Immunological Impairment Research Articles

Transient correlation between viremia levels and IL-10 expression in pigs subclinically infected with porcine circovirus type 2 (PCV2)

Immunological impairment by porcine circovirus type 2 (PCV2) infection is well documented in pigs suffering from postweaning multisystemic wasting syndrome. Nonetheless, little is known about immune status of pigs that remain PCV2 subclinically infected. Thus, seven pigs successfully infected in an experimental inoculation and without developing disease and nine control non-inoculated pigs were examined. Serological, virological and immunological determinations were done throughout ten weeks post-infection (PI). At week 3 PI, inoculated animals presented the peak of viremia and produced higher levels of IL-10 than the controls; correlation between viral load and IL-10 amounts was observed ( p < 0.05). Also, the ratio IgM/IgG suffered a shift skewing IgM production towards an IgG response. By 10 weeks PI, levels of IL-10 disappeared and the viremia decreased. In summary, subclinically PCV2-infected pigs developed a transient PCV2-specific IL-10 response during the viremic phase of infection which coincided with the inversion of the IgM/IgG ratio.

Oral 7, Cutaneous manifestations of disseminated BCG in a child with severe combined immunodeficiency

An 8-month-old girl of consanguineous parents presented with multiple subcutaneous nodules on her limbs and trunk. Over the preceding 2 weeks, her bacillus Calmette–Guerin (BCG) wound, which had been weeping since it was administered at birth, had become significantly worse. Both BCG and skin nodules had progressed to deep ulcers surrounded by areas of erythema with scaling. Previous contacts with health services included concerns regarding delayed development and a prolonged admission for a chest infection at 3 months of age (positive for respiratory syncytial virus with Campylobacter in her stool), associated with significant growth faltering requiring nasogastric feeding. This clinical picture raised the suspicion of severe combined immunodeficiency (SCID). Skin biopsy and Ziehl–Neelsen staining demonstrated numerous acid alcohol-fast bacilli within granulomatous lesions. Analysis of lymphocyte subsets, absent lymphocyte proliferations and molecular genetics confirmed the diagnosis of SCID with maternofetal engraftment complicated by disseminated BCG. The patient has recently received a matched unrelated donor human stem cell transplantation. Severe complications following BCG vaccination are rare and almost exclusively confined to patients with immunological impairment, in particular, SCID, chronic granulomatous disease, AIDS and complete DiGeorge syndrome.1 Individuals may present firstly to a dermatologist with subcutaneous nodules or a rash.2 The case described is used to highlight the importance of recognizing the cutaneous manifestations of disseminated BCG and to discuss the pathogenesis of the disease. References 1 Casanova JL, Jouanguy E, Lamhamedi S et al. Immunological conditions of children with BCG disseminated infection. Lancet 1995; 346:581. 2 Al-Bhal LA. Pathological findings for bacilli Calmette–Guerin infections in immunocompetent and immunocompromised patients. Am J Clin Pathol 2000; 113:703–8.

Identification of a CCR5-Expressing T Cell Subset That Is Resistant to R5-Tropic HIV Infection

Infection with HIV-1 perturbs homeostasis of human T cell subsets, leading to accelerated immunologic deterioration. While studying changes in CD4+ memory and naïve T cells during HIV-1 infection, we found that a subset of CD4+ effector memory T cells that are CCR7−CD45RO−CD45RA+ (referred to as TEMRA cells), was significantly increased in some HIV-infected individuals. This T cell subset displayed a differentiated phenotype and skewed Th1-type cytokine production. Despite expressing high levels of CCR5, TEMRA cells were strikingly resistant to infection with CCR5 (R5)–tropic HIV-1, but remained highly susceptible to CXCR4 (X4)–tropic HIV-1. The resistance of TEMRA cells to R5-tropic viruses was determined to be post-entry of the virus and prior to early viral reverse transcription, suggesting a block at the uncoating stage. Remarkably, in a subset of the HIV-infected individuals, the relatively high proportion of TEMRA cells within effector T cells strongly correlated with higher CD4+ T cell numbers. These data provide compelling evidence for selection of an HIV-1–resistant CD4+ T cell population during the course of HIV-1 infection. Determining the host factors within TEMRA cells that restrict R5-tropic viruses and endow HIV-1–specific CD4+ T cells with this ability may result in novel therapeutic strategies against HIV-1 infection.

Impaired expression of Toll-like receptors in peripheral blood monocytes and granulocytes in type 2 diabetic subjects (52.15)

Abstract Type 2 diabetes represents a prevalent serious health problem worldwide. Type 2 diabetes (non-insulin-dependent) is characterized by chronic hyperglycemia and disturbances of carbohydrate, fat and protein metabolism. Complications among diabetic patients include increased recurrence and severity to many infections. Low-grade inflammation also seems to be involved in the pathogenesis of diabetes. However the underlying mechanisms of the immunological impairment in diabetes are unclear. Toll-like receptors (TLRs) play a key role in pathogen recognition by the innate immunity, interestingly altered TLR expression has been recently reported in diabetic rodent models but it has never been studied in humans. Therefore using flow cytometry we tested if, under basal conditions, TLR expression was altered in peripheral blood monocytes and granulocytes from Type 2 diabetic Mexican subjects. We found a decreased frequency of monocytes and granulocyte expressing TLR3 and TLR4 in diabetic subjects, nevertheless TLR2 and TLR9 expression was not significantly different between diabetic and healthy groups. Whereas in hyperglycemic conditions lower frequencies of TLR2, TLR3 and TLR4 expression were found, TLR9 expression was significantly higher. Our findings support that the increased incidence of infections occurring in diabetes maybe related an impaired TLR expression.

Second Cancer Incidence and Cause-Specific Mortality Among 3104 Patients With Hairy Cell Leukemia: A Population-Based Study

The introduction of new treatments for hairy cell leukemia has resulted in improved patient survival but also engendered increasing concern about the possibility of excess second cancers. The available evidence is conflicting, with most risk estimates based on sparse numbers. To our knowledge, no study has evaluated cause-specific mortality in patients with hairy cell leukemia. We quantified second cancer incidence and cause-specific mortality among 3104 two-month survivors of hairy cell leukemia who were reported to 16 population-based registries in the Surveillance, Epidemiology and End Results (SEER) Program between 1973 and 2002. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were used to quantify the risk of second cancers and causes of death, respectively. The cumulative probability of a second cancer among survivors of hairy cell leukemia was calculated using a competing risk model. All statistical tests were two-sided. Mean follow-up of hairy cell leukemia survivors was 6.5 years (range, 2 months-29.3 years). Second cancer risk was statistically significantly elevated (SIR = 1.24, 95% confidence interval [CI] = 1.11 to 1.37) compared with the general population. Survivors had statistically significantly higher risks of Hodgkin lymphoma (SIR = 6.61, 95% CI = 2.13 to 15.42), non-Hodgkin lymphoma (SIR = 5.03, 95% CI = 3.77 to 6.58), and thyroid cancer (SIR = 3.56, 95% CI = 1.30 to 7.74) and a lower risk of lung cancer (SIR = 0.63, 95% CI = 0.42 to 0.90). The cumulative probability of all second cancers was estimated to be 31.9% (95% CI = 26.2 to 37.6) 25 years after hairy cell leukemia diagnosis. Among 10,000 hairy cell leukemia patients, a total excess of about 34 cancers, including 21 non-Hodgkin lymphomas, 2 Hodgkin lymphomas, and 7 solid tumors (including 2 thyroid cancers), might be observed per year. Deaths due to solid tumors were not elevated compared with the general population (SMR = 0.9), and there were statistically significant deficits in mortality due to both cardiovascular (SMR = 0.67, 95% CI = 0.56 to 0.80) and cerebrovascular (SMR = 0.61, 95% CI = 0.38 to 0.93) disease. Patients with hairy cell leukemia are at increased risk of Hodgkin lymphoma, non-Hodgkin lymphoma, and thyroid cancer. The decrease in lung cancer incidence and smoking-associated vascular mortality may reflect an inverse association of tobacco use with hairy cell leukemia. Future studies should address the roles of immunologic impairment inherent to hairy cell leukemia, treatment modalities, and other factors as codeterminants of morbidity and mortality in hairy cell leukemia survivors.

Human immunodeficiency virus and pemphigus vulgaris: An interesting association

Pemphigus vulgaris is an autoimmune blistering disorder requiring immunosuppressive therapy with corticosteroids. If pemphigus vulgaris occurs in a seropositive patient having immunosuppression and underlying opportunistic infections (OI) steroid therapy proves to be harmful unless the patient is given treatment for OI or antiretroviral therapy. The frequency and spectrum of mucocutaneous manifestations associated with human immunodeficiency virus (HIV) infection increase with clinical and immunological deterioration. In contrast autoimmune-mediated disorders tend to improve with HIV disease progression. We discuss a case of pemphigus vulgaris infected by HIV. Co-presentation of pemphigus vulgaris and HIV raises many clinical and therapeutic issues. The mutual impact of such co-presentation needs to be explored thoroughly. (excerpt)

Virological rebound and its consequences during treatment interruption

This paper provides an overview of the current knowledge on virological rebound during treatment interruption and its consequences in patients with chronic HIV-1 infection. After interruption of antiretroviral therapy, plasma viremia inevitably returns to individual pretherapy set point levels in almost all patients with chronic HIV infection. This virological rebound leads to a state of massive immune activation and consequently an increased turnover of CD4+ and CD8+ T cells resulting in a biphasic decay of T-helper cell numbers. Rebound has been shown to be associated with an increased risk of clinical events by some (albeit not all) randomized trials published during the last few months. Secondary consequences of immunologic deterioration include worsening of comorbidity (e.g. hepatitis and renal impairment) and an increased risk of cardiovascular disease as well as an elevated HIV transmission risk during treatment interruption. The individual course after treatment interruption cannot be predicted by any of the known surrogate markers. Treatment interruptions cannot be recommended in HIV-infected patients outside clinical trials, especially when profound immune deficiency is found to be preexisting.

Diagnosis and Clinical Manifestations of HIV/AIDS

There are various diagnostic methods for detection of HIV infection. Among them, ELISA has been using most widely as a screening test. On the other hand, the Western blot method has been used as a confirmative test. The final confirmative tests are conducted on the seropositive sample and other supplementary methods such as HIV antigen test or molecular tests involving polymerase chain reaction should be performed in addition to Western blot for the confirmation. The clinical consequences of HIV infection encompass a spectrum ranging from an acute syndrome associated with primary infection to a prolonged asymptomatic state and advanced disease. It is best to regard HIV disease as beginning at the time of primary infection and progressing through various stages. Throughout the course of HIV infection, active viral replication and progressive immunologic impairment occur in most patients. With the exception of rare true long-term nonprogressors, HIV disease, when untreated, inexorably progresses even during the clinically latent stage. However, anti-retroviral therapy has had a major impact on blocking or slowing the progression of disease over extended periods of time in a substantial proportion of adequately treated patients. Overall, the clinical spectrum of HIV disease is constantly changing as patients live longer and new and better approaches to treatment and prophylaxis are developed.

Immunosuppression in patients with severe acute pancreatitis

In severe acute pancreatitis (SAP), immunologic impairment in the early phase may be linked to subsequent infectious complications. In this study, immunologic alterations in patients with SAP were analyzed, and immunologic parameters related to infectious complications were clarified. A total of 101 patients with SAP were analyzed retrospectively. Various immunologic parameters on admission were analyzed and compared between the infection group and noninfection group during SAP. Furthermore, chronologic change in the lymphocyte count was investigated, and its utility for predicting infection was compared with conventional scoring systems. Serum immunoglobulin G (IgG), serum IgM, lymphokine-activated killer cell activity, and natural killer cell activity were low, and the incidence of abnormally low values was 50.0%, 65.0%, 45.5%, and 42.4%, respectively. Serum complement factor 3 was significantly negatively correlated with the APACHE II score. The lymphocyte count was decreased below the normal range, and was significantly negatively correlated with the APACHE II score. CD4-, CD8-, and CD20-positive lymphocyte counts were below the normal range, and CD4- and CD8-positive lymphocyte counts were significantly lower in the infection group. The lymphocyte count on day 14 after admission was significantly lower in the infection group and was more useful for predicting infection than conventional scoring systems. Immunosuppression occurs from the early phase in SAP, and quantitative impairment of lymphocytes, mainly T lymphocytes, may be closely related to infectious complications during SAP. CD4- and CD8-positive lymphocyte counts on admission and the lymphocyte count on day 14 after admission may be useful for predicting infection.

Severe Human Traumatic Brain Injury, but Not Cyclosporin A Treatment, Depresses Activated T Lymphocytes Early after Injury

Severe traumatic brain injury (TBI) leads to an immunocompromised state responsible for an increased morbidity and mortality. Our understanding of the mechanisms responsible for this brain damage is incomplete. Damage maybe mediated by a complex cascade of neuroinflammation, and cytokine activation. In addition, translocation and accumulation of T cells in the brain parenchyma could take place and be related to detrimental effects. Our aims in this prospective randomized pilot study, were to detect the early effect of severe TBI upon cell-mediated immunity, to verify if early immunologic impairment correlates with neurologic outcome, and finally, to test the effect of early administration of iv infusion of cyclosporin A upon cell-mediated immunologic function. Forty-nine patients with severe TBI were studied. Thirty-six of these patients received a 24-h intravenous infusion of Cyclosporin A, or two 24-h infusions of the drug. 10 patients were in the placebo group. Three patients, not enrolled in the cyclosporin trial, were studied only for the relationship between cellular immunity, neurological outcome, and infection rate. T cell counts and microbiological cultures were performed in all patients. Sixty-five percent of patients demonstrated reduced T lymphocyte counts on admission. Furthermore, reduction of T cell numbers was related with significantly worse neurologic outcome and an increase in pulmonary infection. There was no significant difference between the placebo and CsA treated patients for the studied immunological parameters, or for incidence of infection. We also observed sequestration/diapedesis of T cells into the brain parenchyma, around contusions, after human TBI and we speculate that this could be responsible for further brain damage.

Stress, age, and immune function: toward a lifespan approach.

Both aging processes and psychological stress affect the immune system: Each can dysregulate immune function with a potentially substantial impact on physical health. Worse, the effects of stress and age are interactive. Psychological stress can both mimic and exacerbate the effects of aging, with older adults often showing greater immunological impairment to stress than younger adults. In addition, stressful experiences very early in life can alter the responsiveness of the nervous system and immune system. We review the unique impact of aging and stress on immune function, followed by evidence of interactions between age and stress. Further, we suggest that prenatal or early life stress may increase the likelihood of maladaptive immune responses to stress in late life. An understanding of the interactive effects of stress and age is critical to efforts to determine underlying mechanisms, clarify the directionality of effects, and develop effective interventions in early and late life.

Primary human immunodeficiency virus type 1 infection: clinical, virological and immunological characteristics of 75 patients (1997-2003)

To describe the epidemiological and clinical characteristics and the evolution of a cohort of patients with primary HIV-1 infection from the Barcelona area. Prospective cohort study of HIV-infected patients diagnosed with primary HIV infection in a tertiary hospital in Barcelona (Spain) from 1997 through 2003. Descriptive analysis of epidemiological and clinical characteristics and effect of highly active antiretroviral treatment (HAART) on outcome. A total of 75 patients were diagnosed, accounting for 2.9% of the total of newly diagnosed HIV patients during the same time period. Eighty-one percent of the patients were males and the median age was 30 years (IQR 26-38). The most frequent transmission route was homosexual (72%), followed by heterosexual (17%) and intravenous drug abuse (11%). Seventy-seven percent of patients presented symptoms, the most frequent being fever (98%), asthenia (86%), arthralgia-myalgia (65%), lymphadenopathy (55%), night sweats (48%) and rash. Sixty-five percent started HAART, although the proportion of patients that received HAART decreased from 79% during the period 1997-2000 to 49% during the period 2001-2003 (p < 0.01). After a median follow-up of 37 months (IQR 26-66), one patient died and eight cases were lost to follow-up. The patients who did not receive HAART had a higher probability of immunological or clinical deterioration during the follow-up when compared to the group that received HAART (42.3% versus 12.3%; p < 0.001). In treated patients, dyslipidemia and lipodystrophy were diagnosed in 58% and 37% of cases, respectively. Primary HIV-1 infection was diagnosed more frequently in homosexual males, and its clinical characteristics were similar to those observed in previous studies. HAART given during primary HIV infection was effective, but was associated with a high percentage of adverse effects.

Inmunofenotipo de progresión a sida: deficiencia, activación y disfunción de células T CD4 y CD8

One key piece of information required when deciding whether to initiate antiretroviral therapy is the risk of AIDS. The aim of this study was to better characterize the baseline immunophenotypic profile of patients with progression to AIDS. A cross-sectional analysis of the distribution of functional subpopulations of CD4+ and CD8+ T-lymphocytes in 85 intravenous drug addicts with HIV infection. The values observed on patient enrolment in a prospective study were analyzed. Those patients who progressed and did not progress were compared to the HIV-negative controls. Lymphocyte subpopulations were studied by flow cytometry, including the markers: CD3, CD4, CD7, CD8, CD45RO, CD38, HLA-DR and CD25. The immunophenotypic profile that precedes progression to AIDS was mainly characterized by an increase in memory (CD45RO) activated cells and total activated CD4+ and CD8+ cells, and by an increase of T CD4+ cells that have loss expression of markers as receptor or the differentiation marker CD7 (CD7-). Patients not meeting laboratory criteria to initiate antiretroviral therapy (> 350 CD4+ T-cells and < 30,000 HIV-ARN-copies/ml) also showed increased levels of CD4+ and CD8+ activation subsets (CD4+CD38+DR+, CD8+CD38+). The fact that immunological activation may contribute to immunological and clinical deterioration of HIV-positive patients might be an additional factor which should be taken into account when deciding whether to initiate antiretroviral therapy.

Recovery of age‐dependent immunological deterioration in old mice by thyroxine treatment

On the basis that multiple interactions exist between thyroid hormones and immune system, and ageing is accompanied by changes in thyroid hormone secretion, it seems possible that thyroid hormones may be involved in the age-related immune dysfunction. The present study was conducted to evaluate in vivo and in vitro effects of thyroxine (T(4)) treatment on both cell-mediated and humoral immune responses of aged mice. In a trial to improve age-associated immune dysfunction, T(4) (0.2, 1.0 and 5.0 microg) was subcutaneously supplemented to BALB/c mice (over 18 months old) for 30 consecutive days. The present results showed that exogenous treatment of aged mice with T(4) was associated with a marked increase in serum T(4) level, and the total number of peripheral blood leukocytes as well as the total cellularity of thymus, spleen, peripheral lymph nodes (PLNs), mesenteric lymph nodes (MLNs) and bone marrow (BM). T(4) treatment also caused a significant increase in the total and differential numbers of peritoneal exudate cells (PECs), while it caused a slight increase in macrophages' phagocytic activity of PEC. Moreover, T(4) treatment elicited a statistically significant increase in both plaque-forming cell and rosette-forming cell responses. In vitro results showed that the addition of T(4) at concentrations of 0.001, 0.005 and 0.025 microg/well substantially potentiated the ability of splenocytes from aged mice to proliferate in the presence of concanavalin-A mitogen. Histological examination of thymuses from T(4)-treated aged mice revealed that the cortex was preferentially enlarged and repopulated with immature thymocytes. The present study postulates that thyroid hormones may be involved in the observed decrease in the immune responsiveness during ageing, and that T(4) treatment to aged mice is able to restore the age-related decline of the immune efficiency.

Senile Epstein-Barr Virus-Associated B-Cell Lymphoproliferative Disorders: a Mini Review

Epstein-Barr virus (EBV) is associated with a number of malignant lymphomas, including Burkitt lymphomas, Hodgkin lymphomas (HLS), immunodeficiency-associated lymphoproliferative disorders (LPDs), and subset of diffuse large B-cell lymphomas. We have recently identified a series of elderly patients afflicted with EBV-associated (EBV-positive) B-cell LPDs in the absence of predisposing immunodeficiencies ; we have named these neoplasms "senile" EBV+ B-cell LPDs. The large series of patients with this disease (n=76) provided additional evidence that this neoplasia, with a median age of onset of 71 years, has the highest incidence in elderly patients aged >50 years, suggesting that this disease may be related to the immunological deterioration that occurs during the aging process. These lesions were pathologically characterized by varying numbers of Hodgkin and Reed-Sternberg (HRS)-like giant cells, often posing a diagnostic problem differentiating this condition from HL. Recent studies, however, have indicated that HL and non-Hodgkin lymphoma (NHL) may be more closely related than previously implied, promoting the general consensus that HRS cells are derived from B cells in most HL cases. The relationship between EBV+ HL and EBV+ B-cell LPDs remains to be clarified. This review provides a unique opportunity to highlight the gray areas between EBV+ HL and EBV+ B-cell LPDs. Further investigations are necessary to clarify the interrelationship, including their overlapping morphological and biological features.

High Thymic Volume Is Associated With Viral Replication and Immunologic Impairment Only Early After HAART Interruption in Chronic HIV Infection

One of the strategies that has been investigated to reduce antiretroviral treatment toxicity in patients infected with human immunodeficiency virus (HIV) is structured treatment interruption (STI). Our aim was to analyze early viral and immune dynamics after interruption of highly active antiretroviral therapy (HAART) and to determine whether thymic function-related markers play a role in preventing CD4 count decline caused by increased viral replication. This was a prospective study of an open cohort of 47 HIV-infected patients with a median 969 CD4 count and prolonged viral suppression. They were followed every 4 weeks though week 24. Thymic volume and TREC level were analyzed at baseline. Increased thymic volume was associated with higher plasma viral load and greater CD4 count decline early after interruption. Three virologic patterns were observed: rapid/high (RH), delayed/high (DH), and low/slow (LS) viral replication. RH correlated with higher thymic volume at baseline and with higher CD4 count decline at week 4. Patients with greater thymic volume was associated with an immune and virologic impairment only early after interruption, probably because of infection of the increased number of available target cells. As the long-term consequences of these observations are unknown, the safety of treatment interruption must be further studied.

Effect of copper and zinc supplementation on peripheral leukocytes in neutropenia due to copper deficiency

Background: Recent quantitative and qualitative studies in animals suggest that copper deficiency causes immunological impairment and a decrease in leukocytes. We investigated the effect of copper supplementation in remedying these effects of its deficiency and whether zinc, a trace element that is significant to the immune status modifies such effects.Methods: In the present investigation, the effects of copper supplementation on circulating lymphocyte levels of 18 patients (aged 61–98 years, mean 85 years) with severe copper deficiency, elicited by a long‐term low copper diet, were examined in comparison with six age and sex‐matched healthy elderly subjects. Every day for 28 days, 2 mg of copper sulfate was added to the diets of 12 of the copper‐deficient subjects. The remaining copper‐deficient subjects received 2 mg of copper sulfate daily in their diets and were also given 17.3 mg of zinc sulfate every day by intravenous infusion, both supplements were also given for 28 days. Two‐color flow‐cytometry was conducted and the blastogenesis of circulating lymphocytes was examined.Results: Copper supplementation increased the number of circulating CD2+, CD4+, CD20+ cells without affecting numbers of NK‐type CD8+ T cells (CD11b+ and CD57+ lymphocytes). The percentage of monocytes to total leukocytes decreased after copper supplementation. Zinc supplementation, however, did not augment these effects and did not increase the total number of CD57+ cells. The ratio of pokeweed mitogen reactivity to concanavalin‐A reactivity was diminished by copper supplementation but not additional zinc. There was no change in the immunological colloid reaction in the zinc sulfate turbidity test.Conclusion: Our results suggest that copper depletion has a deleterious effect on the immune system, with a decrease in circulating lymphocytes numbers. Monocytes seemed to be more resistant to copper deficiency than neutrophils, and to play a significant role in lymphocyte activation. Despite this, however, it seems unlikely that there is any synergy between copper supplementation and zinc supplementation.

Structured treatment interruption in HIV-infected patients failing on multidrug therapy: is there a future for this strategy?

Among factors that might limit the benefits of highly active antiretroviral therapy (HAART) other than suboptimal medication adherence and drug toxicities most concern centred on the development of resistant viral variants which can compromise the virological response rate of treatment regimens. Large surveys of HAART-experienced populations have shown that the probability of developing a multiclass drug resistance is approximately 20–42% after several years of treatment. Therefore interest has grown in developing new strategies for patients with few or no therapeutic options because of the presence of multidrug-resistant viral strains. One of the critical points under discussion is whether complete viral suppression represents the preferred endpoint of clinical strategy in this late phase of the natural history of treatment. Several observations suggest that drug-resistant HIV-1 has differing degrees of decreased replicative capacity compared with wild-type virus. Consequently discontinuation of antiretroviral therapy in patients with multidrug-resistant virus may rapidly cause overgrowth by wild-type virus with a hypothetical decline of resistance and reversion of genotypic mutations. However maintaining a failed regimen to which HIV is resistant may still keep viral replicative capacity low and so the likelihood of immunological deterioration and clinic progression could be reduced. (excerpt)

Estudo cardiológico longitudinal em crianças expostas ao vírus da imunodeficiência humana tipo 1 por via perinatal

To determine the frequency of cardiac abnormalities and its natural history in children perinatally exposed to HIV-1. Eighty-four children exposed to HIV-1 were evaluated by serial clinical, electrocardiographic (ECG), and Doppler-echocardiographic (ECHO) examinations. Group I--(seroreversion)--43 children (51.2%). Absence of clinical abnormalities. ECG: incomplete right bundle branch block (RBBB) 5 cases. ECHO: atrial septal defect (ASD) and ventricular septal defect (VSD)--1 case each. Group II--41 HIV-infected children (48.8%), of whom 51.2% were found to have cardiac abnormalities. Asymptomatic or mildly symptomatic children without immunosuppression: no clinical and echocardiographic abnormalities; ECG: incomplete right bundle branch block (RBBB)--(2 cases). Children with moderate and severe symptoms and immunological impairment: the following abnormalities were found: 1) clinical (31.7%)-isolated tachycardia (1 case), congestive heart failure (12 cases). 2) electrocardiographic (43.9%)- sinus tachycardia associated with other abnormalities (10 cases), incomplete right bundle branch block (5 cases), left anterior hemiblock (1 case), right anterior hemiblock (1 case), changes in ventricular repolarization (11 cases), right ventricular overload (2 cases), left ventricular overload (1 case), right QRS axis deviation (1 case), and arrhythmias (3 cases). 3) echocardiographic (26.8%)- dilated cardiomyopathy (5 cases), pericardial effusion with tamponade (2 cases), pulmonary hypertension (2 cases), and mitral valve prolapse (1 case). Cardiac involvement was a characteristic of the HIV-infected group. Higher prevalence of abnormalities was found among children belonging to the most advanced clinical and immunological category. The most commonly observed clinical, electrocardiographic and echocardiographic findings were congestive heart failure (CHF), changes in ventricular repolarization, and dilated cardiomyopathy, respectively. The latter was reversible in one case. Electrocardiogram changes were significantly more frequent than clinical and echocardiographic changes.

The role of mutation accumulation in HIV progression

The onset of AIDS is characterized by the collapse of the immune system after a prolonged asymptomatic period. The mechanistic basis of this disease progression has remained obscure, hindering the development of effective therapies. Here I present a mechanism that underlies the deterioration of the immune system during HIV infection. The elevated turnover of lymphocytes throughout the asymptomatic period is postulated to result in the accumulation of deleterious mutations, which impairs immunological function, replicative ability and viability of lymphocytes. This mutational meltdown is proposed to occur throughout the hierarchy of lymphocyte progenitors, resulting in the deterioration of lymphocyte regeneration and an ensuing rise in viral loads. A mathematical model is used to illustrate this mechanism of progressive immunological deterioration. Mutation accumulation may explain not only the decline in CD4+T cells, but also the functional deterioration of CD4+T cells, CD8+T cells and B cells, and the exhaustion of lymphocyte regeneration.