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Biomedical subjects

C W Hendrix

Publications and source records attributed to C W Hendrix.

At least 37 records · Page 2Linked to original sources
PubMed1994

Legionnaires' disease in human immunodeficiency virus-infected patients: eight cases and review.

Despite being a well-known pathogen for immunocompromised patients, Legionella pneumophila has infrequently been described in persons with infection due to human immunodeficiency virus (HIV). Since 1986, we have identified eight cases of legionella pneumonia among seven HIV-infected persons enrolled in the HIV Natural History Study of the U.S. Air Force. The median CD4+ T cell count for these patients was 83/mm3; 50% of the cases occurred in persons for whom AIDS was previously diagnosed, and five of the cases were nosocomial. Six of the patients had coexistent pulmonary infections. None of the cases occurred among persons receiving prophylactic therapy with trimethoprim-sulfamethoxazole. Therapeutically, all patients appeared to respond well to standard antilegionella therapy or high doses of trimethoprim-sulfamethoxazole. Overall, these seven patients represent 1.7% of the patients with late-stage HIV infection (Walter Reed stage 5 or 6) in this cohort. L. pneumophila, although remaining an uncommon pathogen for HIV-infected patients, may produce serious disease in this population. HIV-infected persons should be considered at risk for legionnaires' disease, particularly in institutions where potable water supplies have become contaminated.

AIDS-Related Opportunistic Infections↗
PubMed1994

Effect of dipyridamole on zidovudine pharmacokinetics and short-term tolerance in asymptomatic human immunodeficiency virus-infected subjects.

Zidovudine delays the progression of infection and prolongs the survival of human immunodeficiency virus (HIV)-infected patients, but these benefits are limited by dose-related toxicity and the cost of the drug. Dipyridamole, in micromolar concentrations, acts synergistically with zidovudine, reducing the anti-HIV 95% inhibitory concentration of zidovudine 5- to 10-fold in vitro. We sought to establish a well-tolerated dose of dipyridamole for use in combination with zidovudine and to detect clinically significant pharmacokinetic interactions. Both objectives are essential for planning studies of the efficacy of the zidovudine-dipyridamole combination. Eleven asymptomatic HIV-infected subjects (median CD4+ cell count, 311 cells per mm3), 10 of whom had been on zidovudine at 500 mg/day for at least 6 months, were admitted to the study. Zidovudine pharmacokinetics were measured on day 1. Dipyridamole was then begun at 600 mg/day (subjects 1 to 3) or 450 mg/day (subjects 4 to 11), and zidovudine and dipyridamole pharmacokinetics were measured on day 5. All subjects given 600 mg of dipyridamole per day developed headache or nausea, or both. Six of eight subjects given dipyridamole at 450 mg/day developed headache or mild nausea that resolved after a median of 2 days. The area under the zidovudine concentration-time curve was not significantly different on day 1 in comparison with that on day 5 (P = 0.11). Symptoms were significantly correlated with the maximum zidovudine concentrations, which were achieved when dipyridamole was dosed concomitantly (p = 0.03). Total (free and protein-bound) dipyridamole trough concentrations were near those demonstrating synergy with zidovudine against HIV in vitro. Dipyridamole was highly protein bound, with a median free/total dipyridamole ratio of 0.7%; the percent free/total dipyridamole ratio was inversely correlated with alpha 1 acid glycoprotein concentrations (r2 =0.66). Results of the study indicate that adjustment of the zidovudine dose was not required to achieve equivalent zidovudine concentrations when zidovudine was administered in combination with dipyridamole at the doses studied. In the short study described here, the zidovudine-dipyridamole combinations was well tolerated in asymptomatic HIV-infected subjects after the occurrence of mild transient symptoms.

Adult↗
PubMed1994

Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus.

The loss of T helper cell (TH) function in asymptomatic HIV type 1-infected individuals occurs before the decline in CD4+ T cells. At least part of the loss in TH function results from changes in immunoregulatory cytokine profiles. To investigate the role of IL-10 in such dysregulation, we tested whether: (a) expression of IL-10-specific mRNA would be upregulated in PBMC from asymptomatic, HIV-infected (HIV+) individuals; (b) PBMC from these same individuals would produce increased levels of IL-10 when stimulated in vitro with phytohemagglutinin; and (c) defective antigen-specific TH function could be restored by anti-IL-10 antibody. We observed that IL-10-specific mRNA was marginally upregulated, and increased levels of IL-10 were produced by PBMC from HIV+ individuals compared with PBMC from uninfected individuals. Those individuals whose TH function was more severely compromised produced higher levels of IL-10. Additionally, defective antigen-specific TH function in vitro could be reversed by anti-IL-10 antibody, including the response to HIV envelope synthetic peptides. Furthermore, the antigen-specific TH responses of HIV-uninfected PBMC could be reduced with IL-10, a process reversed by anti-IL-10. These results confirm that the early loss of TH function in HIV+ individuals is due at least in part to cytokine-induced immune dysregulation, and support the hypothesis of a switch from a predominant type 1 state to a predominant type 2 condition in HIV infection.

Antigens, CD↗
PubMed1994

Real-time molecular epidemiologic analysis of an outbreak of Streptococcus pyogenes invasive disease in US Air Force trainees.

OBJECTIVE: To determine if molecular epidemiologic techniques, including comparative automated DNA sequencing of polymorphic virulence genes, could be used in the course of a bacterial disease outbreak to unambiguously determine clonal relationships among implicated strains. DESIGN: Strains recovered from all patients with invasive infections and a sample of carriers were analyzed by multilocus enzyme electrophoresis and automated DNA sequencing of a gene encoding an extracellular protease and a highly polymorphic part of the streptokinase gene. SETTING: A US Air Force training facility in San Antonio, Tex. PATIENTS: A squadron with about 800 Air Force trainees, including three recruits with invasive Streptococcus pyogenes infections. RESULTS: Multilocus enzyme electrophoresis and automated DNA sequencing of polymorphic virulence genes unambiguously defined person-to-person spread of an otherwise rare S pyogenes clone in the course of the disease outbreak and clarified strain relationships in real time. CONCLUSIONS: Molecular strain characterization techniques can be employed rapidly in a disease outbreak to definitively resolve complex relationships among pathogenic bacteria, infer patterns of clone spread, and help formulate rational public health control measures. The approach has broad applicability to other infectious agents.

Adult↗
PubMed1993

Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro.

Peripheral blood mononuclear cells (PBMCs) from many asymptomatic individuals infected with human immunodeficiency virus-type 1 (HIV) are unresponsive as measured by in vitro T cell proliferation and interleukin-2 (IL-2) production to influenza virus and synthetic peptides of HIV envelope (Env). Strong influenza virus- and Env-stimulated IL-2 responses and T cell proliferation were restored when cultures were stimulated in the presence of IL-12. Interferon-gamma production by PBMCs from HIV seropositive (HIV+) patients was also restored with IL-12. Furthermore, in vitro antigen-specific production of IL-2 and proliferation of PBMCs from HIV- donors were suppressed by antibody to IL-12, but were not enhanced by addition of exogenous IL-12. Thus, IL-12 may be limiting in PBMCs from HIV+ but not HIV- individuals. These findings demonstrate that IL-12 can restore HIV-specific cell-mediated immunity in vitro in HIV-infected individuals and suggest a potential use of IL-12 in augmenting the diminished immunologic functions associated with HIV infection.

Cells, Cultured↗
PubMed1993

Delayed-type hypersensitivity skin testing predicts progression to AIDS in HIV-infected patients.

OBJECTIVE: To evaluate the prognostic significance of cutaneous delayed-type hypersensitivity (DTH) skin testing in persons infected with HIV. DESIGN: Cohort study. SETTING: United States Air Force (USAF) Medical Center. PATIENTS: Consecutive sample of 889 HIV-infected USAF personnel or dependents undergoing their first staging evaluation from 1985 through August 1990 in the USAF HIV Natural History Study. MEASUREMENTS: All patients were evaluated with DTH skin testing including purified protein derivative and four control skin test antigens: mumps, candida, tetanus toxoid, and trichophyton. In addition, all patients underwent CD4+ T-cell surface marker determinations. The relation between DTH skin test response at first evaluation and progression to Walter Reed stage 6 (presence of an AIDS-defining opportunistic infection) was evaluated using Kaplan-Meier survival analysis. RESULTS: Patients with more than 400 CD4+ T cells/mm3 are more likely than those having fewer than 400 CD4+ T cells per mm3 to respond to at least one (94% compared with 67%, P < 0.001) or at least two (86% compared with 45%, P < 0.001) DTH skin tests. Mean CD4 counts are lower for anergic compared with nonanergic patients and for patients responding to a single control skin test compared with those responding to two or more skin tests (P < 0.05). The DTH skin test response at first evaluation was also found to predict progression to AIDS; the relative risk at 5 years of follow-up was 2.5 (95% CI, 1.2 to 5.2) for anergy compared with a single positive skin test and 3.0 (CI, 1.4 to 6.2) for a single compared with two or more skin test responses. The DTH skin test response at first evaluation was a predictor of progression (P < 0.001) when controlling for initial CD4 count and Walter Reed stage in a Cox proportional hazards regression analysis. CONCLUSIONS: The DTH skin test response, a functional measure of cellular immunity, is an independent predictor of progression to AIDS in persons with HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Total lymphocyte count as a predictor of absolute CD4+ count and CD4+ percentage in HIV-infected persons.

OBJECTIVE: To determine whether the total lymphocyte count (TLC) accurately predicts a low absolute CD4+ T-cell count and CD4+ percentage in persons infected with human immunodeficiency virus (HIV). DESIGN: Retrospective analysis of data collected in the US Air Force HIV Natural History Study. SETTING: Military medical center that performs annual medical evaluation of all HIV-infected US Air Force personnel. PATIENTS: A total of 828 consecutive patients with no prior history of zidovudine use, evaluated from January 1985 through July 1991. For patients with multiple observations over time, a single data point within each 6-month interval was included in the analysis (N = 2866). MEASUREMENTS AND MAIN RESULTS: The sensitivity, specificity, and likelihood ratio (LR) of the TLC, in the range of 1.00 x 10(9)/L to 2.00 x 10(9)/L, in predicting an absolute CD4+ T-cell count less than 0.20 x 10(9)/L or a CD4+ percentage less than 20% were calculated. In addition, the LR and pretest probability of significant immunosuppression were used to calculate posttest probabilities of a low CD4+ count for a given TLC value. The LR of the TLC in predicting an absolute CD4+ count < 0.20 x 10(9)/L increased from 2.4 (95% confidence interval, 2.2 to 2.5) for all TLCs less than 2.00 x 10(9)/L, to 33.2 (95% confidence interval, 24.1 to 45.7) for all TLCs less than 1.00 x 10(9)/L. The specificity for this prediction increased from 57% to 97% over this range. The LR also increased from 1.4 (95% confidence interval, 1.3 to 1.6) for all TLCs less than 2.00 x 10(9)/L to 9.7 (95% confidence interval, 7.1 to 13.1) for all TLCs less than 1.00 x 10(9)/L in predicting a CD4+ percentage less than 20%. CONCLUSIONS: The TLC, between 1.00 x 10(9)/L and 2.00 x 10(9)/L, appears to be a useful predictor of significant immunosuppression as measured by a CD4+ T-cell count less than 0.20 x 10(9)/L in HIV-infected persons. The LR for a given TLC value and the pretest probability of immunosuppression can be used to determine the posttest probability of significant immunosuppression in individual patients. For example, in a patient with a TLC less than 1.50 x 10(9)/L and a pretest probability of 16%, the posttest probability of a low CD4+ T-cell count increases to 53%. In contrast, a TLC greater than 2.00 x 10(9)/L in an individual with a pretest probability of 30% will decrease the posttest probability of a low CD4+ T-cell count to less than 4%. Physicians should find these data useful to help predict the risk for opportunistic infection among HIV-infected persons who present with syndromes that are potentially compatible with opportunistic infection but who have not had recent or prior CD4+ T-cell analysis.

Adolescent↗
PubMed1993

Early markers of HIV infection and subclinical disease progression.

Human immunodeficiency virus (HIV) infection in US Air Force personnel between 1985 and 1989 was examined through a mandatory serological survey, and through annual examination of infected patients. CD4+ cell counts were determined by flow cytometry; beta 2 microglobulin and neopterin were measured by immunoassay. During this period 933 cases were found, of which 161 were documented seroconversions, giving an incidence rate of 15.6/100,000 person-years. For patients with > 400 CD4 cells microliters-1, the rate of initial occurrence of opportunistic infection was 1 and 4% at 1 and 2 years, respectively. HIV-infected persons with < 400 CD4+ cells microliters-1, in contrast, had rates of 21% at 1 year and 36% at 2 years. In a cross-sectional study, beta 2 microglobulin concentration was shown to increase in both the serum and spinal fluid of patients infected with HIV as their blood CD4 numbers declined. Neopterin levels in serum and spinal fluid showed a similar trend, with significantly lower neopterin concentrations in the group that had > 1000 CD4+ T cells compared to the 0-600 CD4+ cell group. Longitudinal studies included correlation of HIV p24 antigen with CD4 counts over a 1 year period. The p24 antigen-positive group had a 21% decline in CD4+ T cells, while the antigen-negative group had a 14% decline. Specific helper T-cell subsets were also examined over a 6 month period. A significant decline was seen in the CD4+/CD29+, CD4+/CD45R+, and overall CD4+ subsets which was not seen in AZT-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerospace Medicine↗
PubMed1993

Cerebrospinal fluid neopterin levels in 159 neurologically asymptomatic persons infected with the human immunodeficiency virus (HIV-1): relationship to immune status.

Monocytes and brain macrophage-microglial cells are thought to play a crucial role in the neurologic dysfunction associated with HIV-1 disease. Since neopterin is produced by monocytes-macrophages, we asked whether cerebrospinal fluid (CSF) neopterin levels increase before the onset of HIV-1 neurologic disease and whether they correlate with other CSF and peripheral blood immunologic parameters. In this study, CSF neopterin levels from 159 neurologically asymptomatic HIV-positive persons were found to increase as the blood CD4+ T-cell count decreased and as CSF IgG, IgG synthesis, IgG index, and beta 2-microglobulin increased. Neopterin levels in the CSF exceeded those in the serum in 32% of patients, while 25% had CSF levels > 13.5 nmol/liter. CSF neopterin levels vary with immune status, may reflect intrathecal production, and can be elevated in asymptomatic HIV-positive patients with normal neurologic examinations. Long-term follow-up of this patient population should be able to define the clinical correlation between CSF neopterin levels during the asymptomatic phase of HIV-1 disease and the risk of subsequent neurologic disease.

Biopterins↗
PubMed1993

Effect of a recombinant CD4-IgG on in vitro T helper cell function: data from a phase I/II study of patients with AIDS.

Ten patients with AIDS were enrolled in a phase I/II protocol of recombinant CD4-IgG (rCD4-IgG) treatment. Patients' peripheral blood leukocytes (PBL) were tested before, during, and after therapy with rCD4-IgG for T helper (TH) cell function assessed by antigen- and mitogen-stimulated proliferation and interleukin-2 production in response to influenza A virus, allogeneic PBL (alloantigens), and phytohemagglutinin. Although clinical benefit was not evident, rCD4-IgG treatment was associated with rapid and potent improved TH cell function for two of three stimuli tested in 90% of the patients. These data are complemented by an in vitro experimental model that demonstrates the opposing immunologic effects of rgp120 and rCD4-IgG on TH cell function of PBL from uninfected individuals. Thus, restoration of TH cell function by rCD4-IgG in the absence of increased CD4 cell counts could be due to removal of an immunosuppressive factor, possibly gp120. These findings suggest that rCD4-IgG can induce partial restoration of immune function in AIDS patients, even in the absence of apparent short-term clinical benefit.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Longitudinal analysis of the humoral immune response to human immunodeficiency virus type 1 (HIV-1) gp160 epitopes in rapidly progressing and nonprogressing HIV-1-infected subjects.

Antibody response to conserved human immunodeficiency virus type 1 (HIV-1)IIIB gp160 epitopes was longitudinally examined in HIV-1-infected persons. Twelve hundred individuals were evaluated, and sequential sera from 25 rapidly progressing (RP) and 30 nonprogressing (NP) subjects collected over an average of 4 years were examined. Initial sera from the RP group contained greater reactivity to a gp120 epitope defined by peptide 503-528 than did sera from the NP group (P < .001). Reactivity declined with sequential sera for the RP group, paralleling disease progression. Conversely, antibody recognition to this site developed in 23% of the NP group with time. However, 60% of the NP group never developed a response to this epitope. This suggests sequential examination of antibody response to an epitope within the gp120 carboxyl-terminus may have prognostic significance. No association between antibodies directed against the gp160 epitopes and in vitro neutralizing activity against HIV-1IIIB was observed.

Adult↗
PubMed1993

Biologic effects after a single dose of poly(I):poly(C12U) in healthy volunteers.

Poly(I):poly(C12U) (mismatched double-stranded RNA; atvogen), an interferon inducer, is active against human immunodeficiency virus in vitro. To determine the extent and duration of the biologic effects of poly(I):poly(C12U), we administered a single dose of the drug to healthy volunteers in a randomized, double-blind, placebo-controlled 2-week crossover study. We analyzed blood for alpha and gamma interferons, neopterin, 2',5'-oligoadenylate synthetase, lymphocyte surface markers, lymphocyte proliferation after exposure to soluble antigens and mitogens, and natural killer cell activity. Minimal biologic effects were observed after administration of a single 200-mg dose to four volunteers; therefore, the dose was increased to 600 mg in 10 subjects. Only neopterin levels and symptoms were greater after administration of 600 mg of poly(I):poly(C12U) than after administration of placebo (Wilcoxon signed rank sum test, P = 0.06). A definite response in 2',5'-oligoadenylate synthetase activity, however, was seen in a few subjects. Neither alpha nor gamma interferon was detectable in serum after poly(I):poly(C12U) dosing. The neopterin changes after administration of poly(I):poly(C12U) were similar at both poly(I):poly(C12U) dose levels, with an early decrease at 6 h, a peak at 1 day, and a gradual decrease toward the baseline over the following 3 days. A mild flu-like syndrome occurred in one-half of the subjects following administration of poly(I):poly(C12U) and in only one subject following administration of placebo. This syndrome resolved within 16 h after poly(I):poly(C12U) dosing. We conclude that poly(I):poly(C12U) does not induce measurable levels of interferon and causes only minimal biologic or toxic effects among those parameters measured after administration of a single dose in the 200- to 600-mg dose range in health volunteers.

2',5'-Oligoadenylate Synthetase↗
PubMed1993

Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals.

Infection with HIV results in an incremental loss of T helper cell (TH) function, which can occur years before CD4 cell numbers are critically reduced and AIDS is diagnosed. All TH function is not affected, however, because B cell activation and hypergammaglobulinema are also characteristic of this period. Recently, in a murine model of AIDS an early loss in production of the CD4 cytokines IL-2 and IFN-gamma was correlated with an increase in the B cell stimulatory cytokines IL-4, IL-5, and IL-10. We therefore assessed the production of IL-4 generated by PBL from HIV-seropositive (HIV+) individuals who did not have AIDS, yet who exhibited different TH functional categories based on their IL-2 production profiles. We observed that the decreases in recall antigen-stimulated IL-2 production were accompanied by an increase in IL-4 production. The loss of recall antigen-stimulated responses in HIV+ individuals could be reversed in vitro by anti-IL-4 antibody. Our results suggest that the TH functions assessed by IL-4 production replace the normally dominant TH function of antigen-stimulated IL-2 production in the progression toward AIDS, and raise the possibility of cytokine cross-regulation in AIDS therapy.

Antisense Elements (Genetics)↗
PubMed1993

Measurement of cerebrospinal fluid antibody to the HIV-1 principal neutralizing determinant (V3 loop).

Antibody to the human immunodeficiency virus (HIV)-1 principal neutralizing determinant (V3 loop) was measured by peptide enzyme-linked immunosorbent assay (ELISA) in cerebrospinal fluid (CSF) and paired serum samples of 21 HIV-seropositive patients. These patients had normal neurologic examinations and were without neurologic symptoms. Peptide ELISA demonstrated intrathecal antibody synthesis against the V3 loop of HIVMN, the V3 loop of HIVNY5, the V3 loop of HIVLAI, and the entire recombinant HIV-1MN gp120 in 21 of 21, 10 of 21, one of 21, and 12 of 21 patients, respectively. Biospecific interaction analysis (BIAcore), which requires only small amounts of CSF, was also used to detect anti-V3 CSF antibody. Fine mapping of linear epitopes within the V3 region was successful in three of five patients by Geysen PIN (PEPSCAN) ELISA and discordance between epitope specificity of CSF and serum antibody was found. While detection of CSF antibody against the V3 loop of HIVMN by peptide ELISA has been recently reported, we add to this finding using the peptide ELISA, PEPSCAN and BIAcore methodologies as well as measuring intrathecal antibody synthesis against V3 loops from HIV strains. Application of these techniques to future studies of anti-V3 antibody in CSF from persons receiving anti-HIV-1 immunizations may provide insight into the immunoregulation of the virus in the nervous system.

Amino Acid Sequence↗
PubMed1992

Fine specificity of the humoral immune response to HIV-1 GP160 in HIV-1 infected individuals from Tanzania.

A total of 160 sera from HIV-1 infected individuals from Tanzania were examined for their fine specificity characteristics relative to 9 synthetic peptides that define HIV-1 gp160 epitopes. Immunorecessive and immunodominant epitopes were identified in both gp120 and gp41 based on serologic reactivity of these HIV-1 infected sera. A significant difference in fine specificity among HIV-1 infected individuals from Tanzania and the United States was observed for an immunodominant gp41 epitope. No significant differences in reactivity among asymptomatic vs. symptomatic HIV-1 infected individuals were detected for the selected HIV-1 gp160 epitopes defined by these peptides. The majority of sera from HIV-1 infected Tanzanians contained antibodies that recognized a peptide corresponding to the V3 region of gp120 from the HIV-1 MN isolate. These data suggest that regional isolates of HIV-1 may exist in Tanzania that differ from HIV-1 isolated in the United States. However, based on serology, HIV-1 isolates exhibiting sequences with HIV-1 MN V3 similarity may also be prevalent in Tanzania. The results of this study may be useful for the design of more effective AIDS diagnostic and therapeutic products for use worldwide.

Amino Acid Sequence↗
PubMed1992

Reconstitution of long-term T helper cell function after zidovudine therapy in human immunodeficiency virus-infected patients.

Peripheral blood mononuclear cells from 12 asymptomatic patients infected with immunodeficiency virus (HIV) and 4 patients with AIDS were analyzed before and during therapy with zidovudine for T helper cell (Th) function. Th function improved by more than fourfold to one or more of three stimuli tested in 9 (75%) of 12 asymptomatic patients on zidovudine therapy and in 3 of 4 patients with AIDS. Only 6 (7.4%) of 80 untreated HIV-infected control patients showed spontaneous improvement in Th function (P less than 10(-6)). Improved Th function was detected as early as 5 weeks into therapy in 6 patients and continued to be evident for greater than 1 year after start of therapy in 6 patients and for greater than 2 years in 2 patients. No correlation was observed between improved Th function and changes in CD4+ or CD8+ cell numbers or in levels of serum HIV p24 antigen or beta 2-microglobulin. These results suggest inclusion of in vitro Th function as a useful marker in determining the efficacy of antiretroviral drug therapy of HIV-infected patients.

Acquired Immunodeficiency Syndrome↗