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Biomedical subjects

H C Lane

Publications and source records attributed to H C Lane.

At least 55 records · Page 3Linked to original sources
PubMed1998

Peripheral expansion of pre-existing mature T cells is an important means of CD4+ T-cell regeneration HIV-infected adults.

The CD4+ T-cell pool in HIV-infected patients is in a constant state of flux as CD4+ T cells are infected and destroyed by HIV and new cells take their place. To study T-cell survival, we adoptively transferred peripheral blood lymphocytes transduced with the neomycin phosphotransferase gene between syngeneic twin pairs discordant for HIV infection. A stable fraction of marked CD4+ T cells persisted in the circulation for four to eighteen weeks after transfer in all patients. After this time there was a precipitous decline in marked cells in three of the patients. At approximately six months, marked cells were in lymphoid tissues in proportions comparable to those found in peripheral blood. In two patients, the proportion of total signal for the transgene (found by PCR analysis) in the CD4/CD45RA+ T-cell population relative to the CD4/CD45RO+ population increased in the weeks after cell infusion. These findings indicate that genetically-marked CD4+ T cells persist in vivo for weeks to months and that the CD4+ T-cell pool in adults is maintained mostly by the division of mature T cells rather than by differentiation of prethymic stem cells. Thus, after elements of the T-cell repertoire are lost through HIV infection, they may be difficult to replace.

Adult↗
PubMed1998

Progression of human immunodeficiency virus disease is associated with increasing disruptions within the CD4+ T cell receptor repertoire.

The immunodeficiency caused by human immunodeficiency virus (HIV) infection may be related to loss of diversity in the T cell receptor (TCR) repertoire. A cross-sectional study of the CD4 TCR repertoire was done for patients at various stages of HIV infection. Semiquantitative polymerase chain reaction was used to study the relative usage of the variable chain beta (BV) subfamilies and the size distributions of transcripts (CDR3 size analysis) within these subfamilies. The relative usage of the TCRBV subfamilies of patients and controls was not significantly different. The proportion of subfamilies with abnormal CDR3 size patterns was higher in the HIV-infected patients (25%, 95% confidence interval [CI], 17%-33%) than in the controls (7.2%, 95% CI, 2.3%-12.1%; P < .001), with a significant negative correlation between the number of CD4 cells and the percentage of abnormal TCRBV subfamilies. These results indicate that progressive loss of CD4 T cells is accompanied by increasing disruptions within the T cell receptor repertoire.

CD4 Lymphocyte Count↗
PubMed1998

Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques.

Parenteral administration of a mouse anti-human CD8 monoclonal antibody (MAb) to rhesus macaques resulted in a transient depletion of CD8+ cells in both the peripheral blood and lymphoid tissues. When administered during primary chimeric simian/human immunodeficiency virus infections, the CD8 MAb caused marked elevations of plasma and cell-associated virus levels in both the peripheral blood and lymphoid tissues and led to prolonged depletion of CD4 cells. Taken together, these results directly demonstrate that CD8+ T lymphocytes are actively involved in controlling the acute phase of primate lentivirus infections.

Animals↗
PubMed1997

Telomere length, telomerase activity, and replicative potential in HIV infection: analysis of CD4+ and CD8+ T cells from HIV-discordant monozygotic twins.

To address the possible role of replicative senescence in human immunodeficiency virus (HIV) infection, telomere length, telomerase activity, and in vitro replicative capacity were assessed in peripheral blood T cells from HIV+ and HIV- donors. Genetic and age-specific effects on these parameters were controlled by studying HIV-discordant pairs of monozygotic twins. Telomere terminal restriction fragment (TRF) lengths from CD4+ T cells of HIV+ donors were significantly greater than those from HIV- twins. In contrast, telomere lengths in CD8+ T cells from HIV+ donors were shorter than in HIV- donors. The in vitro replicative capacity of CD4+ cells from HIV+ donors was equivalent to that of HIV- donors in response to stimulation through T cell receptor CD3 and CD28. Little or no telomerase activity was detected in freshly isolated CD4+ or CD8+ lymphocytes from HIV+ or HIV- donors, but was induced by in vitro stimulation of both HIV+ and HIV- donor cells. These results suggest that HIV infection is associated with alterations in the population dynamics of both CD4+ and CD8+ T cells, but fail to provide evidence for clonal exhaustion or replicative senescence as a mechanism underlying the decline in CD4+ T cells of HIV-infected donors.

Adult↗
PubMed1997

Reactivation of HIV type 1 in chronically infected chimpanzees following xenostimulation with human cells or with pulses of corticosteroid.

Following resolution of a primary HIV-1 infection initially induced by inoculating a mixture of three different virus strains, a chimpanzee was exposed to both immunostimulatory and immunosuppressive agents in an attempt to assess the contributions of different components of the immune system in suppressing circulating virus. The infusion of human leukocytes as an xenogeneic stimulus induced the replication of one of the input virus strains that had not previously been isolated or detected by PCR. The administration of high-dose, 17-day courses of corticosteroids resulted in coordinate and transient increases of each of the three viruses present in the original inoculum and elevation of HIV-1-specific ELISA antibody levels. Steroids administered to a second chimpanzee, chronically infected with a single HIV-1 isolate, also induced elevations of cell-associated virus. These results highlight the intimate relationship between immune system activation/immunosuppression and HIV replication in an animal model.

Animals↗
PubMed1997

Immune reconstitution in HIV infection.

Progressive immune deficiency arising during HIV disease reflects the continual degradation and the ultimate deletion of immune specificites defined by the CD4(+) T lymphocyte repertoire. Recent evidence suggests that improvements in the immune function of patients with HIV who receive therapy primarily reflects the expansion of CD4(+) T lymphocyte populations present before therapy commenced. These observations have implications for clinical management, therapeutic strategies, and future research.

Acquired Immunodeficiency Syndrome↗
PubMed1997

HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies.

Changes in CD4+ T-cell surface marker phenotype and antigen receptor (TCR) repertoire were examined during the course of HIV infection and following therapy. A preferential decline in naive CD4+ T cells was noted as disease progressed. Following protease inhibitor therapy, naive CD4+ T cells increased only if they were present before initiation of therapy. Disruptions of the CD4+ TCR repertoire were most prevalent in patients with the lowest CD4+ T-cell counts. Antiviral or IL-12 therapy-induced increases in CD4+ T-cell counts led to only minor changes in previously disrupted repertoires. Thus, CD4+ T-cell death mediated by HIV-1 infection may result in a preferential decline in the number of naive CD4+ T cells and disruptions of the CD4+ T-cell repertoire that are not immediately corrected by antiviral or immune-based therapies.

CD4-Positive T-Lymphocytes↗
PubMed1997

Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons.

The safety and efficacy were assessed of 5-day cycles of subcutaneous (sc) interleukin-2 (IL-2) every 8 weeks in human immunodeficiency virus type 1-infected outpatients with >200 CD4 cells/mm3. Immunologic, virologic, and toxicity parameters were measured in 18 patients receiving standard antiretrovirals plus 5-day courses of sc IL-2 (3-18 MIU/day) every 2 months. Systemic toxicities established the maximally tolerated dose (MTD) of IL-2 as 15 MIU/day. CD4 cell responses appeared to correlate directly with baseline CD4 cell counts, with several patients experiencing a dramatic rise after 3 cycles. Virus load increased only transiently in the peri-injection period. It was concluded that serial cycles of outpatient sc IL-2 can be administered safely, with an MTD of 15 MIU/day. Patients with higher baseline counts appear to have a greater CD4 cell response to sc IL-2 therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation, and aging.

Telomerase activity and the regulation of telomere length are factors which have been implicated in the control of cellular replication. These variables have been examined during human lymphocyte development, differentiation, activation, and aging. It was found that telomere length of peripheral blood CD4+ T cells decreases with age as well as with differentiation from naive to memory cells in vivo, and decreases with cell division in vitro. These results provide evidence that telomere length correlates with lymphocyte replicative history and residual replicative potential. In contrast, telomere length appears to increase during tonsil B-cell differentiation and germinal center (GC) formation in vivo. It was also found that telomerase activity is highly regulated during T-cell development and B-cell differentiation in vivo, with high levels of telomerase activity expressed in thymocytes and GC B cells, and low levels of telomerase activity in resting mature peripheral blood lymphocytes. Finally, resting lymphocytes retain the ability to upregulate telomerase activity upon activation, and this capacity does not appear to decline with age. Although the precise role of telomerase in lymphocyte function remains to be elucidated, telomerase may contribute to protection from telomere shortening in T and B lymphocytes, and may thus play a critical role in lymphocyte development, differentiation and activation. The future study of telomerase and its regulation of telomere length may enhance our understanding of how the replicative lifespan is regulated in lymphocytes.

Animals↗
PubMed1997

Clarithromycin lowers plasma zidovudine levels in persons with human immunodeficiency virus infection.

The use of antiretroviral agents and drugs for the treatment and prophylaxis of opportunistic infections has lengthened the survival of persons with AIDS. In the era of multidrug therapy, drug interactions are important considerations in designing effective and tolerable regimens. Clarithromycin has had a significant impact on the treatment of disseminated Mycobacterium avium complex infection, and zidovudine is the best-studied and one of the most widely used antiretroviral agents in this population. We conducted a study to determine the maximally tolerated dose of clarithromycin and the pharmacokinetics of clarithromycin and zidovudine individually and in combination. Mixing studies were conducted to simulate potential interaction in the gastric environment. The simultaneous administration of zidovudine and clarithromycin had little impact on the pharmacokinetics of clarithromycin or of its major metabolite. However, coadministration of zidovudine and clarithromycin at three doses (500 mg orally [p.o.] twice daily [b.i.d.], 1,000 mg p.o. b.i.d., and 2,000 mg p.o. b.i.d.) reduced the maximum concentration of zidovudine by 41% (P < 0.005) and the area under the concentration-time curve from 0 to 4 h for zidovudine by 25% (P < 0.05) and increased the time to maximum concentration of zidovudine by 84% (P < 0.05), compared with zidovudine administered alone. Mixing studies did not detect the formation of insoluble complexes due to chelation, suggesting that the decrease in zidovudine concentrations results from some other mechanism. Simultaneous administration of zidovudine and clarithromycin appears to decrease the levels of zidovudine in serum, and it may be advisable that these drugs not be given at the same time. Drug interactions should be carefully evaluated in persons with advanced human immunodeficiency virus infection who are receiving multiple pharmacologic agents.

Adult↗
PubMed1997

Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites.

Two different responses to the therapy were observed in a group of patients receiving the protease inhibitor indinavir. In one, suppression of virus replication occurred and has persisted for 90 weeks (bDNA, < 500 human immunodeficiency virus type 1 [HIV-1] RNA copies/ml). In the second group, a rebound in virus levels in plasma followed the initial sharp decline observed at the start of therapy. This was associated with the emergence of drug-resistant variants. Sequence analysis of the protease gene during the course of therapy revealed that in this second group there was a sequential acquisition of protease mutations at amino acids 46, 82, 54, 71, 89, and 90. In the six patients in this group, there was also an identical mutation in the gag p7/p1 gag protease cleavage site. In three of the patients, this change was seen as early as 6 to 10 weeks after the start of therapy. In one patient, a second mutation occurred at the gag p1/p6 cleavage site, but it appeared 18 weeks after the time of appearance of the p7/p1 mutation. Recombinant HIV-1 variants containing two or three mutations in the protease gene were constructed either with mutations at the p7/p1 cleavage site or with wild-type (WT) gag sequences. When recombinant HIV-1-containing protease mutations at 46 and 82 was grown in MT2 cells, there was a 68% reduction in its rate of replication compared to the WT virus. Introduction of an additional mutation at the gag p7/p1 protease cleavage site compensated for the partially defective protease gene. Similarly, rates of replication of viruses with mutations M46L/I, I54V, and V82A in protease were enhanced both in the presence and in the absence of Indinavir when combined with mutations in the gag p7/p1 and the gag p1/p6 cleavage sites. Optimal rates of virus replication require protease cleavage of precursor polyproteins. A mutation in the cleavage site that enhanced the availability of a protein that was rate limiting for virus maturation would confer on that virus a significant growth advantage and may explain the uniform emergence of viruses with alterations at the p7/p1 cleavage site. This is the first report of the emergence of mutations in the gag p7/p1 protease cleavage sites in patients receiving protease therapy and identifies this change as an important determinant of HIV-1 resistance to protease inhibitors in patient populations.

Anti-HIV Agents↗
PubMed1997

Lack of clinical utility of bronchoalveolar lavage cultures for cytomegalovirus in HIV infection.

This study assessed the presence of cytomegalovirus (CMV) in bronchoalveolar lavage (BAL) in three subpopulations of HIV-infected patients and correlated its presence with clinical status during 3 mo of follow-up. Nineteen asymptomatic volunteers, six patients with CMV retinitis, and 46 patients with acute pulmonary symptoms underwent BAL and were assessed for CMV by cytopathology, conventional shell vial cultures, and antigen detection. Transbronchial biopsies were also obtained when possible and evaluated for histopathologic changes of CMV. All patients were followed for approximately 3 mo. Cytomegalovirus was detected in BAL in nine of 19 (47%) asymptomatic volunteers, in all six patients with CMV retinitis, and in 33 of 46 (72%) patients with pulmonary symptoms. Only one symptomatic patient with a positive CMV BAL culture developed clinically significant CMV pulmonary disease; this patient developed disseminated CMV and died. The only other death occurred in a patient with CMV retinitis who developed staphylococcal bacteremia. None of the asymptomatic volunteers or patients with CMV retinitis developed evidence of CMV pneumonia or any other organ disease with CMV. Cytomegalovirus is frequently detected in BAL from HIV-infected patients regardless of their pulmonary symptoms and its presence does not clinically predict significant pulmonary morbidity or mortality in 3 mo of follow-up.

AIDS-Related Opportunistic Infections↗
PubMed1996

Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus.

BACKGROUND: Interleukin-2 is a cytokine that regulates the proliferation and differentiation of lymphocytes. In preliminary studies, intermittent infusions of interleukin-2 led to increases in CD4 counts in patients with human immunodeficiency virus (HIV) infection and more than 200 CD4 cells per cubic millimeter. We conducted a controlled study to evaluate the long-term effects of such therapy on both CD4 counts and the viral burden. METHODS: Sixty HIV-infected patients with base-line CD4 counts above 200 cells per cubic millimeter were randomly assigned to receive either interleukin-2 plus antiretroviral therapy (31 patients, 1 of whom was lost to follow-up) or antiretroviral therapy alone (29 patients). Interleukin-2 was administered every two months for six cycles of five days each, starting at a dosage of 18 million i.u. per day. Safety and immunologic and virologic measures were monitored monthly until four months after the last treatment cycle. RESULTS: In patients treated with interleukin-2, the mean (+/-SE) CD4 count increased from 428 +/- 25 cells per cubic millimeter at base line to 916 +/- 128 at month 12, whereas in the control group, the mean CD4 count decreased from 406 +/- 29 cells per cubic millimeter to 349 +/- 41 (P < 0.001). There were no significant differences between the groups in serial measurements of the plasma HIV RNA or p24 antigen concentration during the 12 months of treatment. Constitutional symptoms (fever, malaise, and fatigue) and asymptomatic hyperbilirubinemia were the chief dose-limiting toxic effects of interleukin-2 therapy. CONCLUSIONS: In patients with HIV infection and base-line CD4 counts above 200 cells per cubic millimeter, intermittent infusions of interleukin-2 produced substantial and sustained increases in CD4 counts with no associated increase in plasma HIV RNA levels.

AIDS-Related Opportunistic Infections↗
PubMed1996

The effect of thalidomide on the pathogenesis of human immunodeficiency virus type 1 and M. tuberculosis infection.

Tumor necrosis factor alpha (TNF-alpha), a cytokine produced during the host defense against infection, is associated with fevers, weakness, and progressive weight loss. Thalidomide inhibits the synthesis of TNF-alpha both in vitro and in vivo and may have clinical usefulness. We therefore initiated a pilot study of thalidomide treatment in patients with human immunodeficiency virus type 1 (HIV-1)-associated wasting with or without concomitant infection with tuberculosis. Thirty-nine patients were randomly allocated to treatment with either thalidomide or placebo in a double-blind manner for 21 days. Thirty-two patients completed the study. In patients with concomitant HIV-1 and tuberculosis infections, thalidomide therapy was associated with a reduction in both plasma TNF-alpha levels and HIV-1 levels. No significant reduction in either TNF-alpha or HIV- 1 levels was observed in patients with HIV-1 infection only. During the study period, patients receiving thalidomide treatment (n=16) showed a significant weight gain (mean +/- SEM: 6.5 +/- 1.2%; p<0.02) relative to placebo-treated patients (n=16). Patients with simultaneous HIV-1 and tuberculosis infections experienced a higher mean weight gain during thalidomide treatment than the group of patients with HIV-1 infection only. The results of this pilot study suggest that thalidomide may have a clinical role in enhancing weight gain and possibly reducing TNF-alpha and HIV-1 levels in patients with HIV-1 and concomitant mycobacterial infections.

Adult↗
PubMed1996

Combination therapy with didanosine and interferon-alpha in human immunodeficiency virus-infected patients: results of a phase I/II trial.

A nonrandomized trial was undertaken to evaluate the combination of didanosine and interferon-alpha (INF-alpha) in human immunodeficiency virus (HIV)-infected patients. Thirty-six volunteers with >200 x 10(6) CD4 cells/L received didanosine (one 100-, 250-, or 375-mg sachet twice daily) for at least 6 weeks, following which IFN-alpha (1, 5, 10, or 15 MU/day) was begun. Didanosine (one 375-mg sachet twice daily) was substituted for zidovudine in 14 additional patients who had received IFN-alpha and zidovudine for 7-45 months. Thirty-five patients completed the 34-week study. Clinical or chemical pancreatitis was the most common (6 patients) dose-limiting toxicity. CD4 cell counts increased with didanosine but declined following the addition of IFN-alpha; CD4 cell percents tended to increase and remain elevated. Thus, combination therapy with didanosine and IFN-alpha can be safely administered to patients with HIV infection. The clinical benefit of this combination therapy will require further evaluation.

Antiviral Agents↗
PubMed1996

Inhibition of immunoreactive tumor necrosis factor-alpha by a chimeric antibody in patients infected with human immunodeficiency virus type 1.

Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine known to stimulate human immunodeficiency virus type 1 (HIV-1) replication, has been implicated in the pathogenesis of HIV-1 infection. Inhibition of TNF-alpha by a chimeric humanized monoclonal antibody, cA2, was investigated in 6 HIV-1-infected patients with CD4 cell counts < 200/mm3. Two consecutive infusions of 10 mg/kg 14 days apart were well tolerated, and a prolonged serum half-life for cA2 (mean, 257 +/- 70 h) was demonstrated. Serum immunoreactive TNF-alpha concentrations fell from a mean prestudy value of 6.4 pg/mL (range, 4.2-7.9) to 1.1 pg/mL (range, 0.5-2.2) 24 h after the first infusion and returned to baseline within 7-14 days. A similar response was seen after the second infusion. No consistent changes in CD4 cell counts or plasma HIV RNA levels were observed over 42 days. Future studies evaluating the therapeutic utility of long-term TNF-alpha suppression using anti-TNF-alpha antibodies are feasible and warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Immune-based therapies in HIV infection: recent developments.

A wide variety of different immunologic approaches have been evaluated as potential therapies for HIV disease. Whether any of these approaches will play a role in clinical management will require the completion of the appropriate clinical trials. Importantly, all clinical trials present opportunities to evaluate aspects of the pathogenesis of HIV infection that are perhaps unevaluable in vitro. Clinical trials of antiretroviral drugs have defined the dynamics of HIV replication [37,38]. The complexities and heterogeneity of the immune system and particularly its responses to HIV are being unveiled in the setting of clinical trials of immune-based therapies. Truly effective treatments for HIV will result in long-term preservation of immune function allied to control of virus replication in infected individuals. Immune-based therapy might well play a significant role in such strategies.

Cytokines↗