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Biomedical subjects

M P Busch

Publications and source records attributed to M P Busch.

At least 37 records · Page 2Linked to original sources
PubMed2001

Leukocyte-reduced red blood cell transfusions in patients with anemia and human immunodeficiency virus infection: the Viral Activation Transfusion Study: a randomized controlled trial.

CONTEXT: Allogeneic blood transfusions have immunomodulatory effects and have been associated with activation of human immunodeficiency virus (HIV) and cytomegalovirus (CMV) in vitro and of HIV in small pilot studies. Retrospective studies suggest that transfusions adversely affect the clinical course of HIV. Data in selected non-HIV-infected patients requiring blood transfusion have suggested clinical benefit with leukocyte-reduced red blood cells (RBCs). OBJECTIVE: To compare the effects of leukoreduced and unmodified RBC transfusions on survival, complications of acquired immunodeficiency syndrome, and relevant laboratory markers in HIV-infected patients. DESIGN AND SETTING: Double-blind randomized controlled trial conducted in 11 US academic medical centers from July 1995 through June 1999, with a median follow-up of 12 months (24 months in survivors). PATIENTS: A total of 531 persons infected with HIV and CMV, aged 14 years or older, who required transfusions for anemia; 259 received leukoreduced transfusions and 262 received unmodified transfusions (10 did not receive the planned transfusion). MAIN OUTCOME MEASURES: Survival and change in plasma HIV RNA level 7 days after transfusion, compared by type of transfusion. RESULTS: At entry, the groups were similar in demographic, clinical, and relevant laboratory characteristics. A total of 3864 RBC units were transfused. Two hundred eighty-nine deaths occurred (151 with leukoreduced transfusion; 138 with unmodified transfusion); median survival was 13.0 and 20.5 months, respectively (relative hazard [RH], 1.20; 95% confidence interval [CI], 0.95-1.51; log-rank P =.12). Analyses adjusted for prognostic factors suggested possible worse survival with leukoreduction (RH, 1.35; 95% CI, 1.06-1.72). There was no difference in time to new opportunistic event/death or frequency of transfusion reactions. No changes in plasma HIV RNA level were seen in either group at days 7, 14, 21, or 28, even in patients not taking antiretroviral drugs. There were no differences in trends between groups in CMV DNA, CD4 cell counts, activated (CD38% or human leukocyte antigen-DR) CD8 cell counts, or plasma cytokine levels. CONCLUSIONS: We found no evidence of HIV, CMV, or cytokine activation following blood transfusion in patients with advanced HIV infection. Leukoreduction provided no clinical benefit in these patients. These data demonstrate the importance of conducting controlled studies of effects of leukoreduction in different patient populations, since smaller studies in other patient populations have suggested leukoreduction may be beneficial.

AIDS-Related Opportunistic Infections↗
PubMed2001

Microchimerism does not induce tolerance and sustains immunity after in utero transplantation.

BACKGROUND: To date, over 40 in utero transplants have been performed in humans; the only successes were documented in the treatment of severe combined immunodeficiency syndromes. Hemoglobinopathies and metabolic disorders are candidate diseases for this approach; however, when applied clinically, the results have been discouraging. To address the role of the fetal immune system in the outcome of in utero transplantation, we have developed a murine model of in utero transplantation in immunologically intact murine recipients and have studied chimerism and tolerance/immunity to allogeneic donor cells through the lives of the animals. METHODS: We have performed experiments in which purified murine sca-1+/lin- cells and c-kit+/lin- cells of C57BL/6 (H2b) mice were injected into Balb/c (H2d) fetal recipients at early gestational ages. Chimerism was tested by highly sensitive semiquantitative polymerase chain reaction assay and tolerance/immunity to donor cells was studied by in vivo (skin grafts, responses to postnatal boosts) and in vitro (mixed lymphocyte culture, cytotoxicity, and cytokine release) assays. RESULTS: One hundred percent (10/10) of mice transplanted with c-kit+ cells and 44% (4/9) of mice transplanted with sca+ cells showed circulating donor cells within the first 6 months of life (P=0.031). Mice in the sca+ group rejected donor skin grafts at a mean time of 9.1+/-0.2 days, whereas mice in the c-kit+ group rejected donor skin grafts at a mean time of 15.1+/-0.7 days (P=0.001). The difference between the transplanted groups and non-transplanted controls was also significant (P<0.05). All mice transplanted with sca+/lin- cells showed greater response to donor cells than to third-party cells at all effector to target ratios (P=0.002). Differences in response to donor alloantigen between sca+ and c-kit+ groups were significant (P=0.003). Cytokine quantification demonstrated higher TH1 than TH2 cytokine release in all groups, and the response to donor cells was higher in the sca+ compared with c-kit+ mice (P=0.031). CONCLUSION: These results demonstrate a low level of chimerism and tolerance in mice transplanted in utero with sca+/lin- and c-kit+/lin- cells. The possibility of active in utero immunization to donor cells is supported by accelerated skin graft rejection in mice transplanted with sca+ cells and enhanced in vitro immune responses in mice with persistent microchimerism.

Animals↗
PubMed2001

Insights into the epidemiology, natural history and pathogenesis of hepatitis C virus infection from studies of infected donors and blood product recipients.

Studies of patients with post-transfusion non-A, non-B hepatitis and their implicated donors were critical to the discovery of hepatitis C virus (HCV) and to the development and progressive enhancement of HCV immunoassays for donor screening and diagnostic applications. Post-transfusion HCV cases have also been used to define the time course of viral and immunological markers following acute infection. Even more precise data on the timing and characteristics of viremia and immune responses during primary HCV infection have been derived from studies of serial samples from source plasma donors who were identified while in the process of infection and seroconversion. Such data have been critical to the derivation of estimates for the viremic, pre-seroconversion window period, and hence projections of the yield of addition of nucleic acid amplification technology (NAT) or HCV core antigen enzyme immunoassays (Ag-EIAs) to antibody screening in donor and diagnostic settings. In addition to these implications for screening and diagnosis, studies of HCV in the blood donor and blood product recipient settings have yielded substantial insights into the epidemiology, pathogenesis and prognosis of HCV infection. In the future, prospective studies of blood and plasma donors detected in the primary phase of HCV infection by NAT screening, will be important for defining viral and host genetic and immunological determinants of clearance of acute viremia, as well as for investigating the benefits of early treatment. Thus, the findings from studies of HCV among donors and blood product recipients have yielded and should continue to provide important insights into HCV pathogenesis leading to novel diagnostic, therapeutic and vaccination strategies.

Antigenic Variation↗
PubMed2001

Detection of microchimerism by PCR is a function of amplification strategy.

BACKGROUND: Suitable detection methods are needed to support larger studies of microchimerism and the allogeneic exposures that may be etiologically related to it. STUDY DESIGN AND METHODS: A twotier PCR strategy for microchimerism detection was developed on the basis of the observation that assay sensitivity for the detection of microchimerism depends on the specificity with which primer pairs recognize sequences unique to the minor population. First, specimens are tested to determine the host HLA class II genotype by using a locus-specific PCR strategy with low sensitivity for microchimerism. Then, a sequence-specific PCR analysis having high sensitivity for detection of microchimerism is applied to detect and quantitate the minor population. Locus-specific, group-specific, and sequence-specific amplification strategies for the detection of distinct minor WBC populations prepared ex vivo were compared. In addition, 39 clinical samples from patients with known transfusion-associated microchimerism and 20 umbilical cord blood (CB) specimens containing maternal WBCs were studied. RESULTS: Locus-specific amplification detected 17 (94%) of 18 cases in which microchimerism was present at 10 percent, but only 1 of 51 cases with microchimerism < or = 1 percent. Group-specific amplification detected all 63 cases with minor populations present at > or = 0.10 percent, but only 16 of 21 cases at the 0.01 percent level. Sequence-specific amplification detected 100 percent of cases down to the 0.01 percent level. When applied to clinical samples, locus-specific amplification reliably identified the major population but proved insensitive to low-level minor populations. CONCLUSIONS: For the detection of microchimerism, assay sensitivity is a function of amplification strategy. These results suggest a simple approach to population screening for microchimerism: the background population of WBCs is typed by a locus-specific method, while minor population(s) can then be sought by using one or several sequence-specific amplifications.

Alleles↗
PubMed2001

Quantitation of genomic DNA in plasma and serum samples: higher concentrations of genomic DNA found in serum than in plasma.

BACKGROUND: Plasma and serum samples have been used to detect cell-free genomic DNA in serum or plasma in certain pathologic conditions such as systemic lupus erythematosus, pulmonary embolism, and malignancies, as well as in fetal cell chimerisms in maternal serum and/or plasma. In this study, baseline concentrations of cell-free DNA in serum and plasma samples were evaluated for the study of posttransfusion chimerism. STUDY DESIGN AND METHODS: DNA was extracted from fresh or stored (4 degrees C for 1-6 days) normal donor serum or plasma samples (ACD; EDTA) by using reagents from an HIV assay kit. After incubation and washing of samples, purified DNA was amplified with HLA DQ-alpha primers (GH26 and 27) or human Y-chromosome primers (SA and SD) to quantitate the concentration of genomic DNA. RESULTS: Fresh serum samples had concentrations of cell-free DNA that were about 20-fold higher than the concentrations in fresh plasma samples. The concentration of cell-free genomic DNA in serum samples increased daily, to a level more than 100 times baseline after clotted blood tubes were stored at 4 degrees C for 4 to 5 days. There was a small increase in cell-free plasma DNA in stored ACD whole blood samples. Male WBCs, spiked into fresh nonanticoagulated female blood, were lysed during the process of clotting, with male DNA liberated into the serum samples. CONCLUSION: Most cell-free DNA in serum samples is generated during the process of clotting in the original collection tube. The concentration of cell-free genomic DNA in fresh plasma is probably the same as that in circulation. Consequently, while serum samples should not be used to monitor the concentration of cell-free DNA in a patient's circulation, serum collected from sample tubes containing clots (i.e., without anticoagulant), 3 to 5 days after the date of phlebotomy, could be useful as a source of DNA with which to screen for posttransfusion microchimerism.

Blood Donors↗
PubMed2001

Donor WBCs can persist and transiently mediate immunologic function in a murine transfusion model: effects of irradiation, storage, and histocompatibility.

BACKGROUND: Donor WBCs are responsible for numerous transfusion complications, but little is known concerning the natural history of their clearance following transfusion or of their function in the recipient's circulation. A murine transfusion model was developed to investigate the effects of blood component characteristics and histocompatibility on donor WBC survival kinetics and function. STUDY DESIGN AND METHODS: To investigate the effects of storage and irradiation, fresh whole blood and blood stored for 1, 2, and 6 weeks at 4 degrees C, all from male C57b (H2K(b)) mice, was transfused to female Balb/c (H2K(d)) mice. To study the effect of histocompatibility, blood was also transfused from C57b mice to Balb/c, FVB, C3H, and SW (outbred) mice. To investigate the xenogeneic setting, blood from humans, rats, and rabbits was transfused to Balb/c mice. Samples were collected weekly after transfusion, and the donor WBCs were analyzed, targeting the Y-chromosome with quantitative PCR. To investigate donor WBC function, dinitrochlorobenzene (DNCB) sensitivity was induced in donor and recipient mice, and the transfusion recipients were observed for hypersensitivity to DNCB. RESULTS: Donor WBCs had reduced in vivo survival equivalent to their period of storage ex vivo at 4 degrees C. Irradiation of donor blood produced no observable difference in donor WBC survival. Allogeneic male donor WBCs persisted (100-<1 cell/microL) in female Balb/c recipient mice blood over 6 weeks. Donor WBC survival kinetics displayed an early MHC-dependent phase, which was followed by a more rapid phase that was not influenced by donor-recipient MHC differences. All donor WBCs were cleared within 24 to 48 hours. DNCB sensitivity was passed through transfusion, where it was transiently expressed in naive recipients. CONCLUSION: The clearance of donor WBCs in the murine transfusion model is much slower than that in humans. Allogeneic donor WBC clearance may be biphasic, involving MHC-dependent as well as MHC-independent mechanisms. DNCB sensitivity can be transferred transiently to a naive recipient.

Animals↗
PubMed2001

Incidence rates of viral infections among repeat donors:are frequent donors safer?

BACKGROUND: Incidence rates (IRs) for viral infections may vary with the frequency of donation among repeat, community, whole-blood (WB) donors, with IRs thought to be lower among donors with higher frequency of donation. STUDY DESIGN AND METHODS: IRs for HIV, HTLV, HCV, and HBV infection were stratified by frequency of donation among 868,403 repeat WB donors who gave approximately 4 million donations at five United States blood centers from 1991 through 96. All donors had given at least 2 donations during those years, with the first donation being nonreactive on confirmatory testing. Frequency of donation was measured in three ways: by the number of donations per year; at the time of donation, by the number of donations given within the preceding 2-year period; and by the number of donations given from 1991 through 1993. RESULTS: The IRs for HIV, HCV, and HBV infection did not appear to differ among donors with lower or higher numbers of donation per year. However, the IR for HTLV infection decreased as the number of donations per year increased (p = 0.0004). IRs for all viral markers remained stable, regardless of the number of donations given within the 2-year period before the donation. Although IRs for HIV, HTLV, and HCV infection did not vary by the number of donations given in 1991 through 1993, the IR for HBV infection appeared to be lower in donors who gave more donations in that period (p = 0.01). CONCLUSION: These findings do not provide evidence of a lower IR for transfusion-transmissible viral infections among repeat WB donors who give more frequently. Abbreviated screening histories for frequent repeat donors might not be advisable.

Adult↗
PubMed2001

WBC reduction in RBC concentrates by prestorage filtration: multicenter experience.

BACKGROUND: As universal leukocyte (WBC) reduction (ULR) is being considered as a new standard, few data are available on the performance of WBC-reduction filtration in routine practice. The performance of WBC-reduction in RBCs, using varied filtration practices, in meeting the current FDA requirement (<5 x 10(6)), Council of Europe (EC) recommendation, the proposed FDA requirement (<1 x 10(6)), and a more stringent proposal (<5 x 10(5)) for residual WBCs per RBC unit was assessed and compared. STUDY DESIGN AND METHODS: Participating facilities were the 11 sites of the Viral Activation Transfusion Study (VATS), a prospective study of the impact of transfusion with and without WBC-reduction on survival and HIV viral load in HIV-1-infected patients. Patients randomly assigned to undergo WBC reduction were required to receive RBCs < or =14 days old that had undergone prestorage (within 72 hours of collection) WBC-reduction filtration by a method devised to achieve a postfiltration WBC count of <5 x 10(6). Residual WBC quantitation was performed by PCR in the central VATS laboratory by using frozen WBC-reduced RBC samples obtained at issue for transfusion. RESULTS: A total of 1869 WBC-reduced RBC units were studied. Filtration practices varied within and between sites. There were significant differences in mean residual WBC counts at the 11 sites (p<0.001). Among the WBC-reduced RBC units, 0.8 percent exceeded 5 x 10(6) WBCs per unit, 8.3 percent exceeded 1 x 10(6) WBCs per unit, and 14.3 percent exceeded 5 x 10(5) WBCs per unit. CONCLUSION: Residual WBCs in WBC-reduced RBC units vary within and between sites. WBC reduction was successful, in that over 99 percent and 91 percent of VATS WBC-reduced RBC units met US and EC thresholds, respectively. However, the small but measurable failure rate indicates that not every unit will meet these guidelines.

Blood Component Removal↗
PubMed2001

Multicenter evaluation of PCR methods for detecting CMV DNA in blood donors.

BACKGROUND: CMV DNA screening may be a useful adjunct to serologic tests in distinguishing potentially infectious blood donations from those that are "CMV-safe." However, there is currently no consensus on the optimal assay method for accurate detection of CMV DNA in donors. STUDY DESIGN AND METHODS: A blinded multicenter evaluation of seven CMV PCR assays was performed by five laboratories by using coded sets of analytical controls and donor blood samples. RESULTS: Five assays displayed sufficient sensitivity for donor screening, as judged by consistent detection of a minimum of 25 CMV genome equivalents (geq) in analytical controls constructed to contain from 1 to 100 CMV geq in background DNA from 250,000 cells, while the other two assays displayed inadequate sensitivity. Three sensitive assays, two based on nested PCR directed at the UL93 and UL32 regions of the CMV genome and another test (Monitor Assay, Roche), did not detect CMV DNA in samples from any of 20 pedigreed CMV-seronegative, Western blot-negative (S-/WB-) donors. Two other assays based on nested PCR occasionally detected CMV DNA in S-WB- samples, and one sensitive nested PCR assay directed at UL123 detected CMV DNA in a large proportion (85%) of S-WB- samples. CONCLUSION: Seven CMV PCR assays currently used for research and/or diagnostic applications displayed marked variations in sensitivity, specificity, and reproducibility when applied to coded analytical and clinical control samples containing cellular DNA from the equivalent of 250,000 WBCs. These results will be useful in the selection of assays with performance characteristics appropriate to donor screening objectives. They may also help explain discrepant findings from previous studies that used PCR to determine CMV DNA prevalence in seronegative and seropositive blood donors.

AIDS-Related Opportunistic Infections↗
PubMed2001

Kinetics of fetal cellular and cell-free DNA in the maternal circulation during and after pregnancy: implications for noninvasive prenatal diagnosis.

BACKGROUND: Fetal genetic material is detectable in the maternal circulation and has been used for noninvasive prenatal diagnosis. However, few data are available concerning its quantity and natural history during gestation. STUDY DESIGN AND METHODS: This study prospectively characterized the kinetics of cellular and cell-free fetal DNA in the circulation of 25 healthy women during and after uncomplicated pregnancy. Real-time kinetic PCR was used to quantitate human Y-chromosome sequences, and liquid oligomer hybridization with (32)P-labeled probes was used to verify the identity of amplified products. RESULTS: In all male pregnancies, but no female pregnancies, low-level fetal Y-chromosome DNA was detected in both cellular and cell-free compartments beginning at 7 to 16 weeks but increasing steadily after 24 weeks and reaching a peak at parturition. The fetal DNA decreased rapidly after birth. CONCLUSION: Fetal genetic material can be detected throughout pregnancy, and its quantity is a function of gestational age and of whether the plasma or cellular compartment is examined. Both the absolute quantity of fetal DNA and its ratio to total DNA (maternal + fetal) are greater in the plasma than in the cellular compartment. Fetal DNA is cleared rapidly from both compartments after parturition, which suggests that turnover is dynamic. Because they provide prospective and quantitative data concerning fetal DNA levels, these observations and kinetic PCR methods may have implications for noninvasive prenatal diagnosis. Further studies will be needed to determine the immunologic implications of fetal-maternal DNA exchange and cellular microchimerism.

Adult↗
PubMed2001

Emerging infectious disease issues in blood safety.

Improvements in donor screening and testing and viral inactivation of plasma derivatives together have resulted in substantial declines in transfusion-transmitted infections over the last two decades. Most recently, nucleic acid testing techniques have been developed to screen blood and plasma donations for evidence of very recent viral infections that could be missed by conventional serologic tests. Nonetheless, the blood supply remains vulnerable to new and reemerging infections. In recent years, numerous infectious agents found worldwide have been identified as potential threats to the blood supply. Several newly discovered hepatitis viruses and agents of transmissible spongiform encephalopathies present unique challenges in assessing possible risks they may pose to the safety of blood and plasma products.

Blood Donors↗
PubMed2000

Failure of routine HIV-1 tests in a case involving transmission with preseroconversion blood components during the infectious window period.

CONTEXT: Current screening practices for blood donations have been successful in reducing human immunodeficiency virus (HIV) transmission through receipt of contaminated blood products. However, HIV-infected blood donations made prior to seroconversion and before high levels of viral replication occur could test negative using both serologic antigen and antibody tests. Testing based on nucleic acid amplification (NAT) is being implemented to screen for HIV-infected blood donated during this period, yet the issue of single vs minipool donation screening remains unresolved. OBJECTIVES: To determine HIV-1 genetic linkage between virus in 2 HIV-1-infected recipients of blood components and virus in the donor, who was HIV antigen and antibody negative at the time of donation; to screen the blood donor's plasma with HIV NAT assays, including those currently proposed for use in US blood donation screening. DESIGN AND SETTING: Case study conducted in October 1997 involving the Communicable Disease Centre, Singapore General Hospital, and the Singapore Blood Transfusion Service, Singapore. SUBJECTS: The blood donor and the 2 recipients of donor platelets and red blood cells. MAIN OUTCOME MEASURES: Genetic analysis of the HIV-1 p17 coding region of gag and the C2V5 region of env to determine the genetic relatedness of virus from the donor and recipients; reactivity in quantitative and qualitative assays, and reactivity in donor screening HIV NAT assays in single donation and minipool screening contexts. RESULTS: Direct DNA sequencing demonstrated identical HIV-1 subtype E viral sequences in the donor and recipients. Based on comparisons of a qualitative and quantitative assay for HIV-1 RNA levels, a low level of viremia (range, 5-39 copies/mL in plasma) was estimated to be in the donor's undiluted blood at the time of donation. Additional testing using donor-screening NAT assays showed consistent detection of HIV RNA in the undiluted donor plasma whereas detection was inconsistent at the 1:16 and 1:24 dilution levels currently used in minipool screening of blood donations in the United States. CONCLUSIONS: Transmission of HIV from a blood donor to a platelet recipient and a red blood cell recipient occurred in the preseroconversion infectious window period. The viral load in the implicated donation was estimated to be less than 40 copies/mL of plasma. Current US minipool HIV NAT screening protocols may not be sufficiently sensitive to detect all infectious window-period donations. JAMA. 2000;284:210-214

AIDS Serodiagnosis↗
PubMed2000

Trends in incidence and prevalence of major transfusion-transmissible viral infections in US blood donors, 1991 to 1996. Retrovirus Epidemiology Donor Study (REDS)

CONTEXT: Evaluating trends in blood donor infectious disease rates is essential for monitoring blood supply safety and donor screening effectiveness. OBJECTIVE: To determine changes over time in blood donor population infection rates of human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), hepatitis C virus (HCV), and hepatitis B virus (HBV). DESIGN: Cross-sectional survey data from the National Heart, Lung, and Blood Institute-sponsored Retrovirus Epidemiology Donor Study. SETTING: Five blood centers in different regions of the United States. PARTICIPANTS: A total of 1.9 million volunteer blood donors with 1 or more nonautologous donations from January 1991 to December 1996. MAIN OUTCOME MEASURES: Changes in rates of HIV, HTLV, HCV, and HBV infections were evaluated by comparing yearly prevalence estimates (per 100,000 donations) for first-time allogeneic donors and period-specific incidence rates (IRs) (per 100,000 person-years) for repeat allogeneic donors between 1991 and 1996 (for HCV, from about March 1992 to June 1996). RESULTS: Prevalence of HIV decreased in first-time donors from 0.030% to 0.015% (P=.006) and HCV prevalence decreased from 0.63% to 0.40% (P<.001). Trends were not statistically significant for the proportion of first-time donors with hepatitis B surface antigen (HBsAg) or HTLV. For repeat donors, IRs did not change significantly, indicating a stable but low level of seroconversion. The overall IRs (95% confidence intervals) per 100,000 person-years were 2.92 (2.26-3.70) for HIV, 1.59 (1.12-2.19) for HTLV, 3.25 (2.36-4.36) for HCV, and an estimated 10.43 (7.99-13. 37) for HBV (based on an HBsAg rate of 2.66 [2.04-3.41] with presumed false-positive results considered negative). The HBV IR estimate with presumed false-positive results considered positive (for comparability to previous analyses) was 17.83 (14.60-21.56). CONCLUSION: The decrease in HIV and HCV prevalence rates, combined with the previously documented lower rates of infection in first-time donors compared with the general population, suggests the continued benefit of behavioral risk factor screening. JAMA. 2000;284:229-235

Blood Banks↗
PubMed2000

'Modeling' relationships among HIV-1 replication, immune activation and CD4+ T-cell losses using adjusted correlative analyses.

OBJECTIVE: To model the relationships among HIV-1 replication, immune activation and CD4+ T-cell losses in HIV-1 infection. METHODS: Cross-sectional analysis of baseline data from the Viral Activation by Transfusion Study. Comparisons of unadjusted and adjusted correlative analyses to establish models for mechanisms of cell loss in AIDS. RESULTS: Using these analyses, significant correlations were found among plasma levels of tumor necrosis factor alpha (TNFalpha) and its type two receptor (TNFrII), interleukin-6 (IL-6), beta2-microglobulin, expression of CD38 and HLA-DR on CD8+ T lymphocytes and plasma levels of HIV-1 RNA. When correlations among these indices were adjusted for possible intermediary correlations, the relationship between HIV-1 RNA levels and all plasma markers of immune activation could be accounted for by the correlation between plasma HIV-1 RNA and plasma TNFrII levels. In addition, the negative correlations that both HIV-1 RNA levels and TNFrII levels had with CD4+ T-cell counts were partially accounted for by the correlations of HIV-1 RNA and TNFrII with CD38 expression on CD8+ T cells. In persons with advanced disease (CD4+ T cells < 50 x 10(6)/l) IL-6 levels were inversely correlated with CD4+ T-cell counts. CONCLUSIONS: This analysis is consistent with a model wherein HIV-1 replication induces TNFalpha expression that induces multiple other indices of immune activation. In this model, HIV-1 replication and TNFalpha expression induce CD4+ T-cell losses at least in part through mechanisms reflected in heightened CD38 expression.

ADP-ribosyl Cyclase↗