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Biomedical subjects

Michael M Lederman

Publications and source records attributed to Michael M Lederman.

At least 19 recordsLinked to original sources
PubMed2003

Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy.

OBJECTIVE: To determine the extent to which HIV-infected patients, including those with advanced immunodeficiency, can reverse peripheral CD4 T-cell depletion while maintaining long-term viral suppression on highly active antiretroviral therapy. DESIGN: Cohort study. PARTICIPANTS: Four-hundred and twenty-three HIV-infected patients who initiated HAART prior to 1998 and achieved a viral load </= 1000 copies/ml by 48 weeks were evaluated for up to 4 years or until plasma HIV RNA levels increased to > 1000 copies/ml. MAIN OUTCOME MEASURE: CD4 count changes. RESULTS: Among patients who maintained plasma HIV RNA levels </= 1000 copies/ml, CD4 counts continued to increase through year 4 of HAART. In the last year examined, from year 3 to 4 of HAART, mean CD4 count gains were +89 x 10(6), +86 x 10(6), +95 x 10(6), and +88 x 10(6)/l in patients with pre-therapy CD4 counts of < 50 x 10(6), 50 x 10(6)-199 x 10(6), 200 x 10(6)-349 x 10(6), and >/= 350 x 10(6)/l, respectively (all gains were significantly greater than zero; P < 0.05). Among those with a pre-therapy CD4 count of < 50 x 10(6)/l, 88% achieved a CD4 cell count of >/= 200 x 10(6)/l and 59% achieved a count of >/= 350 x 10(6)/l by year 4. Factors associated with increased CD4 cell count gains from month 3 to year 4 included lower pre-therapy CD4 cell count, younger age, female sex, and infrequent low-level viremia (versus sustained undetectable viremia). CONCLUSIONS: Most patients who achieve and maintain viral suppression on HAART continue to experience CD4 T-cell gains through 4 years of therapy. The immune system's capacity for CD4 T lymphocyte restoration is not limited by low pre-therapy CD4 counts.

Adult↗
PubMed2003

Plasma levels of B-lymphocyte stimulator increase with HIV disease progression.

We measured the plasma levels of B-lymphocyte stimulator (BLyS) in 101 HIV-1-infected patients and 18 controls. BLyS levels were higher among HIV-positive patients [median 5.70 (3.90) versus 4.62 (1.04) ng/ml, P = 0.002], who had significantly higher BLyS and total serum globulin levels with decreasing CD4 cell counts. Moreover, BLyS levels increased exponentially below 100 CD4 cells/microl. BLyS and globulin levels increase as HIV dis ease progresses, suggesting a role for BLyS in the hypergammaglobulinemia of HIV infection.

Adult↗
PubMed2003

Viral dynamics and their relations to baseline factors and longer term virologic responses in treatment-naive HIV-1-infected patients receiving abacavir in combination with HIV-1 protease inhibitors.

From a study of 71 HIV-1-infected patients receiving abacavir in combination with 1 of 5 different HIV-1 protease inhibitors (indinavir, ritonavir, saquinavir, nelfinavir, or amprenavir), we found that the baseline HIV-1 RNA levels were highly predictive of the viral decay rates. The baseline HIV-1 RNA levels were negatively correlated with the first phase viral decay rates (r = -0.77, P < 0.001) and positively correlated with the second phase viral decay rates (r = 0.68, P < 0.001). In addition, the first phase viral decay rate was positively correlated with CD4+ cell increases. No significant correlation was found between viral decay rates and longer term (24 weeks) virologic responses, and no difference in viral decay rates was found among the 5 study regimens. These data suggest that the potency of the 5 treatment regimens was similar and was not predictive of long-term virologic failure.

Adolescent↗
PubMed2003

Role of Baseline pol Genotype in HIV-1 Fitness Evolution.

Viral fitness can be modified upon development of antiretroviral drug resistance, usually by selection of compensatory mutations. In this study, we have used HIV-1 isolates from individuals receiving a protease inhibitor (PI)-based regimen to analyze the impact of basal genetic background on viral fitness evolution. Paired plasma samples and HIV-1 isolates were obtained from 10 PI-naive HIV-infected individuals enrolled in 2 different studies of combination antiretroviral therapy. Genomic regions from pol and env were sequenced. Viral fitness was measured using growth competition experiments followed by heteroduplex tracking analysis. Baseline genotypic analyses of pol showed that 9 of 10 viruses had a different degree of secondary mutations in the protease gene at codons associated with PI resistance (i.e., 10I, 36I, 63P, 71T, and 77I). After 48 weeks of PI-based therapy, a strong correlation was observed between protease genetic divergence and viral fitness difference (r = 0.78, P = 0.03), but not with reverse transcription or Env divergence, suggesting that genotypic changes in the protease gene were driving HIV-1 evolution in these patients. As expected, an inverse correlation was observed between the number of protease and reverse transcription primary mutations and viral fitness (r = -0.65, P < 0.0001). However, our results suggest that the preexistence of secondary mutations in protease genetic background may have implications in HIV-1 fitness evolution and virologic response to antiretroviral therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2003

R5 HIV productively infects Langerhans cells, and infection levels are regulated by compound CCR5 polymorphisms.

Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4+ T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4+ T cells were mediated by CCR5-dependent as well as DC-specific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORF Delta 32 revealed that LCs isolated from ORF Delta 32/wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt/wt individuals (P = 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORF Delta 32/wt heterozygous individuals revealed that LCs isolated from -2459A/G + ORF Delta 32/wt individuals were markedly less susceptible to HIV than were LCs from -2459A/A + ORF Delta 32/wt individuals (P = 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection.

Antibodies, Monoclonal↗
PubMed2003

Age-related immune dysfunction in health and in human immunodeficiency virus (HIV) disease: association of age and HIV infection with naive CD8+ cell depletion, reduced expression of CD28 on CD8+ cells, and reduced thymic volumes.

Older age is a strong predictor of accelerated human immunodeficiency virus (HIV) disease progression. We investigated the possible immunologic basis of this interaction by comparing older (>/=45 years) and younger (</=30 years) HIV-infected adults with simultaneously enrolled, aged-matched, healthy volunteers. Cross-sectional comparisons suggested age-associated reductions in naive CD8(+) cells and in the expression of CD28(+) on CD8(+) cells among both HIV-infected subjects and control subjects. Opposite patterns of CD4(+) and CD8(+) cell differences were apparent between these subject groups. HIV infection, but not age, was associated with impairments in delayed-type hypersensitivity responses, lymphoproliferation, and spontaneous apoptosis and with alterations in expression of chemokine receptors CCR5 and CXCR4. Reduced thymic volumes were associated with age and with HIV infection among younger, but not older, subjects. Because of their common association with age and HIV disease, naive CD8(+) cell depletion, diminished CD28 expression on CD8(+) cells, and reduced thymic volumes are possible correlates of the interaction of age with HIV disease.

Adolescent↗
PubMed2003

T cells containing T cell receptor excision circles are inversely related to HIV replication and are selectively and rapidly released into circulation with antiretroviral treatment.

OBJECTIVE: To examine baseline predictors of T-cell receptor rearrangement excision circle (TREC) levels and their changes during treatment with combined antiretroviral therapy. METHODS: Peripheral blood and lymph node lymphocytes were examined for the presence of TREC by real-time polymerase chain reaction and circulating lymphocyte phenotypes were examined by flow cytometry. Correlates for CD4 and CD8 cell TREC levels at baseline were identified among CD4 and CD8 immunophenotypes, viral load and patient demographics; the significance of TREC changes after initiation of antiretroviral therapy was assessed. RESULTS: Circulating TREC levels correlated inversely with age, with HIV RNA levels, with activation markers on circulating T cells and with naive CD4 but not CD8 cell frequencies. With initiation of antiretroviral therapy, TREC and naive T cell frequencies increased in peripheral blood during the first 2 weeks of treatment and these changes correlated negatively with TREC frequencies in lymph node aspirates, particularly among CD8 T cells. CONCLUSIONS: These findings suggest that recent thymic emigrants are sequestered in lymphoid tissue during uncontrolled HIV replication and are selectively released into circulation rapidly after initiation of antiretroviral therapies.

Adult↗
PubMed2003

A study of the immunology, virology, and safety of prednisone in HIV-1-infected subjects with CD4 cell counts of 200 to 700 mm(-3).

Adult Clinical Trials Group Study 349 examined the immunology, virology, and safety of 40 mg/d prednisone as an adjunct to antiretroviral therapy in 24 HIV-infected subjects with >200 CD4+ T cells/mm in a randomized placebo-controlled trial. After 8 weeks, median lymphocyte and CD4+ cell numbers increased >40% above baseline values (p =.08). No effect was observed on markers of cell activation or apoptosis, although the proportion of CD28+ CD8+ T cells increased (p =.006). Prednisone inhibited monocyte TNFalpha production without affecting T-cell responses to antigens or mitogens. Two subjects assigned to prednisone were subsequently found to have asymptomatic osteonecrosis of the hip. Many questions remain regarding the role of activation-induced sequestration and apoptosis as causes of progressive CD4+ T-cell loss in AIDS. The potential role of corticosteroids as tools to examine this question will be limited by concerns regarding their toxicity; however, further studies of other agents to limit cellular activation in AIDS are warranted.

Adult↗
PubMed2003

Effect of GB virus C coinfection on response to antiretroviral treatment in human immunodeficiency virus-infected patients.

To study how GB virus C (GBV-C) coinfection affects the response to highly active antiretroviral therapy (HAART), 146 human immunodeficiency virus (HIV)-infected patients were tested for GBV-C RNA and antibodies against GBV-C E2 protein, and responses to HAART were evaluated. GBV-C-infected patients exhibited a complete virological response to HAART more often than patients without [correction] GBV-C and had a greater increase in median CD4 cell count and a marginally greater median HIV RNA level decrease. This association was found to be independent of baseline CD4 cell count and plasma HIV RNA, which indicates that an association exists between GBV-C infection and response to HAART.

Adult↗
PubMed2003

Interleukin-2 Increases CD4+ lymphocyte numbers but does not enhance responses to immunization: results of A5046s.

To ascertain whether CD4(+) lymphocyte increases induced by interleukin (IL)-2 enhanced in vivo immune responses, 38 human immunodeficiency virus (HIV)-infected patients who had received highly active antiretroviral therapy (HAART) or HAART and IL-2 for at least 60 weeks were immunized with tetanus toxoid, inactivated glycoprotein 120-depleted HIV-1, and hepatitis A and B vaccines. Despite dramatic increases in CD4(+) lymphocyte counts, IL-2 did not enhance immunization responses.

AIDS Vaccines↗
PubMed2002

Limited immune restoration after 3 years' suppression of HIV-1 replication in patients with moderately advanced disease.

OBJECTIVE: To describe the magnitude of immune restoration after long-term control of HIV-1 replication. DESIGN Prospective study of immune restoration in patients starting highly active antiretroviral therapy (HAART). METHODS: Patients with moderately advanced HIV-1 infection (CD4 cells between 100 x 10 and 300 x 10 /l) who enrolled in a trial of HAART and who had suppression of HIV-1 replication during 3 years of therapy were evaluated for phenotypic and functional indices of immune restoration. RESULTS: Almost all immune restoration achieved occurred during the first year. The median CD4 lymphocyte count increased by 159 x 10 cells/l during the first year (P < 0.001); CD4 lymphocyte rises during the second and third years were not significant. Most decreases in activation antigen expression (CD38/HLA-DR) on CD4 and CD8 lymphocytes occurred during the first year, and after 3 years, patient lymphocytes were still abnormally activated. The proportion of CD4 lymphocytes expressing CD28 increased during the first and second years, but even after 3 years, CD28 expression on CD4 cells remained abnormally low. Lymphocyte proliferative responses to normalized during the first 12 weeks of HAART while responses to tetanus increased only after immunization and enhanced responses to HIV-1 p24 antigen were not observed. CONCLUSIONS: Immune restoration was incomplete in patients who started HAART with moderately advanced HIV-1 disease and most changes occurred during the first year. These data suggest that this degree of suppression of HIV-1 replication alone will not suffice to restore immune competence. The clinical significance of incomplete reconstitution of CD4 lymphocyte number, phenotype, and proliferative function in HIV-1 infection remains to be determined.

Adult↗
PubMed2002

End-stage liver disease in persons with hemophilia and transfusion-associated infections.

Many persons with hemophilia were infected with hepatitis C and B viruses (HCV, HBV) and HIV, but the consequences of these transfusion-acquired infections are poorly defined. We estimated the risk of HCV-related end-stage liver disease (ESLD) and the associations of age, HBV, and HIV with that risk. All 1816 HCV-seropositive hemophilic patients at 16 centers were followed for up to 16 years. Of these, 624 were HIV(-) and 1192 were HIV-coinfected; 135 had persistent HBV surface antigenemia, 1374 had resolved HBV infection, and 287 were HBV-uninfected. ESLD was defined as bleeding esophageal varices, hepatic encephalopathy, persistent ascites, or death excluding nonhepatic causes of these conditions. Competing risk models were used to estimate the annual hazard rate and cumulative incidence of ESLD. Proportional hazards models were used to estimate relative hazards of ESLD with covariates. ESLD developed in 127 of the HCV/HIV-coinfected participants, with an estimated 16-year cumulative incidence of 14.0% (95% confidence interval [CI], 11.6%-16.4%). Without HIV, 10 HCV-infected participants developed ESLD, for a significantly lower cumulative incidence of 2.6% (95% CI, 1.0%-4.3%, P <.0001). ESLD risk increased steeply with age in both groups. With HIV, ESLD risk was increased 8.1-fold (95% CI, 1.9-35.2) with HBV surface antigenemia, 2.1-fold (95% CI, 1.3-3.3) with fewer than 0.2 x 10(9)/L (200/microL) CD4(+) lymphocytes, and 1.04-fold (95% CI, 1.03-1.06) per year of age. Thus, HIV is associated with a markedly increased risk of HCV-related ESLD for persons with hemophilia, particularly with HBV infection, low CD4(+) lymphocytes, or older age.

Adolescent↗
PubMed2002

Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic.

Despite the frequency of HIV-specific CD8 T cells, most HIV-infected patients do not control viral replication without antiviral drugs. Although CD8 T cells are important in containing acute HIV and simian immunodeficiency virus (SIV) infection, CD8 T-cell functions are compromised in chronic infection. To investigate whether functional deficits are specific to HIV, the phenotypic and functional properties of HIV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV)-specific CD8 T cells, labeled with HLA A2.1 or B8 tetramers, were compared in 35 HIV-infected and 9 healthy donors. Cytotoxic T lymphocytes express the cytolytic molecules perforin and granzymes, and are thought to be CD45RA(+)CD27(-). Although most HIV- specific cells are antigen experienced and express granzyme A (median, 85%), few express high levels of perforin (median, 10%) or CD45RA (median, 14%) or have down-modulated CD27 (median, 12%). Perforin expression by HIV-specific cells is not significantly different from that of EBV- or CMV-specific cells in the same donors or in healthy donors. EBV- and CMV-specific cells, like HIV-specific cells, are often not cytotoxic when tested directly ex vivo. HIV-specific T-cell expression of other phenotypic markers is similar to that of EBV- and CMV-specific CD8 T cells in healthy donors. However, CMV-specific cells (and, to a lesser extent, EBV-specific cells) in HIV-infected donors are more likely to be CD27(-), CD45RA(+), and GzmA(+). These results suggest that the chance to eradicate an infection by T-cell-mediated lysis may be undermined once an infection becomes chronic. Impaired antiviral cytotoxicity during chronic infection is not specific to HIV but likely represents the immune response to chronic antigenic exposure.

CD8-Positive T-Lymphocytes↗
PubMed2002

Effect of etanercept (Enbrel) on interleukin 6, tumor necrosis factor alpha, and markers of immune activation in HIV-infected subjects receiving interleukin 2.

The effect of etanercept, a soluble p75 tumor necrosis factor (TNF) receptor:Fc fusion protein (Enbrel; Immunex, Seattle, WA) on plasma cytokines was evaluated in 11 HIV-infected subjects receiving highly active antiretroviral therapy (HAART) for 28 weeks with or without subcutaneous or intravenous recombinant human interleukin 2 (rhIL-2). Plasma IL-6 and C-reactive protein (CRP) levels increased after rhIL-2 treatment. Etanercept pretreatment attenuated these increases. Median plasma IL-6 levels were 20.29 pg/ml 4 days after rhIL-2 and 7.87 pg/ml 4 days after etanercept and rhIL-2 (p = 0.22); median CRP levels were 78.73 and 46.16 microg/ml, respectively (p = 0.03). An effect on TNF bioactivity could not be assessed as all measurements were below limits of detection. No significant changes were seen in temperature or plasma levels of IL-4, IL-10, IL-12, interferon gamma, or HIV-1 RNA levels. All subjects had undetectable or low-level HIV-1 RNA levels before etanercept dosing. One subject died; however, her death was thought to be unrelated to etanercept. Pretreatment with etanercept may blunt activation of IL-6 and CRP expression induced by rhIL-2. The safety and utility of etanercept in HIV-infected persons should be explored further.

Antiretroviral Therapy, Highly Active↗
PubMed2002

HIV long-term non-progressors maintain brisk CD8 T cell responses to other viral antigens.

OBJECTIVE: To examine the specificity of heightened CD8 cell responses in HIV-1-infected long-term non-progressors. DESIGN: Cross-sectional study examining CD8 cell responses to hepatitis C virus (HCV) peptides in HCV-HIV LTNP (n = 6), HCV-HIV progressors (n = 11), HCV singly infected patients (n = 32), HCV singly infected patients with self-limited disease (n = 10), HIV singly infected progressors (n = 7) and HCV-negative, HIV-negative controls (n = 10). METHODS: The frequency of HCV-reactive interferon gamma-producing cells in peripheral blood was assayed by enzyme linked immunospot assay using a panel of 61 HCV-1-derived peptides. RESULTS: Five of six HCV-HIV LTNP had HCV-specific CD8 responses. In contrast, responses were observed in 2 of 32 HCV singly infected patients, 2 of the 10 HCV singly infected patients with self-limited disease, and 0 of 11 HCV-HIV progressors (P < 0.001). Both frequency of HCV-specific CD8 cells and number of HCV peptides recognized were greater in HCV-HIV LTNP than in other groups. CONCLUSIONS: HIV-infected LTNP maintain heightened CD8 cell responses to HCV in addition to heightened HIV specific responses. Common mechanisms may underlie preservation of CD8 immune responses in these individuals. An improved understanding of these mechanisms will help to gain insight into protective antiviral immunity as well as to the means whereby these viruses impair host defenses.

AIDS-Related Opportunistic Infections↗