Early HIV Disease Research Articles

Cutting Edge: JAK3 Activation and Rescue of T Cells from HIV gp120-Induced Unresponsiveness

In early HIV disease, immunodeficiency is characterized by the inability of CD4+ T cells to produce a critical cytokine, IL-2, and to express the receptor for IL-2 (IL-2R) in response to antigenic or mitogenic stimulation. The shared common gamma-chain (gamma(c)) of IL-2R and its associated Janus kinase, JAK3, are indispensable for normal T cell function. Here, we show that the inhibition of IL-2R expression and proliferation induced by ligation of CD4 by HIV envelope glycoprotein, gp120, is correlated with inhibition of expression and activation of JAK3. Stimulation through the gamma(c)-related cytokine receptors restores JAK3 expression and activation and rescues CD4-mediated T cell unresponsiveness. Collectively, these data argue that inhibition of JAK3 expression and activation may, in part, explain the T cell dysfunction seen in early HIV disease. In addition, rescue from gp120-mediated T cell unresponsiveness by activation of JAK3 suggests a novel therapeutic approach for enhancing immune function in HIV disease.

Guidelines of care for dermatologic conditions in patients infected with HIV

Guidelines of care for dermatologic conditions in patients infected with HIV

EARLY SIGNS AND SYMPTOMS OF HIV INFECTION IN AN ALLERGY PRACTICE

An allergist probably may see several patients early in the course of HIV infection. Recognition of the signs and symptoms of early HIV disease should allow better patient care. Immunizations are more likely to be effective when given during a time of relative immunocompetence, and early treatment of HIV infection holds promise for limiting disease progression. Decisions regarding immunotherapy for atopic disease, potential pathogens in chronic sinusitis, and timing of steriod use in allergy treatment are best made when a patient's HIV status is known. This article discusses the prevalence of AIDS and methods of early disease recognition in infection.

Severe life stress as a predictor of early disease progression in HIV infection

Although there is evidence that stress is associated with alterations in immunity, the role of emotional factors in the onset and course of immune-based diseases such as cancer and AIDS has not been established. This prospective study was designed to test the hypothesis that stressful life events accelerate the course of HIV disease. Ninety-three HIV-positive homosexual men who were without clinical symptoms at the time of entry into the study were studied for up to 42 months. Subjects received comprehensive medical, neurological, neuropsychological, and psychiatric assessments every 6 months, including assessment of stressful life events during the preceding 6-month interval. Several statistical approaches were used to assess the relation between stress and disease progression. The time of the first disease progression was analyzed with a proportional hazard survival method, which demonstrated that the more severe the life stress experienced, the greater the risk of early HIV disease progression. Specifically, for every one severe stress per 6-month study interval, the risk of early disease progression was doubled. Among a subset of 66 subjects who had been in the study for at least 24 months, logistic regression analyses showed that higher severe life stress increased the odds of developing HIV disease progression nearly fourfold. the degree of disease progression was also predicted by severe life stress when a proportional odds logistic regression model was used for analysis. This report presents the first evidence from a prospective research study that severe life event stress is associated with an increased rate of early HIV disease progression.

Aeroallergen-specific IgE changes in individuals with rapid human immunodeficiency virus disease progression.

Progression of human immunodeficiency virus type 1 (HIV-1) infection to the acquired immunodeficiency syndrome (AIDS) is associated with elevated total IgE; however, previous cross-sectional studies have differed in their assessment of concurrent changes in allergic disease prevalence. Assessment of changes in aeroallergen-specific IgE during progression from early to late HIV disease. Total IgE, aeroallergen-specific IgE (rye grass, ragweed, Alternaria, dust mite, and cat), IFN-gamma, IL-4, and soluble CD23 (sCD23) were measured in a longitudinal study of 20 subject who had progressed from early-HIV infection (mean CD4 lymphocyte count of 650/mm3) to AIDS (mean CD4 lymphocyte count of 40/mm3) over an average of 4 years. Prevalence of positive aeroallergen specific-IgE assays in early HIV disease (T1 subjects with 13 positives) decreased with progression to late disease (five subjects with nine positive, P = .057), while total IgE increased from a median of 69 to 116 IU/mL. IFN-gamma and IL-4 were unchanged, while sCD23 decreased from a median of 72 to 9 U/mL (P = .0005) with disease progression in the full cohort. In contrast to other subjects, the subgroup of individuals with total IgE > 150 IU/mL in both early and late HIV disease demonstrated an increased frequency of aeroallergen-specific IgE. The elevation of total IgE associated with rapid HIV-1 disease progression was unexplained by concurrent changes in aeroallergen-specific IgE, IL-4, IFN-gamma, or sCD23. Overall, aeroallergen-specific IgE expression was less prevalent with HIV-1 progression, except in those individuals with elevated total IgE both before and after progression to AIDS.

Evidence for reliability, validity and usefulness of the Medical Outcomes Study HIV Health Survey (MOS-HIV).

The Medical Outcomes Study HIV Health Survey (MOS-HIV) is a brief, comprehensive measure of health-related quality of life (HRQoL) used extensively in human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). The 35-item questionnaire includes ten dimensions (health perceptions, pain, physical, role, social and cognitive functioning, mental health, energy, health distress and quality of life (QoL) and takes approximately 5 minutes to complete. Subscales are scored on a 0-100 scale (a higher score indicates better health) and physical and mental health summary scores can be generated. The MOS-HIV has been shown to be internally consistent, correlate with concurrent measures of health, discriminate between distinct groups, predict future outcomes and be responsive to changes over time. Limited experience suggests acceptable reliability and validity in women, injecting drug users and African-American and lower socioeconomic status patients. The MOS-HIV is available in 14 languages and has been included as a secondary outcome measure in numerous clinical trials for all stages of disease. In several studies it has detected significant differences between treatments; in some cases concordant with conventional endpoints and, in others, discordant. The interpretation of scores is facilitated by an explanation in terms meaningful to the intended audience. Research is needed to compare the MOS-HIV to other strategies for HRQoL assessment in early HIV disease.

Changes in parietal cell structure and function in HIV disease

The mechanisms underlying acid secretory failure in patients with HIV disease are unknown. We evaluated, in a series of preliminary studies, changes associated with parietal cell structure and function in early and late HIV disease, in an attempt to elucidate possible underlying mechanisms. Gastric acid and intrinsic factor secretion, vitamin B12 absorption, and light and electron microscopic evaluation of gastric mucosa were evaluated in patients with early and late HIV infection (AIDS) and compared to non-HIV-infected controls. Immunolocalization of HIV-related antigens in gastric mucosa was also examined. Fasting gastric juice pH and intrinsic factor (IF) concentration in AIDS and HIV infected subjects were significantly different from controls (P = 0.012 and P = 0.025, respectively for pH, and 0.029 and 0.035 for IF; ANOVA LSD test). By contrast, maximal acid output (MAO) was significantly lower in AIDS, but not HIV-infected subjects (P = 0.043 and P = 0.322, respectively). Similarly, Schilling test phases 1 and 2 results were significantly lower in AIDS, but not HIV-infected subjects. Varying degrees of vacuolar degeneration of parietal cells were seen on light microscopy. On electron microscopy (EM), tubulovesicles were reduced and intracellular canaliculi dilated with striking loss of microvilli. Immunofluorescent staining with antibodies to gp120, gp41, p24, and p17 demonstrated positive punctate signals in the cytoplasm of gastric glands, which includes parietal cells. Immunogold EM with anti-gp120, localized predominantly to the microvilli of intracellular canaliculi in parietal cells. Abnormal secretory function of parietal cells occurs early in HIV disease, affects acid as well as intrinsic factor secretion, and is associated with morphological changes in the acid secretory apparatus.

Zidovudine Side Effects As Reported by Black, Hispanic, and White/Non-Hispanic Patients with Early HIV Disease: Combined Analysis of Two Multicenter Placebo-Controlled Trials

The objective of this study was to determine whether HIV patients' subjective tolerance of zidovudine differs by racial or ethnic grouping by conducting a post hoc analysis of reported symptoms in two multicenter, placebo-controlled trials of zidovudine monotherapy for early HIV disease. Ratios of rates of developing new or worsening symptoms as reported by patients assigned to active drug or placebo were compared in groups of white/non-Hispanic, black, or Hispanic origin. Patients were included in the study if they had asymptomatic HIV disease and entry absolute CD4 lymphocyte counts below 500 cells/microL and were enrolled in National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group (ACTG) protocol 019 or had mild symptoms of HIV disease, were enrolled in ACTG protocol 016, met protocol eligibility criteria for the respective trial, and were categorized at entry as white/non-Hispanic (N = 1801), black (N = 195), or Hispanic (n = 214). The primary outcome measure was development of a new or worsening symptom of any severity. Among patients treated with zidovudine compared with placebo, the estimated risk for developing a new or worsening symptom was not significantly greater for blacks or Hispanics than for white/non-Hispanics for any of the most frequently reported symptoms (p > 0.05 after adjustment for the multiple comparisons performed). Our analysis of 195 black and 214 Hispanic patients did not reveal a significantly increased risk of subjective zidovudine intolerance compared with white/non-Hispanic subjects. If there is an increased risk of such intolerance in minority groups compared with white/non-Hispanics, it is not likely to be clinically important.

Management of the Female HIV-Infected Patient

Management of women with HIV infection or AIDS should follow the established guidelines for antiretroviral therapy and prevention and treatment of opportunistic complications of HIV infection. Gynecological manifestations of HIV are primarily cervical dysplasia and cancer associated with human papillomavirus (HPV) infection and vaginal and mucocutaneous candidiasis. Human papillomavirus-associated cervical dysplasia/neoplasia is more common in women with advanced rather than early HIV disease, and monitoring with Pap smears should probably increase to every 6 months in patients with CD4+ cell counts 350 cells/μl, cryotherapy is probably adequate, but therapy should be increasingly aggressive at lower CD4+ cell counts. Results of ongoing studies should be available soon to guide therapy. Optimal treatment of candidiasis in HIV-infected women include...

The use of methylphenidate for cognitive decline associated with HIV disease.

Complaints of cognitive changes are often expressed by patients at all stages of HIV infection. Such changes include decreased memory and attention span, diminished concentration, apathy, and "slowing." Methylphenidate (MPD) has been used in several clinical studies in men with late-stage HIV disease in an attempt to ameliorate these difficulties. The objectives of this review article are to review salient psychopharmacological characteristics of MPD and to describe the research and clinical literature supporting the use of MPD in patients at all stages of HIV infection. Seven studies, case reports, or abstracts from International Conferences on AIDS were available in the English literature through August, 1993, directly addressing the use of MPD in patients with HIV disease. Twenty-nine papers were reviewed for pharmacokinetic data, eighteen for safety and side effects issues, and seventeen for relevant contributions from the neuropsychological testing literature. Studies in clinical settings have used doses ranges from 10-90 mg. per day in two or three divided doses with reportedly good results in improving both affective and cognitive symptoms associated with HIV disease. Side effects have been relatively mild and patient satisfaction with treatment has been high. However, no studies have been conducted in early stage HIV disease, where a significant minority of patients have similar complaints in the absence of clinically apparent immunosuppression. Likewise, placebo-controlled, dose-finding studies in AIDS patients are entirely lacking, and no studies in women with HIV disease and cognitive changes have been published. In spite of these important research short-comings, clinical experience with MPD treatment of cognitive changes in men with HIV/AIDS is consistent with the notion that this medication holds significant promise to improve the quality of life for persons living with HIV/AIDS. Controlled studies to test this hypothesis are warranted.

A longitudinal study of the neuropsychiatric consequences of HIV-1 infection in gay men. II Psychological and health status at baseline and at 12-month follow-up

The aim of this study was to determine whether HIV infection is associated with increased psychosocial distress in the asymptomatic and early symptomatic stages of disease and to determine the factors associated with reporting health symptoms. Subjects included 61 gay men (41 HIV--, 20 HIV+) who were assessed at the time of requesting their first HIV test and again 12 months later. Measures included a detailed standardized psychiatric interview (Present State Examination, PSE), a range of psychosocial self-report measures and a physical symptom checklist. There were no differences between the HIV+ and HIV-- groups in terms of self-reported symptoms. Multiple regression analysis showed that the symptom reporting was not associated with clinical or immunological markers of disease progression but was associated with measures of psychosocial distress. Although both groups showed elevated levels of psychosocial distress at the time of HIV testing, there were no differences between serostatus groups at follow-up. Multiple regression analysis indicated that the best predictors of PSE scores at follow-up were baseline PSE score and a history of psychiatric illness. Early HIV disease is not associated with increased psychosocial distress and symptom reporting is more closely related to psychological measures than to clinical or immunological markers of disease.

Management of the female HIV-infected patient.

Management of women with HIV infection or AIDS should follow the established guidelines for antiretroviral therapy and prevention and treatment of opportunistic complications of HIV infection. Gynecological manifestations of HIV are primarily cervical dysplasia and cancer associated with human papillomavirus (HPV) infection and vaginal and mucocutaneous candidiasis. Human papillomavirus-associated cervical dysplasia/neoplasia is more common in women with advanced rather than early HIV disease, and monitoring with Pap smears should probably increase to every 6 months in patients with CD4+ cell counts < 500 cells/microliter (and certainly when this value falls below 200), with positive Pap smears confirmed by colposcopy and biopsy. For patients with CD4+ cell counts > 350 cells/microliter, cryotherapy is probably adequate, but therapy should be increasingly aggressive at lower CD4+ cell counts. Results of ongoing studies should be available soon to guide therapy. Optimal treatment of candidiasis in HIV-infected women includes prevention of recurrence with a combination of topical and systemic antifungal agents. Women with child-bearing potential should be treated as medically indicated for other HIV-infected patients, including during pregnancy. In fact, preliminary results of ACTG 076 indicated that zidovudine therapy during pregnancy reduces vertical transmission of HIV about threefold.

Audit of endoscopic surveillance biopsy specimens in HIV positive patients with gastrointestinal symptoms.

An audit of upper gastrointestinal endoscopy in HIV infected patients with gastrointestinal symptoms assessed the frequency of disease detected by endoscopy and routine laboratory analysis of surveillance biopsy specimens. Sixty nine consecutive endoscopies were performed in 59 HIV infected patients. Endoscopic biopsy specimens were taken from the lower oesophagus, gastric antrum, and third part of the duodenum for virology, histopathology, parasitology, bacteriology, and mycobacterial culture. Endoscopic appearances detected disease in 25/59 (42.4%) patients (oesophageal candida, 14; oesophageal ulcer, 3; Kaposi's sarcoma, 4; others, 4), but only 4/43 (9.3%) specimens showed evidence of disease in the absence of endoscopic abnormality. Virology for cytomegalovirus (detection of early antigenic fluorescent foci and culture) was positive in 6/59 (10.2%) patients, but parasitology and mycobacterial culture were negative in all cases. Histopathology was abnormal in 11/52 (21%) oesophageal biopsy specimens, 13/47 (28%) gastric biopsy specimens, and 4/65 (6%) duodenal biopsy specimens. Abnormal findings were found predominantly in those with advanced HIV disease (CDC Stage IV) (21/33 patients (64%)) compared with those with early HIV disease (CDC Stage II) (5/26 (19%)). In conclusion, upper gastrointestinal endoscopy detects macroscopic disease in AIDS patients and those with low CD4 counts, but routine surveillance biopsy specimens of apparently normal bowel in early HIV disease (or where CD4 counts are greater than 0.2 x 10(9)/1) are of little value.

A Screening Test for Subtle Cognitive Impairment Early in the Course of HIV Infection

The authors report on the use of the Rey-Osterrieth Complex Figure Copy (ROC) and Memory (ROM) test as a bedside screening measure of cognitive impairment in 67 HIV-seropositive persons (43 men, 24 women). HIV-seropositive individuals scored significantly worse than 49 HIV-seronegative matched individuals (33 men, 16 women) in the control group on the ROC (P = 0.045, effect size = 0.39), but not on the ROM test. The scores did not correlate with stage of HIV infection, CD4a cell counts, cerebrospinal fluid parameters, or measures of affective state. No gender effects on performance were noted. It is concluded that while cognitive deficits may occur early in asymptomatic HIV disease, the ROC/ROM test as the authors used it is not a useful screening tool for clinicians. The study also suggests that the growing number of HIV-positive women should be included in neuropsychological studies of early HIV disease.

A pilot study on the use of self-mononuclear cell vaccines for tertiary prevention in early HIV disease

A pilot study on the use of self-mononuclear cell vaccines for tertiary prevention in early HIV disease

A prospective study of psychiatric aspects of early HIV disease in women

Few studies of psychiatric morbidity associated with HIV disease have included women. The authors prospectively studied a cohort of HIV-seropositive women, none of whom had AIDS, to assess changes in their psychiatric status over time. All seropositive women admitted to the U.S. Air Force's HIV evaluation unit for comprehensive evaluations since 1987 were eligible for enrollment in an open-ended prospective study. Forty-three women without AIDS enrolled between 1987 and 1991 (83% of those eligible), 29 of whom have been interviewed at least twice. The Structured Clinical Interview for DSM-III-R and a semistructured interview were administered to assess psychiatric diagnoses, suicidality, sexual functioning, affective status, and other psychosocial variables. Women were more likely to have a psychiatric diagnosis at follow-up, largely accounted for by a substantial increase in sexual dysfunction (41% of reevaluated groups). None engaged in suicidal behavior or required psychiatric hospitalization during the 86.9 woman-years of observation. High-risk sexual behavior occurred after seroconversion in at least 35% of the group, with no interval decline. Most women with early stage disease were free of major psychiatric disorders at both assessments. Many developed sexual dysfunction that impaired intimate relationships and detracted from quality of life. The psychiatric natural history of HIV infection in women appears to differ from that observed in studies of men.

The management of early human immunodeficiency virus infection

The outcome of treatment in patients with early asymptomatic HIV disease has recently improved. Clinical trials with zidovudine have demonstrated efficacy and greatly reduced toxicity when the drug is used in asymptomatic HIV-infected persons who have fewer than 500 CD4+ cells/mm3, and resistance to this drug in these patients is less frequent and severe. Also, the optimum dosage of zidovudine is less than previously believed, probably in the range of 500-600 mg daily given in oral divided doses. The use of antibiotics to prevent Pneumocystis carinii pneumonia is also of clear value in HIV-infected asymptomatic or symptomatic persons with fewer than 200 CD4+ cells/mm3. Oral regimens such as trimethoprim/sulfamethoxazole or dapsone alone appear to be effective and are gaining preference over aerosolized pentamidine that is considerably more expensive. Together these medical advances argue for the encouragement of voluntary HIV testing to enable early diagnosis and, hence, optimum medical monitoring and appropriate intervention. These issues and recommendations for laboratory and clinical monitoring will be provided in this review.

Canadian Multicenter Azidothymidine Trial

The study objective was to describe the pharmacokinetics of azidothymidine (AZT) in a large population of early, asymptomatic human immunodeficiency virus (HIV)-infected individuals. The study design was a multicenter, prospective, descriptive single-dose pharmacokinetic study. Each of 66 fasting, male, HIV-infected homosexuals older than 18 years of age and in CDC classifications II, III, and IVC2 received a single 400-mg oral dose of AZT with subsequent pharmacokinetic measurements performed during an 8-h period for AZT and its major metabolite, glucuronylazidothymidine (GAZT). Results were obtained in 65 patients (36 smokers, 29 nonsmokers), of whom 3 were noted to have hepatic dysfunction. In those with normal hepatic function, the following parameters were described: AZT, area under the curve (AUC) +/- SD, 9.9 +/- 5.7 microM.h, maximum concentration (Cmax) +/- SD, 7.3 +/- 4.7 microM; time to maximum concentration (Tmax) +/- SD, 0.93 +/- 0.42 h, and half-life (t1/2) +/- SD, 1.0 +/- 0.8 h. Corresponding values for GAZT were: AUC +/- SD 35.7 +/- 10.3 microM.h, Cmax +/- SD 21.3 +/- 7.3 microM, Tmax +/- SD 1.2 +/- 0.50 h, t1/2 +/- SD 0.98 +/- 0.62 h, No significant differences were found in comparisons of study site, CDC classification of disease, smokers versus nonsmokers, and in patients with hepatic dysfunction, although a higher AUC and earlier Cmax for AZT was noted in the latter group. It is concluded that AZT pharmacokinetics are similar in patients with early asymptomatic HIV disease when compared with previous reports in patients with later disease.(ABSTRACT TRUNCATED AT 250 WORDS)

HIV-associated dementia: review of some conceptual and terminological problems

It is well established that the central nervous system is often significantly affected in HIV disease, either as a result of secondary infections and other processes, or possibly as a direct effect of HIV. There is some debate about the nature, extent and significance of central nervous system impairments in early HIV disease, and the search for markers of nervous system involvement is an important area of investigation. There is far less controversy about the development of neuropsychiatric disorders in advanced HIV disease, and specifically, a syndrome of HIV-associated dementia has been described. There are, however, problems in the way this dementia syndrome has been described and named, and conceptual and terminological confusion has adversely affected understanding of the prevalence, course and aetiological mechanisms of HIV-associated dementia. In addition, hypotheses have been put forward about its aetiology, which need to be satisfactorily tested. Possible ways of dealing with these problems are considered, and suggestions made for further research.

CD4+ Monocyte Counts in Persons with HIV-1 Infection

In this study, we asked whether there is a difference in the number of CD4+ and CD4- peripheral blood monocytes as CD4+ T cells decrease during HIV-mediated immunodeficiency. Monocytes and T cells from 90 HIV-positive and 43 HIV-negative persons were analyzed by flow cytometry. The 90 HIV-positive patients represented the entire spectrum of CD4+ T-cell counts. We report that as CD4+ T cells decrease, the number of CD4+ monocytes decrease in parallel. Moreover, significantly higher CD4+ monocyte counts were observed in persons with early stage HIV disease, i.e., greater than 800 CD4+ T cells/mm3, than in HIV-negative persons with greater than 800 CD4+ T cells/mm3. Potential implications of these findings are discussed.