment constant receptors on the natural killer cell. Thus, natural killer cells contribute to both innate and adaptive immune host defenses. Early studies have demonstrated impairments in natural killer cell activity in persons with AIDS and HIV infection, 90,91 and functional impairments of these cells have been attributed to a failure of the postbinding lytic event.
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The antigen-binding sites of T-cell receptors of these lymphocytes are comprised of gamma and delta heterodimers as contrasted with the alpha and beta chains of most T lymphocytes. These T cells can recognize microbial antigens directly without processing and presentation on host human leukocyte antigen HLA molecules. Although the genes encoding these receptor chains also undergo rearrangement, the diversity of these receptors is more restricted than that of T cells with alpha-beta chain receptors.
The cytokinetic and cytolytic functions of cytokinetic are often perturbed, whereas proliferation responses are variably affected in HIV infection. In HIV infection, T cells are also more extensively primed to enter the replication phases of the cell cycle.
This propensity is evidenced by an increased frequency both of cells expressing the nuclear antigen Ki67and of cells exhibiting increased DNA content and 5-bromo-2'-deoxyuridine BrdU incorporation, a reflection of spontaneous progression to the synthesis phase of the cell cycle. In this regard, it should be noted that expression of CD38 may limit the susceptibility of cells to productive HIV replication.
A natural host of SIV, the sooty mangabey permits high-level SIV replication but manifests limited evidence of disease. Although antibody levels are high, neutralizing antibody responses against HIV are not strong, and are followed in rapid sequence by the emergence of viruses resistant to the neutralizing activity of these antibodies.
First, binding of these cells to viral peptides presented by HLAs on the surface of infected cells can trigger a cytolytic response resulting in the destruction of the target cell that is producing virus. This function is largely mediated through the liberation of perforin, which generates a hole in the target cell through which granzymes can enter and destroy the cell before it can produce large numbers of progeny virions.
These include interferon-gamma, which can, via a complex cascade of receptor-mediated binding and activation, render nearby cells relatively resistant to productive viral infection.
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CD8-mediated suppression of HIV may be related to disease outcome since this cellular response is augmented by supernatants prepared from cells from long-term nonprogressors persons with stable CD4 cell counts and sustained low levels of HIV replication in the absence of antiretroviral treatment.
The emergence of viral escape mutations that render virus-infected cells undetectable by host cytotoxic T-lymphocyte assay may help to explain this observation. Whether this is a consequence of sustained exposure to high levels of viral antigen or is related to the lack of CD4 help or direct exposure to toxic viral products and the effects of chronic inflammation remains to be determined.
For example, the persistence of HIV-specific interferon-gamma responses even in persons with advanced disease suggests that the ability of HIV-specific CD4 cells to expand may be selectively impaired while other HIV-specific immune functions such as interferon production may be preserved.
Conceivably, HIV-reactive cells potentially capable of proliferation are selectively targeted and destroyed, or their replication capacity is impaired in the setting of viral activity. Sequestration in Lymphoid Organs Much of the immune damage that is seen in HIV infection probably results from viral replication and its consequences in lymphoid tissue. In early stages of HIV infection, generalized lymphadenopathy is commonly recognized.
These inflammatory lymph nodes are also characterized by heightened expression of molecules such as intercellular adhesion molecules and vascular cell adhesion molecules. As disease advances, there is progressive destruction of lymphoid architecture and ultimately lymphoid tissues are, as is the circulation, depleted of lymphocytes. Heightened Destruction As noted above, the immune deficiency of HIV infection is characterized by immune activation, with an increased frequency of circulating lymphocytes that have been activated to enter the cell cycle.
Interestingly, this heightened entry to the cell cycle is often aborted at least after in vitro cultivation as the activated cells tend to die by mechanisms of programmed cell death and also, in some studies, by necrotic cell death. Therefore, cellular activation and cell death in HIV infection appear to be entirely determined neither by direct cytopathic effects of the virus nor by immune activation driven by specific peptide recognition.
Alternative explanations, such as dysregulated activation of T cells though mechanisms other than T-cell receptor activation, are yet unproven. Diminished Production Whereas HIV infection clearly is characterized by heightened cellular destruction and turnover, there is also evidence that immune cellular production may be impaired, at least at certain stages of infection.
With advancing stages of HIV infection, there is evidence of cellular hypoproductivity in bone marrow. Pancytopenia is not uncommon in advanced AIDS and bone marrow biopsies often reveal evidence of hypoplasia.
Nonetheless, with administration of suppressive antiretroviral therapies, peripheral blood cytopenias characteristically improve. The population of antigen-naive T lymphocytes that emerges contains a diverse distribution of T-cell receptors with specificities capable of recognizing a broad array of peptide antigens bound to the host's own cell-surface HLAs.
Although thymic activity is greatest during development and childhood, there is evidence of thymic function in adulthood as well. Thymus size is often preserved in HIV-infected adults particularly in older personsand there is indication that thymic output often is maintained in infected persons. Studies of IL-7 administration in SIV-infected macaques and in humans are ongoing and may help to elucidate a possible role for this agent in the treatment of HIV-associated immune deficiency.
Predictors of Immune Deterioration in HIV Infection The rate of disease progression in untreated HIV infection is highly variable, with some individuals progressing rapidly to experience opportunistic infection and death within months of acquisition of infection and others ie, long-term nonprogressors remaining entirely well and maintaining normal CD4 cell counts more than 15 years after infection in the absence of antiretroviral treatment.
Approximately half of persons who acquire HIV infection will develop severe disease--AIDS--within 10 years if not treated with antiretroviral therapies. From a clinical perspective, rates of disease progression can be quantified by measuring decreases in circulating CD4 cell numbers over time. This index is highly variable among infected persons.
Immunopathogenesis of HIV Infection
Both viral factors and host factors, and likely their interaction, may predict the risk of HIV disease progression.
For example, in a small cohort of individuals who were infected by blood transfusion from a single donor in Australia and subsequently experienced a milder disease course than was expected, the infecting viral isolate was found to have a truncated Nef protein.
Switches in envelope sequences resulting in a phenotype that utilizes the CXCR4 coreceptor are associated with evidence of accelerated HIV disease progression, but the details of how coreceptor use determines disease outcome remain to be established.
The complex interplay between viral fitness and disease progression is potentially significant. Since replicative fitness correlates with plasma HIV RNA levels, more "fit" viruses might be expected to produce faster CD4 cell declines, as has been found to be the case in the context of antiviral drug resistance mutations. In the presence of antiviral drug selection pressure, resistance mutations either to nucleoside reverse transcriptase inhibitorsor to protease inhibitorstend to attenuate the CD4 cell decline induced by wild-type virus.
Although this effect may be due in part to diminished replicative capacity of these viruses, there is also reason to believe that decreased plasma HIV RNA levels do not completely explain the effect of fitness on CD4 cell levels and that the intrinsically diminished ability of these viruses to cause immunopathology also may play a role.
Persons homozygous for a noncoding sequence in the gene for stromal cell-derived factor 1, the natural ligand for CXCR4, were found to have a delayed risk for progression to AIDS but this observation has not been confirmed in other cohorts. For example, certain HLA alleles indicate greater or lesser risks of disease progression. In addition, homozygosity for HLA alleles is associated with a significantly greater risk of disease progression.
Finally, even a single amino acid substitution in an HLA molecule that determines which peptides can be bound and presented by this HLA type can determine a differential risk of HIV disease progression.
Less is known about the innate immune responses that may limit HIV replication. Innate defenses are responsible for the most rapid responses to microbial invasion; they help to control microbial replication and to activate the more specific adaptive immune responses.
Additional studies indicate that preservation of the function and numbers of plasmacytoid dendritic cells--the major sources of interferon-alfa--is associated with protection of persons with advanced HIV disease from the occurrence of opportunistic infection. For example, plasma concentrations of beta-2 microglobulin, TNF and its receptors, neopterin, and the soluble IL-2 receptor CD25 each correlate with magnitude of HIV replication and risk of disease progression.
Data from large cooperative cohort studies indicate that the correlation of age with risk of disease progression and HIV-related mortality persists after adjusting for CD4 cell counts and plasma HIV RNA level. Nonetheless, the existing data permit us to propose a model for the pathogenesis of immune deficiency in HIV infection.