Onset Of Opportunistic Infections Research Articles

Dwindled serum IgG levels of Rubella, Diphtheria toxin, Hepatitis B virus and Tetanus Toxoid after chemotherapy; a report from Iranian children with malignancy

Backgrounds: Epigenetic regulation such as DNA methylation plays a major role in chromatin organization Background: Chemotherapy suppresses immunoglobulin production as a result of cell toxicity. Decreased immunoglobulin levels can result in the onset of opportunistic infections. The aim of the current study is to compare the immunoglobulin G (IgG) levels of the selected vaccine-preventable disease (VPD) before and six months after chemotherapy in a group of Iranian children with malignancies. Materials and Methods: In this interventional study, serum levels of Rubella, Diphtheria toxin, Hepatitis B virus (HBV), Tetanus Toxoid, Mumps, and Measles IgG were measured in 30 children with malignancy and previously vaccinated for these diseases. Six months after chemotherapy, serum IgG levels were reassessed and compared with their corresponding pre-chemotherapy levels. Results: In this study, 17 (56.7%) male and 13 (43.3%) female were included. The mean age was 7.69±3.09 years. After chemotherapy, Rubella IgG levels dropped from 73.88±85.11 to 56.59±72.84 IU/mL (P<0.05; r= 0.956; 33.4% become serum negative (SN)). Diphtheria toxin IgG was diminished from 0.683±0.454 to 0.174±0.248 IU/mL (P<0.05; r=0.601; 26.7% SN). Anti-HBV IgG showed a reduction from 46.26±101.56 to 25.56±80.49 IU/mL (p<0.05; r= 0.524; 60% SN) and Anti-Tetanus Toxoid IgG fell down from 1.031±0.582 to 0.321±0.408 IU/mL (p<0.05; r= 0.365; 33.4% SN). Anti-Measles and Anti-Mumps IgGs showed no significant change (p>0.05). Conclusion: Pediatric chemotherapy was associated with dropped serum IgG levels of most VPDs. A good correlation was also observed between serum levels of IgG before and six months after chemotherapy. Revaccination of children with malignancies may be necessary upon declined serum IgG titers.

Short- and Long-term Risks of Highly Active Antiretroviral Treatment with Incident Opportunistic Infections among People Living with HIV/AIDS

Highly active antiretroviral therapy (HAART) causes a rapid increase of CD4 + T cells counts during the first 3–6 months of treatment and may enhance the development of opportunistic infections (OIs). However, the short- and long-term effects of HAART exposure on the development of incident OIs has not been extensively studied. This nationwide longitudinal study followed up a total of 26,258 people living with HIV/AIDS (PLWHA) to ascertain the short- and long-term effects of HAART on incident OIs. During 150,196 person-years of follow-up, 6,413 (24.4%) PLWHA had new onset of OIs. After adjusting for demographics, comorbidities, and AIDS status, PLWHA who received HAART were more likely to develop OIs than those who did not receive HAART. Considering the short- and long-term effects of HAART on the development of OIs, HAART was found to be a risk factor for developing OIs during the first 90 days of treatment, but a protective factor against OIs after 180 days of HAART use. The risk for the development of active OIs significantly decreased as the duration of HAART increased (P < 0.001). Our study suggests that HAART is a risk factor for developing OIs in the short term, but is a protective factor in the long term.

Epidemiology of Opportunistic Infections in HIV Infected Patients on Treatment in Accredited HIV Treatment Centers in Cameroon.

Background:The African continent accounts for over 70% of people infected with Human Immunodeficiency Virus (HIV). The HIV sero-prevalence rate in Africa is estimated at 4.3%. In developed countries, such as France, pneumocystis is indicative of AIDS in 30% of patients; however, in Africa, pulmonary tuberculosis (TB) is the most-documented opportunistic infection (OI) and the leading cause of death in HIV-infected patients. In 2016, Cameroon had 32,000 new cases of OI and 29,000 deaths as a result of these infections. However, there is little existing data on the epidemiological profile of OIs in Cameroon, which is why we conducted this study in accredited HIV treatment centers and care/treatment units in the two cities of Douala and Yaounde, Cameroon.Methods:This was a retrospective descriptive and analytical study carried out in 12 accredited HIV treatment centers in the cities of Yaoundé and Douala, Cameroon, over a period of seven months from October 2017 to April 2018. A stratified sampling method was used with three sampling levels: the city, type of health facility and size of active files. Ethical clearance and administrative authorization were obtained from the appropriate authorities and data were collected using a pre-tested survey form. The data collected was entered and analyzed using Epi Info version 3.5.4.Results:Out of a total of 1,617 HIV-infected patients sampled, 419 (25.9%) had at least one OI. Of these patients with an OI, 246 or 65% had a baseline CD4 count of <200/mm3. There was a significant relationship between the male gender and the onset of OI (OR = 1.47; p = 0.01). Age ≥ 50 years was associated with the occurrence of OI (OR = 2.57; p = 0.01). A CD4 count of <200/mm3 was also associated with the risk of developing an OI (OR = 3.12; p = <0.01).Conclusion and Global Health Implications:The prevalence of OI is high among people living with HIV (25.9%). Shingles was the most common OI found followed by pulmonary tuberculosis. Male gender, age ≥ 50 years, and CD4 <200/mm3 were the most common factors associated with the occurrence of these OI. These findings suggest that public health interventions for reducing HIV related co-morbidities (and implicitly mortality) should especially target the male gender for greater impact in addition to other measures.

Incidence and Type of Opportunistic Infections during Ibrutinib Treatment at a Single Academic Center

BACKGROUNDIbrutinib is an irreversible inhibitor of Burton's tyrosine kinase (BTK) in the B-cell receptor (BCR) signaling cascade and is a practice changing treatment for chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Ibrutinib also inhibits Interleukin-2 Inducible Kinase (ITK) in T-cells and has demonstrated immunomodulatory effects. Recently, cases of opportunistic infections (OI) have been reported during ibrutinib treatment including pneumocystis jirovecii pneumonia (PJP), cryptococcus, and fusarium. To date there are no reports on OI in large unselected cohorts of patients taking ibrutinib. We conducted a single-institution retrospective study to determine the incidence and type of OI during ibrutinib treatment as well as outcomes and characteristics associated with risk. METHODSWe reviewed medical records of all patients treated with ibrutinib at the Ohio State University between June 1st 2010 and March 31st 2016. Patients who received ibrutinib for graft versus host disease were excluded. All charts were initially reviewed by one of the investigators and patients with OI were independently reviewed by a second investigator. Baseline patient and disease characteristics were captured at time of starting ibrutinib. All OI occurring after the first dose of ibrutinib were recorded. Onset of OI was considered as the time of first presentation for a complaint related to OI. Time to OI was calculated from the date of starting ibrutinib until the onset of OI or censored at the last assessment date, discontinuation of ibrutinib, or death prior to OI as competing risks. The cumulative incidence of OI was estimated and the Fine and Gray regression models were used to examine the association between patient characteristics and risk of OI. Covariates with significance level of p<0.20 from univariable analyses were further evaluated in a multivariable analysis using a stepwise selection procedure, retaining those with p<0.05 in the final model. RESULTSThe cohort included 566 patients. Median age was 65 (range 23-89) and 70.1% (397/566) were men. The majority of patients had CLL (73.7%, 417/566). Other diagnoses included mantle cell lymphoma (9.9%, 56/566), indolent B-cell malignancies (8.1%, 46/566; 11 Waldenström's Macroglobulinemia, 13 Hairy Cell Leukemia, 15 Follicular Lymphoma, 6 Marginal Zone Lymphoma, and 1 Prolymphocytic Leukemia), and aggressive lymphoma (8.3%, 47/566; 35 diffuse large B-cell or transformed lymphoma and 12 Richter's syndrome). Median number of prior treatments was 3 (range 0-18) and 6.5% (37/566) of patients were treatment naïve. Ibrutinib was prescribed on clinical trial for 80.9% (458/566) of patients with the rest receiving it as standard of care. A second agent was given with ibrutinib in 30.9% (175/566) of cases and was most often a monoclonal antibody (81.7%, 143/175). Use of antiviral prophylaxis was common (78.6%, 445/566) with fewer patients receiving PJP (44.9%, 254/566) or fungal (11.5%, 65/566) prophylaxis. The most utilized prophylactic antifungal agent was fluconazole (70.8%, 46/65). Total ibrutinib exposure for the cohort was 1,225 person-years with a median exposure of 1.98 (range 0.008-6.40) years. Median duration of follow-up was 2.69 (range 0.03-6.40) years. Twenty-three of 566 (4.1%) patients developed an OI at a median of 0.39 (range 0.03-4.33) years after starting ibrutinib. The cumulative incidence of OI was 2.3% (95% CI: 1.3-3.8%) at 0.5 years and increased to 4.7% (95% CI: 3.0-7.0-%) at 5 years. Types of OI and outcomes are detailed in Table 1. Median survival of the entire cohort was not reached. Among 23 OI patients, the median survival after infection was 1.39 years. Univariable analysis revealed ≥3 prior treatments (HR 2.61), diabetes (HR 3.03), pulmonary disease (HR 2.81), chronic kidney disease (HR 2.56), and liver disease (HR 6.42) were associated with an increased risk for OI (p<0.05). In a multivariable analysis ≥3 prior treatments (HR 2.87, 95% CI: 1.12-7.35; p=0.028), diabetes (HR 3.63, 95% CI: 1.50-8.77; p=0.004), and liver disease (HR 7.53, 95% CI: 2.14-26.49; p=0.002) retained independent association with OI development. CONCLUSIONSThe cumulative incidence of OI during ibrutinib treatment was low (4.7% at 5 years) and the most common type was invasive fungal (61%) with no PJP cases. Three or greater prior treatments, diabetes, and liver disease were independently associated with risk for OI. [Display omitted] DisclosuresByrd:Janssen: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding.

Cumulative D-Index Predicts the Duration of Febrile Neutropenia in AML Patients

Background: Prolongation of severe neutropenia is known to predict the onset of pneumonia and invasive fungal infection in patients undergoing chemotherapy. The D-index is a promising tool to assess the severity of neutropenia, and the utility of the D-index is being investigated in clinical research. However, there are a few reports regarding the association between the D-index and the onset of opportunistic infection. We undertook this study to examine whether the D-index is useful to predict the onset of various infections in febrile neutropenia (FN) patients.Methods: The D-index was originally developed by Portugal et al. It is calculated as the area between <500 cells/μL and over the neutrophil curve when grade 4 neutropenia is present. We retrospectively investigated the events of febrile neutropenia among patients with acute myeloid leukemia (AML) treated at our institute. We recruited consecutive patients, younger than 65 years of age, newly diagnosed between November 1998 and February 2015. We collected all FN events from a chart review and evaluated the association between FN degree and infectious events. Survey periods covered the start of the induction chemotherapy to the end of the last consolidation therapy. Patients with a poor performance status (≥3) were excluded. We also calculated the total cumulative D-index (cD-index) from the first chemotherapy to the onset of FN, and the total D-index from the first chemotherapy to the last chemotherapy, to evaluate additive effects of the neutropenia. We tentatively determined the possible infection sites of the patients at the onset of FN in each event to analyze the presumable focus of infection.Results: In total, 35 cases and 122 FN events were enrolled (18 females and 17 males). The median age was 51 years (range, 18-65 years). The demography of FAB classification was M0, n = 1; M1, n = 5; M2, n = 14; M4, n = 3; M5, n = 3; M6, n = 2; and secondary AML, n = 7. Induction therapy consisted of idarubicin and Ara-C, and consolidation therapy consisted of high-dose Ara-C or rotated anthracyclines and Ara-C. The chemotherapy regimen was applied according to the JALSG AML201 or AML97 protocols. The response rate to induction chemotherapy was 60.0% (21/35), and 97.1% (34/35) of patients were alive at the end of follow-up. Only one patient died during chemotherapy; the cause of death was bacteremia due to Stenotrophomonas maltophilia (UNP 24). The total D-index was associated to the onset of infection with or without an identification of documented pathogens. However, high-dose Ara-C regimen and total D-index statistically significantly contributed to the onset of infection according to multivariate analysis (P = 0.0009 and 0.0205, respectively). Furthermore, the cD-index was a statistically significant contributing factor to predict the duration of FN according to multivariate analysis (P = 0.0378). Subsequently, we performed subgroup analysis and defined a significantly prolonged FN duration in the patients with respiratory focus compared with other focus sites.Conclusion: The total D-index was associated to the onset of infection during FN. However, the total D-index is a retrospective assessment index, calculated after neutropenic recovery. Therefore, the total D-index cannot be applicable to the prediction of infection upon FN. Our study identified respiratory foci of infection upon FN in the patients with high cD-index (≥5000) is a risk marker for the prolongation of FN. Then, we speculate that a respiratory manifestation at the onset of FN after consolidation therapy indicates a need for more intensive antimicrobial therapy. DisclosuresNo relevant conflicts of interest to declare.

The Impact of Azathioprine-Associated Lymphopenia on the Onset of Opportunistic Infections in Patients with Inflammatory Bowel Disease

BackgroundThiopurines are known to cause lymphopenia (<1,500 lymphocytes/μl). As severe lymphopenia (<500C/μl) is associated with opportunistic infections, we investigated severity of thiopurine-related lymphopenia and development of opportunistic infections in our tertiary referral centre.MethodsWe retrospectively screened medical records of 1,070 IBD patients and identified 100 individuals that developed a total of 161 episodes of lymphopenia during thiopurine treatment between 2002 and 2014. Occurrence of opportunistic infections was documented. A control group consisted of IBD patients receiving thiopurines but without developing lymphopenia.ResultsOf a total of 161 episodes of lymphopenia, 23% were severe (<500C/μl). In this subgroup, thiopurine dosing was modified in 64% (dosage reduction: 32%, medication discontinued: 32%). We identified 9 cases (5.5%) of opportunistic infections, of which only two occurred during severe lymphopenia. One opportunistic infection (4.5%) was identified in the control group. No association was found between opportunistic infections and severity of lymphopenia. All patients who suffered from opportunistic infections were receiving additional immunosuppressive medication.ConclusionOur patients treated with thiopurines rarely developed severe lymphopenia and opportunistic infections did not occur more often than in the control group. A careful monitoring of lymphocytes and prophylactic adjustment of thiopurine therapy might contribute to this low incidence.

Pathogenesis of HIV-1

The human immunodeficiency virus type 1 (HIV-1) establishes a chronic, lifelong infection finally leading to the acquired immunodeficiency syndrome (AIDS), which is characterized by the onset of opportunistic infections and tumors. The natural course of HIV-1 infections is very variable and depends on the virus and its replication competence as well as the host. This review summarizes our current knowledge on HIV-1 and host factors influencing the pathogenesis of HIV-1.

Innate immune correlates of HIV pathogenesis in response to opportunistic mycobacteria (INC8P.428)

Abstract HIV infection of humans and SIV infection of Rhesus macaques generally results in onset of opportunistic infections (OIs) and AIDS when left untreated. In contrast, SIV infection of African monkeys, such as sooty mangabeys, results in high levels of viral replication, but the immune system remains resilient to dysfunction, OIs and progression to AIDS. Here, we set out to identify innate immune correlates associated with acquisition of OIs in HIV+ humans (and the lack thereof in SIV+ mangabeys), through an ex vivo cytokine and transcriptomic assessment of PBMC and monocyte responses to the opportunistic pathogen, BCG. Our data reveal that HIV+ donors have significantly altered NK cell gene expression profiles and deficient monocyte IL-12 production (p=0.017) in response to BCG stimulation compared to HIV-negative donors. In contrast, SIV+ mangabeys maintain similar gene expression profiles and increase the percentage of monocytes producing proinflammatory cytokines TNFα (p=0.03) and IL-12 (p=0.06) following BCG stimulation compared to uninfected mangabeys. These data suggest that a lack of monocyte-derived IL-12 and deficient NK cell response to opportunistic pathogens may be associated with increased susceptibility to OIs. Further, they raise potential to augment innate immune function through NK cell-targeted IL-12 therapy during pathogenic lentiviral infections.

Challenging New Targets for CNS–HIV Infection

The central nervous system (CNS) represents an important target for HIV infection during multiple stages of the disease: early, after invasion of the host, acting as a viral reservoir; lately, subverting its function and causing peripheral neuropathies and neurocognitive disorders; and lastly, during the final stage of NeuroAIDS, triggering opportunistic infections, cancers, and dementia. Highly active antiretroviral therapy, a combination of drugs that inhibits enzymes essential for HIV replication, can reduce the viremia and the onset of opportunistic infections in most patients, and prolong the survival. Among the limits of the current treatments the most noticeable is the inability to eradicate HIV-infected cells, both, limiting the time frame in which antiretroviral therapies initiated after exposure to HIV can prevent infection, and allowing replication-competent virus that persists in infected cells to emerge rapidly after the cessation of treatments. Many strategies are currently under evaluation to improve HIV treatment, unfortunately more than 98% of drug candidates for CNS disorders never make it to the clinic; here in we report how nanoformulated strategies might be adapted and applied to the field of CNS–HIV infection.

Oral Manifestations Related To CD4 Lymphocyte Count in HIV-Positive Patients.

Background and aims The onset of opportunistic infections in HIV-positive patients is generally associated with a low CD4 count. Oral manifestations can be the first clinical sign of the infection and also determine the progression of disease. The purpose of this study was to determine the prevalence of oral soft tissue manifestations and their relationship with the degree of immunosuppression observed in HIV-positive patients. Materials and methods 100 HIV-positive patients were examined. Oral lesions were evaluated according to EEC clearing house criteria. The degree of immunosuppression was based on the CD4 count closest to the oral examination. Data were analyzed using Student’s t-test and chi-square test. Results The most common oral lesions were rampant caries (54%), periodontal disease (44%), and hyperpigmentation (42%). Salivary glands enlargements and leukoplakia were associated with more severe immunosuppression. Conclusion According to the results, it seems that occurrence of only some of oral lesions are related to the degree of immunosuppression and such lesions can be considered as indicators of the progression of the HIV infection.

Onset of opportunistic infections in patients co-infected by HTLV-1 and HIV-1, with high CD4+ cells count

We reported two cases of patients with coinfection by human immunodeficiency virus (HIV) type 1 and human T-cell lymphotropic virus (HTLV) type I who developed opportunistic infections despite of relatively high CD4+ cells count. These cases showed clinical evidence to consider an earlier antiretroviral treatment for coinfected patientes regardless CD4+ cells counts.

Common protozoans as an uncommon cause of respiratory ailments in HIV-associated immunodeficiency

Opportunistic infections (OIs) are the leading cause of mortality and morbidity among HIV-positive subjects. The breadth of reports of the rare occurrence of OIs in HIV/AIDS has been increasing over the years and more recent studies have outlined the changing trends in the emergence of newer pathogens. Recent reports of the association of certain protozoans that normally do not infect sites other than their normal sites of localization have generated huge interest among scientists. The complete depression of the immune system, followed by the onset of OIs, especially due to protozoans, i.e. toxoplasmosis, isosporiasis, leishmaniasis, cyclosporosis, microsporidiosis and cryptosporidiosis, is not uncommon in AIDS. The immunologic and pathologic basis behind the susceptibility of immunodepressed individuals to these 'non-site-specific parasites' is likely to have a huge impact on HIV disease progression. Certain possible shortcomings in the immunologic armory of immunodeficient subjects, their failure to contain the establishment of these 'uncommon' agents in the human host and their significance in HIV disease progression are discussed.

Evidence for circulating activated cytotoxic T cells in HIV-infected subjects before the onset of opportunistic infections

The activity of both cytotoxic T lymphocyte (CTL) and natural killer (NK) cells were measured cross-sectionally in 43 subjects seropositive for HIV, in 27 HIV- blood donors and in 24 HIV- persons from the Outpatients Clinic for sexually transmitted diseases. CTL activity was evaluated using the HL-60 cells coated with OKT3 as the targets and freshly separated peripheral blood lymphocytes as the effectors. In 20 out of 43 HIV+ subjects, CTL activity was significantly enhanced in comparison to the HIV- subjects. This lytic activity correlated positively with the percentages of CD3+ HLA-DR+, of CD8+ CR3- and of CD57+ CD16- lymphocytes, and was greatly reduced after elimination of CD8+, of HLA-DR+ or of CD57+ cells. The median CTL activity seemed to increase from CDC group II to CDC group IV (Centers for Disease Control classification), but to return back to control levels in those patients with a history of opportunistic infections. NK function in HIV+ subjects was not significantly different from that in the blood donors. In seropositive patients, NK activity correlated positively with the percentages of both CD16+ CD57+ and of CD8+ CR3+ cells and was strongly diminished after elimination of CD16+ or of CD57+ cells. There was no significant change in NK function according to the clinical stage. The data show that circulating CD8+ HLA-DR+ CD57+ T cells in HIV+ subjects are activated cytotoxic T cells and point to progressive (over) activation of this T cell compartment until the onset of opportunistic infections.

Changes in natural immunity during the course of HIV-1 infection.

The role of natural killer (NK) and lymphokine-activated killer (LAK) cell-mediated cytotoxicity in AIDS has yet to be established. The objective of this study was to determine inducible LAK cell responses at different stages of HIV-1 infection, and specifically to establish the participation of CD8 lymphocytes in these responses. Peripheral blood lymphocytes (PBL) were isolated from healthy seronegative (CDC-0) subjects and HIV-1+ individuals who were clinically asymptomatic (Centre for Disease Control group 2, CDC-2) or symptomatic (CDC-4) with regard to secondary opportunistic infection (OI). LAK cells were generated upon incubation of PBL with IL-2 and their cytolysis of K562 and U-937 targets was determined using chromium release assays. The role of CD8+ lymphocytes as progenitors and effectors of these LAK cell responses was determined by immunomagnetic depletion of CD8+ cells from precursor PBL and LAK cells, respectively. LAK cell-mediated cytotoxicities in HIV-1-infected individuals were reduced compared with seronegative controls without any corresponding changes in the relative proportions of CD56+ (NK) cells among groups. Depletions of CD8+ subsets from either PBL or LAK cells dramatically reduced total LAK cytotoxic responses and LAK activities per unit CD56+ cell in the OI-/CDC-2 seropositive population. No corresponding changes in LAK activities in seronegative control or HIV+/OI+/CDC-4 groups were observed. Levels of LAK activity against K562 targets in CDC-0/HIV- and CDC-4/HIV+ groups correlated with the percentage of CD56+ LAK cells; corresponding LAK activity in the CDC-2/HIV+ group correlated with the percentage of both CD56+ and CD8+ subsets. These findings suggest that adaptive changes in non-MHC restricted cytotoxic responses occur in HIV-1 individuals at early stages post-HIV infection, before the onset of opportunistic infection.

Dendritic cell (DC) reconstitution is associated with less opportunistic infections (OI) after allogeneic hematopoetic stem-cell transplantation (HSCT)

6539 Background: Dendritic cells are key antigen presenting cells which coordinate immune responses against infections. We investigated the correlation between DC reconstitution after HSCT and the onset of OI. Methods: We prospectively studied immune reconstitution of DC in 124 patients with predominantly high-risk hematopoetic malignancies. Peripheral blood underwent flow cytometry analysis for DC, defined as lineage negative, HLA-DR+, CD11c+ and CD123+. Cluster analysis demonstrated patients at engraftment with high DC (&gt;6.92/mm3) (n =68), low DC (n=56), and at 60 days with high DC (&gt;3.95/mm3) (n=48), and low DC (n=43). Primary study endpoint was onset of OI, defined as viral and invasive fungal (proven and probable) OI within 6 months of HSCT. A cox proportional hazard multivariate model was adjusted for important covariates, including age, transplant conditioning (myeloablative vs. non-myeloablative), graft source (peripheral blood vs. bone marrow), donor-type (HLA-matched related vs. unrelated), and ANC. Results: Patients with low DC at engraftment had significantly increased onset of acute grade II-IV GVHD by Kaplan-Meier analysis (p=0.004). Patients with onset of GVHD prior to day 60 were less likely to have high DC (32% with GVHD, 72% without GVHD) (p=0.001). Furthermore, low DC at 60 days was adversely associated with: time to viral OI (p=0.04), time to composite of viral OI and death (p=0.02), time to viral or fungal OI (p=0.009), and time to composite of viral or fungal OI and death (p=0.02). In the Cox model, low DC at 60 days, was associated with a 3.7 relative risk (RR) (1.2, 11.8) for onset of OI. Patients with onset of OI prior to day 60 were significantly less likely to have high DC (41% with OI, 61% without OI) (p=0.05). Conclusions: This study emphasizes the clinical importance of measuring DC after transplant. Patients with low DC reconstitution are at an increased risk of OI and death. Measuring DC, and further understanding of the likely complex factors involved in DC reconstitution, may provide rationale towards future therapeutic immune interventions. No significant financial relationships to disclose.

Estimation of mRNA levels of interleukin (IL)-10, tumor necrosis factor (TNF)-α, IL-4 and interferon (IFN)-γ in HIV infected children in Mumbai.

Cytokines, viral load and opportunistic infections play an important role in HIV-disease progression. Hundred children vertically infected with HIV were enrolled to determine mRNA levels of TNF-α, IL-10, IL-4 and IFN-γ. These levels were estimated by amplifying cytokine mRNA from peripheral blood mononuclear cells. Severity of HIV was staged by the reduction in CD(4) (+) T cells and the onset of opportunistic infections. IL-10 mRNA levels were observed to increase with the severity. Despite the rising IL-10 mRNA levels, TNF-α mRNA levels increased with severity of HIV and decrease in CD(4) (+) T cell counts. IL-4 mRNA levels increased with the reduction in CD(4) (+) T cell numbers. Depleting mRNA levels of IFN-γ contributed to the worsening of HIV disease. Increase in TNF-α and IL-4 levels appended to the disease severity by upregulation of the viral replication. Increased IL-10 levels and decreased IFN-γ levels predisposed the children to HIV associated opportunistic infections, which in return contributed to cytokine disarray.

Immune evasion strategies of the primate lentiviruses.

Individuals infected with human immunodeficiency virus (HIV) and macaques infected with simian immunodeficiency virus (SIV) make vigorous virus-specific antibody and cellular immune responses. Despite these responses, virus replication continues at all stages of infection and ultimately leads to immunological collapse, onset of opportunistic infections and death of infected hosts. Thus, the strategies by which HIV and SIV evade antiviral immune surveillance are fundamental to understanding lentiviral pathogenesis and crucial for our ability to develop effective strategies. It has become increasingly clear that the primate lentiviruses have evolved multiple and complementary mechanisms to circumvent host immune responses. Here we review these mechanisms of immune evasion considering contributions from both human and non-human primate systems.

Relation Between CD4 Cell Counts and HIV RNA Levels at Onset of Opportunistic Infections

To evaluate the relation between CD4 and HIV RNA levels at the onset of specific opportunistic infections (OIs) in HIV-infected patients. The OIs occurring between June 1996 and December 1998 were retrospectively reviewed, considering only the episodes of major and minor OIs in patients with simultaneously available CD4 and plasma HIV RNA determinations before clinical onset who had been untreated or on stable antiretroviral therapy (ART) for at least 2 months. Two hundred seventy-four episodes of different OIs were considered in 216 patients; the median CD4 count was 35 cells/mm3 (range: 0-1154 cells/mm(3)), and the median HIV RNA count was 5.1 log cp/mL (range: < 1.9-6.7 log copies/ml). The different HIV RNA levels were significantly associated with different OIs regardless of CD4 and ART (p < .0001), even when only those occurring in patients with a CD4 count of < or = 50 cells/mm(3) were considered (p = .0049). Kaposi sarcoma, esophageal candidiasis, oropharyngeal candidiasis, and Mycobacterium avium complex disease were associated with significantly above-average median HIV RNA levels, and varicella-zoster virus infection was associated with below-average levels. Different OIs are associated at their onset with significantly different HIV RNA levels, regardless of CD4 cell counts and ART.

Relation Between CD4 Cell Counts and HIV RNA Levels at Onset of Opportunistic Infections

Summary: We assessed the incidence and determinants of bacteremia, pneumonia, and sinusitis/otitis in HIV-positive people receiving cotrimoxazole (CTX) or dapsonepyrimethamine (DP) for primary prophylaxis of Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis (TE) within a randomized clinical trial. In total, 244 patients were randomized: 122 were assigned to CTX and 122 to DP. In the cohort, 22 bacteremia, 63 pneumonia, and 39 sinusitis/otitis cases were observed. Incidence rates of bacteremia, pneumonia, and sinusitis/otitis as well as the 2-year probability of remaining free from any bacterial infection were not significantly different between the two groups. At multivariate analysis, the risks of developing bacteremia and pneumonia were found to be independently increased by the use of a central venous catheter (hazard ratio [HR], 4.48; p < .05 and HR, 4.13; p < .01, respectively) and by hospitalization (HR, 28.82; p < .05 and HR, 10.15; p < .05, respectively). In conclusion, CTX at the dosage employed for primary PCP/TE prophylaxis does not seem to protect against bacterial infections more than second-line DP.

Apoptosis in AIDS.

Infection with the human immunodeficiency virus type 1 (HIV-1) leads to progressive immunodeficiency and onset of opportunistic infections and neoplasms. The loss of immune competence is associated with declines in both the functionality and the number of CD4+ lymphocytes. Multiple mechanisms have been proposed to explain death and dysfunction of CD4+ T-cells. The mechanisms of HIV-1-mediated cell death which are relevant in vivo are unclear at present. However, in vitro explorations on the cytopathic effects of HIV-1 have yielded a wealth of potential triggering events, and signaling and effector pathways leading to apoptosis. The types of pro- and anti-apoptotic stimuli that have been associated with HIV-1 are multiple and often appear overlapping or even contradictory. This review focuses on the various molecular determinants from HIV-1 that play a role in induction of apoptosis in T-lymphocytes. Special attention is devoted to the viral genes, env, nef, tat and vpr, for which a significant body of literature on apotosis-related effects is available.