Dolores M. Peterson

HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression.

The role of HIV-1-specific CD4+ T-cell responses in controlling HIV-1 infection remains unclear. Previous work has suggested that such cells are eliminated in the early stages of infection in most subjects, and thus cannot substantially contribute to host defense against HIV-1. Here, using flow cytometric detection of antigen-induced intracellular cytokines, we show that significant frequencies of gag specific, T-helper-1 CD4+ memory T cells are detectable in most subjects with active/progressive HIV-1 infection (median frequency, 0.12% of memory subset; range, 0–0.66%). Median frequencies of these cells were considerably higher in nonprogressive HIV-1 disease (0.40%), but there was substantial overlap between the two groups (range of nonprogressors, 0.10–1.7%). Continuous HIV-1 suppression with anti-retroviral therapy was associated with a time-dependent reduction in median frequencies of gag-specific CD4+ memory T cells: 0.08% in subjects treated for 4–24 weeks, and 0.03% in subjects treated for 47–112 weeks. Thus, functional HIV-1-specific CD4+ T cells are commonly available for support of anti-HIV-1 effector responses in active disease, but their decline with anti-retroviral therapy indicates that immunologic participation in long-term HIV-1 control will probably require effective vaccination strategies.

Determination of antigen-specific memory/effector CD4+ T cell frequencies by flow cytometry: evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency.

The highly regulated secretion of effector cytokines by CD4+ T cells plays a critical role in immune protection against pathogens such as cytomegalovirus. Here, we directly compare the frequency and functional characteristics of cytomegalovirus-specific CD4+ memory/effector T cells in normal and HIV+ subjects using a novel, highly efficient multiparameter flow cytometric assay that detects the rapid intracellular accumulation of cytokine(s) after short-term (6 h) in vitro antigen stimulation. Responses in this assay correlate precisely with independent measures of sensitization history (e.g., seroreactivity), and allow the simultaneous assessment of multiple cytokines in single effector T cells. Healthy HIV- individuals manifested an average of 0.71, 0.72, 0.38, and 0.06% CD4+ T cells responding to cytomegalovirus with gamma-IFN, TNF-alpha, IL-2, and IL-4 production, respectively, with the simultaneous production of gamma-IFN, TNF-alpha, and IL-2 being the most common effector phenotype. Significantly, overall cytomegalovirus-specific CD4+ effector frequencies were markedly higher among 40% of HIV+ subjects (2.7-8.0%), and demonstrated a predominately polarized gamma-IFN+/TNF-alpha+/IL-2-/IL-4- phenotype. In contrast, CD4+ effector frequencies for heterologous, nonubiquitous viruses such as the mumps virus were low or absent in the HIV+ group. These data suggest the existence of homeostatic mechanisms in HIV disease that selectively preserve memory T cell populations reactive with ubiquitous pathogens such as cytomegalovirus-likely at the expense of T cell memory to more sporadically encountered infectious agents.

A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals : Selection of thymidine analog regimen therapy (START II)

ObjectiveComparison of stavudine (d4T), didanosine (ddI) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients. DesignRandomized, open-label. SettingFourteen HIV Clinical Research Centers. PatientsTwo-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts ⩾ 200 × 106/l and plasma HIV-1 RNA levels ⩾ 10 000 copies/ml. InterventionsStavudine 40 mg and ddI 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV. Main outcome measuresThe proportion of patients with plasma HIV-1 RNA levels < 500 copies/ml and ⩽ 50 copies/ml and changes in CD4 cell counts were compared. ResultsIn an analysis of the primary endpoint, 61% of patients on d4T + ddI + IDV and 45% of patients on ZDV + 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 < 500 copies/ml [95% confidence interval (CI) for the difference between proportions, 1.7–30.3%;P = 0.038]. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels < 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddI + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% CI, −1.4% to 25.7%;P = 0.068). At 48 weeks 41% and 35% were ⩽ 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P > 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 × 106/l cells for the d4T arm and 106 × 106/l cells for the ZDV arm (P = 0.001). The occurrence of serious adverse events was not significantly different between arms. ConclusionThe combination of stavudine, ddI and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddI and a protease inhibitor as an initial antiretroviral treatment.

Primary prophylaxis with fluconazole against systemic fungal infections in Hiv-positive patients

ObjectiveTo investigate the efficacy of fluconazole prophylaxis against systemic fungal infections in HIV-positive patients. DesignOpen label treatment compared with historical controls. SettingPatients were seen at the Parkland Memorial Hospital HIV Clinic, Dallas, Texas, USA between 1 March 1990 and 28 February 1991. Patients, participantsThree hundred and thirty-seven historical controls were followed for 157 patient-years, and 329 fluconazole-treated patients for 145 patient-years. InterventionsFluconazole (100 mg daily) was administered to all patients with CD4 lymphocyte counts < 68 × 106/l seen at our HIV clinic after 1 March 1990. Main outcome measuresLysis-centrifugation blood cultures were recorded monthly for all patients during both study periods. ResultsTwenty infections (16 cryptococcosis, four histoplasmosis) occurred in 337 historical reference control patients (product-limit 1-year incidence, 7.5 × 2.0/year). Four infections (one cryptococcosis, three histoplasmosis) occurred in the treated patient group (product-limit 1-year incidence, 1.8 × 0.9/year). ConclusionsFluconazole warrants further evaluation for prophylaxis against systemic fungal infections in HIV-positive patients.

The role of diet, exercise and smoking in dyslipidaemia in HIV-infected patients with lipodystrophy

Lipodystrophy in HIV‐infected (LDHIV) patients receiving protease inhibitors (PIs) is associated with dyslipidaemia. Whether lifestyle factors play a role in dyslipidaemia in LDHIV subjects on PIs is not well characterized.

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.

Safety and antiretroviral effects of combined didanosine and stavudine therapy in HIV-infected individuals with CD4 counts of 200 to 500 cells/mm3.

The safety and antiretroviral effects of didanosine and stavudine in combination were evaluated in 86 people infected with HIV with CD4 counts between 200 and 500 cells/mm3 who had received <7 days of prior nucleoside analogue antiretroviral treatment. Patients were randomized to receive blinded treatments with one of five weight-adjusted, twice-daily regimens of didanosine and stavudine (100 + 10 mg, 100 + 20 mg, 100 + 40 mg, 200 + 20 mg, and 200 + 40 mg) for up to 1 year. Dosages were adjusted appropriately for patients weighing <60 kg and reduced in response to adverse effects. No clear dose-related differences among treatment groups were detected with regard to suppression of plasma HIV RNA level or reduction in infectious titers in peripheral blood mononuclear cells (PBMCs), improvement in CD4 count, or adverse effects. However, trends toward greater decreases in viral load and increases in CD4 count were detected when treatment groups containing the full recommended dosage of one or both agents (high-dose subgroup; arms 3, 4, and 5) were compared with the groups receiving lower dosages. At 28 weeks the mean log 10 HIV RNA decrease was 1.12 (n = 52) and at 52 weeks it was 0.97 (n = 32). Combination therapy was well tolerated, with no apparent dose-related adverse effects. Peripheral neuropathy occurred in 2 of 86 (2.3%) of patients. Didanosine and stavudine together appear to be a good nucleoside analogue foundation for aggressive triple- or quadruple-drug therapy. Full therapeutic doses of each of these two agents should be used to achieve optimal suppression of HIV replication.

Regional body fat distribution in HIV-infected patients with lipodystrophy.

Background Objective criteria for the assessment of patients with lipodystrophy syndrome in human immunodeficiency virus infection (LDHIV) have not emerged. Methods We compared regional body fat changes in 13 men with severe LDHIV on protease inhibitor-inclusive antiretroviral therapy with 13 control HIV-infected men using anthropometry, dual-energy X-ray absorptiometry (DEXA), and whole-body magnetic resonance imaging (MRI). Results LDHIV patients, compared with control subjects, had thinner gluteal, suprailiac, and triceps skinfolds (p < .01) and increased waist circumference (98 ± 5 cm vs 86 ± 9 cm, respectively; p = .0008). DEXA studies revealed reduced lower extremity fat (12 ± 5% vs 22 ± 9%; p = .0006), increased head and neck fat (18 ± 3% vs 16 ± 1%; p = .01), and increased proportion of total body fat in the trunk (65 ± 7% vs 53 ± 8%; p = .0005). MRI analysis revealed reduced thigh fat (12 ± 5% vs 22 ± 12%; p = .01), increased dorsocervical fat depth (47 ± 24 mm vs 19 ± 7 mm; p = .0009), and nearly significant increase in intra-abdominal fat (218 ± 90 cm2 vs 157 ± 70 cm2 ; p = .057). Interestingly, control subjects showed a positive relationship between intra-abdominal and dorsocervical fat (r = .57, p = .04), but the LDHIV patients showed a negative relationship (r = -.55, p = .05), suggesting a novel split phenotype among LDHIV patients of either dorsocervical or intra-abdominal fat accumulation. Conclusions We conclude that MRI provides the best tools for definition of LDHIV syndrome and reveals variable phenotypes among LDHIV patients.

Correlation of quantitative bone marrow and blood cultures in AIDS patients with disseminated Mycobacterium avium complex infection

The relationship between Mycobacterium avium complex (MAC) infection of blood and bone marrow was studied in human immunodeficiency virus-infected patients before and during treatment. Quantitative cultures were obtained at baseline from 17 persons with newly detected MAC bacteremia. Serial blood cultures were obtained, and a second bone marrow sample was obtained at 4 or 8 weeks. At baseline, the median MAC load in bone marrow core samples was 3 log10 higher than in blood. Bone marrow MAC loads ranged widely (866-847,315 cfu/g), and no significant correlation was found between MAC load in blood and that in bone marrow core samples. MAC loads in bilateral bone marrow biopsy samples from 7 subjects were highly correlated. MAC loads declined in blood and bone marrow at similar rates during therapy, but blood was sterilized before bone marrow. Length of survival was inversely associated with initial bone marrow core MAC load but not with blood MAC load. Initiation of treatment when tissue MAC load is low may increase the likelihood of favorable clinical outcome.

Blepharoptosis and External Ophthalmoplegia Associated with Long-Term Antiretroviral Therapy

BACKGROUND Long-term antiretroviral therapy (ART) is associated with lipodystrophy, peripheral neuropathy, lactic acidosis, and myopathy. Blepharoptosis, without prior ART association, is usually caused by age-associated involutional ptosis, but it is also seen in mitochondrial myopathies with external ophthalmoplegia, cardiac conduction disturbances, and neurological impairments. METHODS Patients presented over a 2-year period. Four patients underwent surgical blepharoptosis repair. RESULTS Five human immunodeficiency virus type 1-infected patients (median age, 50 years; range, 46-53 years) who were receiving ART presented with severe blepharoptosis; 2 of these 5 also presented with external ophthalmoplegia. Findings included decreased palpebral fissure height (median, 6.5 mm; normal height, 9 mm), mildly impaired levator function (median, 10 mm; normal, >13 mm), and markedly decreased marginal reflex distance (median, 0.5 mm; normal, 4 mm). A greater advancement of the levator aponeurosis was required during surgical repair, a finding consistent more with myogenic than with involutional blepharoptosis. All patients had severe lipodystrophy, which preceded blepharoptosis by a median interval of 4.7 years (range, 2.8-5.7 years). Four patients also presented with peripheral neuropathy and metabolic abnormalities before the onset of blepharoptosis, and 3 had cardiac conduction disturbances. Patients received ART for a median of 7.8 years (range, 4.9-11.2 years), thymidine analogue-containing ART for a median of 7.1 years (range, 1.2-7.9 years), and protease inhibitor-containing ART for a median of 7.1 years (range, 4.9-8.9 years). CONCLUSIONS We report the novel findings of blepharoptosis and external ophthalmoplegia in patients who are receiving ART. Ptosis was preceded by lipodystrophy with long-term use of both thymidine-analogue- and protease inhibitor-containing ART. The findings are most consistent with myogenic ptosis in a generalized mitochondrial myopathy syndrome. Clinicians should also be watchful for other potential myopathic ptosis-associated complications, including proximal weakness, dysphagia, deafness, and cardiac conduction disturbances.