This program was designed to encourage basic and applied research on the development and evaluation of procedures to remove or destroy the infectivity of HIV-1 and/or other transfusion-transmitted viruses in blood and blood components, while maintaining the therapeutic effectiveness of these preparations.
Five grantees were supported through this program, which terminated in fiscal year 93.
R01 HL41179 - Charles Isaacs - Institute for Basic Research in Developmental Disability,
New York, NY
R01 HL41221 - Bernard Horowitz - New York Blood Center, New York, NY
R01 HL41238 - Roger Dodd - American Red Cross, Rockville, MD
R01 HL41361 - Girsh Vyas - University of California, San Francisco, CA
R01 HL41374 - David Bing - Center for Blood Research, Boston, MA
Many different approaches to the problem of inactivating viruses in blood components were tried by investigators in this program. However, none was entirely successful. One grantee studied a promising photoactive dye (hematoporphyrin) that, when activated by light of specific wavelength, has been shown to inactivate various infectious agents, including Simian Immunodeficiency Virus (SIV), a retrovirus closely related to HIV-1. This finding paved the way for infectivity studies of Rhesus monkey blood in a new photodynamic flow cell system. Preliminary results indicate that 20,000 SIV particles can be inactivated per milliliter of blood without any deleterious effects to the red blood cells. This treatment approach may provide a means of further reducing the risk of infection by viral agents transmitted through blood transfusion.
This program was designed to study the nature of bone marrow suppression in HIV-1 infection. The bone marrow is a target organ for the human immunodeficiency virus. Although studies have concentrated on the mechanisms by which suppression of blood cell production (hematopoiesis) occurs during the course of HIV infection, the pathobiology is still incompletely understood. Indeed, recent studies discussed below suggest this phenomenon may be multifactorial.
Twelve grants were awarded from fiscal year 87 to fiscal year 93.
R01 HL42069 - Anne Hamburger - University of Maryland, Baltimore, MD
R01 HL42087 - John Byrnes - University of Miami, Miami, FL
R01 HL42090 - Michael Prystowski - University of Pennsylvania, Philadelphia, PA
R01 HL42105 - Brian Davis - Medical Research Institute, San Francisco, CA
R01 HL42107 - David Golde - University of California, Los Angeles, CA
R01 HL42112 - Jerome Groopman - New England Deaconess Hospital, Boston, MA
R01 HL42114 - Stephan Hauptman - Thomas Jefferson University, Philadelphia, PA
R01 HL42115 - Eugene Cronkite - Brookhaven National Laboratory, Upton, NY
R01 HL42125 - Jean-Pierre Sommadossi - University of Alabama, Birmingham, AL
R01 HL42142 - Jeannette Mladenovic - State University of New York, Stony Brook, NY
R01 HL42148 - Howard Steinberg - Beth Israel Hospital, New York, NY
R01 HL42283 - Brian Davis - Medical Research Institute, San Francisco, CA
Bone marrow biopsies from patients with a spectrum of HIV-1 disease were studied by in situ hybridization utilizing riboprobes to most of the HIV-1 genome. Results indicated that bone marrow HIV expression in patients correlated with advanced disease. Bone marrow biopsies (T cell-depleted) indicated that the majority of cells in some specimens became stained by markers for cells of the macrophage lineage and myeloid precursors. Results have now established that CD34+ progenitor infection, if it occurs, is of very low frequency. This suggested that vertical passage of virus from marrow stem/progenitor cells to mature cells may not be a significant mechanism of viral transmission in HIV-infected individuals. Furthermore, these studies supported the feasibility of novel treatment modalities for HIV that potentially involve reinfusion of purified CD34+ autologous bone marrow cells together with anti-virals following marrow purging/ablative therapy to eradicate virus and virus-infected cells.
Recent studies by these investigators indicate that, although exposure of CD34+ hematopoietic cells to HIV-1 rarely gives rise to productive or latent infection, such exposure can induce defects in CD34+ cells and may even kill these cells. Also, the ability of HIV-1 to induce hematological abnormalities in HIV-infected patients likely depends on the type of HIV-1 isolate present in vivo. HIV infection of hematopoietic accessory cells such as T cells, monocytes, macrophages, and stromal cells has been reported. Thus, these recent studies suggest that depressed cytokine production by accessory cells/subclasses may lead directly to the cytopenias observed in HIV-infected patients. Follow-up studies on cellular and molecular regulation of cytokine production by accessory cells in HIV-infected patients will provide new insights into the mechanism of marrow suppression in this patient population.
This large natural history study of HIV-1-related lung disease is supporting research on the prevalence, incidence and types of lung disease that occur in people with HIV-1 infection and it will describe the course and outcome of these disorders.
Seven contracts were supported originally and the program was continued with grant support; the program ended in 1995.
U01 HL48779 - Kenneth Poole - Research Triangle Park, Triangle Park, NC
U01 HL48516 - Jeanne Wallace - University of California, Los Angeles, CA
U01 HL48518 - Mark Rosen - Mt. Sinai School of Medicine, New York, NY
U01 HL48500 - Lee Reichman - NJ Univ. of Medicine and Dentistry, Newark, NJ
U01 HL48511 - Paul Kvale - Henry Ford Hospital, Detroit, MI
U01 HL48501 - Phillip Hopewell - University of California, San Francisco, CA
U01 HL48534 - Jeffrey Glassroth - Northwestern University, Evanston, IL
Incidence rates at 18 months of follow-up in this study have been determined for a variety of pulmonary processes. The overall rate for any pulmonary infection was 10.3 percent. For opportunistic infections, rates of 3.9 and 1.1 were seen for P. carinii and nontuberculosis Mycobacterium, respectively. The major types of non-opportunistic infections observed were bacterial pneumonia syndrome (4.8 percent), unspecified pneumonia (0.7 percent), and M. tuberculosis (0.9 percent). The rates for pulmonary neoplasms and idiopathic pulmonary processes were, 0.5 and 0.7 percent. For miscellaneous pulmonary events, such as pulmonary embolus, pneumothorax and congestive heart failure, the incidence rates were in the 0.1-0.2 percent range. By far the largest category, ambulatory respiratory illness had an overall incidence rate of 46.8 percent. This category subsumed upper respiratory infections (33.4 percent), bronchitis (16.0 percent), sinusitis (5.3 percent), influenza syndrome (4.2 percent), and otitis media (2.2 percent). Bacterial pneumonia occurred significantly more frequently in injection drug users than in homosexual/bisexual men; by contrast, the incidence of P. carinii pneumonia was significantly greater in homosexual/bisexual men than in injection drug users.
Interesting findings were obtained for prevalence of reactivity to tuberculin-purified protein derivative (PPD) and skin test anergy and for predictors of delayed-type hypersensitivity (DTH) responsiveness in HIV-positive compared to HIV-negative controls. Among HIV-infected individuals, tuberculin reactivity varied directly and anergy varied inversely with absolute CD4-lymphocyte count. The strongest predictors of tuberculin responsiveness were reported as: injection drug use, black ethnicity, a reported history of a positive PPD, and a reported history of BCG vaccination. The strongest predictor of anergy was HIV-seropositivity. The ability to react to DTH antigens was highly dependent upon immune status. The decrease in tuberculin responsiveness associated with HIV infection and low CD4 counts was accompanied by a proportional increase in skin test anergy. The value of PPD and anergy testing in HIV-seropositives ultimately depends on their ability to predict subsequent TB risk, which is imprecisely known at present. Until more data or better methods are available, DTH testing, including tuberculin, should be performed as early as possible in the course of HIV infection, even in those with greatly reduced CD4-lymphocyte counts.
An analysis of the use of interventions designed to prevent lung infections in HIV-infected people has also been done. It appears that interventions such as administration of pneumococcal and influenza vaccine and drug prophylaxis for TB are not widely used by HIV-infected people, although use of such interventions appears to increase as HIV infection progresses; however, even among those with the most advanced symptoms, anti-viral treatment was not given to 25 percent of the cohort.
Bacterial pneumonia occurred among HIV-positive individuals at a rate that was nearly nine times that of HIV-negative controls. Among HIV-positives, bacterial pneumonia occurred almost six times more frequently in individuals with CD4 cell counts less than 500 than in those with counts above 500. Mortality was increased three-fold among persons who had an episode of pneumonia. The use of trimethoprim-sulfamethoxazole as prophylaxis against pneumocystic pneumonia was associated with a 41 percent reduction in the risk of bacterial pneumonia.
Individuals with CD4 cell counts below 200 had slightly reduced pulmonary diffusion capacity (DLCO) and all three measurements were reduced in injection drug users with DLCO more substantially reduced in this subgroup. After accounting for other factors such as cigarette smoking, the prevalence of abnormal DLCO seen in injection drug users was 2-3 times that in other groups (homosexual men and females). Overall, the results indicate that, although advanced HIV infection is associated with slightly reduced DLCO, this finding in an asymptomatic patient may be influenced by factors unrelated to HIV infection -- factors such as cigarette smoking, ethnicity and injection drug use.
This study was designed to determine the nature of heart disease in AIDS patients. Its emphasis was on the etiology, pathogenesis, and improved diagnosis and management of cardiac dysfunction. Each year, 5,000 patients with AIDS in the United States have clinically symptomatic cardiac disease. As greater numbers of patients are treated with anti-retroviral therapy, thereby increasing survival times, the number of HIV-1-related heart disease patients is expected to rise.
Six grants were awarded, three for five years and three for three years (see*). The study ended in 1992.
R01 HL41495 - Melvin Cheitlin - University of California, San Francisco, CA
R01 HL41400*- William Lewis - University of California, Los Angeles, CA
R01 HL42090 - Judith Hsia - George Washington University, Washington, DC
R01 HL41514 - Ahvie Herskowitz - Johns Hopkins University, Baltimore, MD
R01 HL41531* - Azorides Morales - University of Miami, Miami, FL
R01 HL41502* - John Craighead - University of Vermont, Burlington, VT
Results from this study corroborated the annual incidence rate of 5,000 AIDS patients contracting clinical heart disease. The study also showed that the most common form of symptomatic heart disease in HIV-1-infected patients is the development of cardiomyopathy with congestive heart failure. Fundamental questions remain: (1) Is this form of cardiomyopathy an HIV-related disease or is it associated with some of the same life-style factors associated with increased risk for HIV-1 infection? (2) If it is HIV-1-related, is it associated with direct HIV-1 infection of the heart or does HIV-1 facilitate infection with some other cardiotropic virus(es)? (3) If cardiotropic virus(es) are involved, is cardiac injury caused directly by viral replication within myocardial cells or is it secondary to virally induced autoimmunity?
Current hypotheses concerning the etiology of cardiomyopathy related to HIV-1 infection include: direct myocardial infection with HIV-1 or co-infection with other cardiotropic viruses, post-viral cardiac autoimmunity, selenium deficiency, autonomic dysfunction, and cardiotoxicity from illicit drugs such as cocaine and heroin. Cardiac hypersensitivity and/or toxicity from iatrogenic pharmacologic agents has been suggested, particularly for nucleoside analogues and pentamidine. Early in the AIDS epidemic, studies were limited to autopsy descriptions of cardiac abnormalities associated with patients infected with HIV-1. Marantic endocarditis, metastatic Kaposi's sarcoma and opportunistic infection of the myocardium and pericardium were the most commonly noted. Later studies confirmed that clinically symptomatic and life-threatening cardiomyopathy was also part of the spectrum of HIV-1-related cardiac disease.
Prospective echocardiographic and electrocardiographic studies have further documented both symptomatic cardiac disease in 10-20 percent of HIV-1-seropositive adults as well as clinically silent abnormalities (e.g., pericardial effusions, non-bacterial thrombotic endocarditis, mild global left ventricular dysfunction) in 30 to 50 percent patients. One clearly emerging concept is the association between HIV-1-related left ventricular dysfunction and lymphocytic myocarditis.
Studies involving 37 consecutive endomyocardial biopsies have shown a 51 percent prevalence of myocarditis in HIV-1-seropositive patients undergoing endomyocardial biopsy for suspected myocarditis, as compared with 9 percent in a series of 534 patients without HIV risk factors. Several other laboratories have demonstrated the presence of HIV-1-gene transcripts within cardiac tissue, presumably in cardiac myocytes.
The significance of descriptions of HIV-1-gene transcripts within the myocardium is unclear at this point and requires further study, particularly since transcripts have been demonstrated in cardiac tissues from patients with and without known cardiac dysfunction during life. It is not known whether myocyte injury in HIV-1-related myocarditis can be explained by HIV-1 infection of interstitial dendritic cells (myocardial resident macrophages), cytoxicity mediated by cytokines, viral proteins or the direct infection of myocytes by HIV-1 or other cardiotropic viruses. Recent studies have shown non-permissive or latent infection of myocytes with cytomegalovirus, demonstrated by immediate-early (CMV IE-2) gene expression, in approximately 50 percent of HIV-1-infected patients who have severe left ventricular dysfunction; 15 percent of samples contain myocytes with HIV-1 gene transcripts.
A number of published prospective studies, when combined, have assessed a total of 450 HIV-1-seropositive patients by two-dimensional echocardiography; a total of 6.2 percent (n=28) had or eveloped congestive heart failure. Although the reported prevalence of left ventricular dysfunction varied from 3-41 percent, the combined crude prevalence across these studies was 17.5 percent (79/450). In all the combined prospective echocardiographic studies, 80 percent of the affected patients had either AIDS or ARC. This is in agreement with findings from this study that 61 percent of patients with asymptomatic left ventricular dysfunction and 83 percent of symptomatic patients with congestive heart failure had CD4 counts of <200/mm³. These data suggest that severe, symptomatic HIV-1-related cardiomyopathy may be largely a disease of late-stage HIV-1 infection.
Cocaine is a cardiotoxic agent and case reports have associated cocaine use with the development of cardiomyopathy. In a series of 534 consecutive endomyocardial biopsies performed in Baltimore between 1985 and 1990, only 6 cases of cardiomyopathy in HIV-1-seronegative intravenous cocaine users were identified, suggesting that the entity was rare. There are reports from a variety of investigators showing conflicting data regarding any clear relationship between cocaine use and cardiomyopathy in the HIV-1-infected population. One investigator reported a 41 percent prevalence of global left ventricular hypokinesis in predominantly intravenous drug users with AIDS; however, another found a prevalence of only 10.5 percent. Further studies are clearly needed to determine the role of illicit drug use in the development of HIV-1-related cardiac disease.
One investigator, Dr. Herskowitz, has recently described myocarditis and severe left ventricular dysfunction in HIV-1-infected patients receiving nucleoside analogs such as zidovudine (AZT), dideoxyinosine (ddI), or dideoxycytosine (ddC). The mechanisms of cardiotoxicity are poorly understood and likely require multiple concurrent factors to manifest severe disease, one of which would be lengthy exposure to drug. Rats treated with AZT develop morphologic evidence of mitochondrial toxicity on electron microscopic examination, although they do not develop symptoms or histologic evidence of cardiomyopathy. Drug-induced hypersensitivity or allergic hypersensitivity may arise at any time during treatment. In one biopsy situation, two patients with severe congestive heart failure were found to have eosinophilic myocarditis that was consistent with drug-induced hypersensitivity secondary to IV penicillin therapy; both rapidly regained normal function after discontinuation of the drug.