Trial to Determine If Viral Activation Is Associated with Transfusion in Individuals Infected with HIV-1 (VATS)

Current transfusion practice for HIV-positive patients varies widely and is controversial. Although theoretical arguments for allowing autologous donations by HIV-positive patients (when possible) are compelling, concerns over unit mixups and exposure of blood bank staff to infection have led many hospitals to discourage this practice. Recent studies showing reduced blood utilization in HIV-infected patients treated with erythropoietin (EPO) are promising. However, these studies indicate that EPO is most effective in mild anemias, rarely eliminates the need for allogeneic blood in HIV-positive patients, and is relatively (if not prohibitively) expensive. Consequently, transfusion of allogeneic blood components will probably continue to be the major modality for managing HIV-associated anemias and thrombocytopenia for the foreseeable future. Unfortunately, there are few data and certainly no consensus on how best to manage allogeneic transfusion support of HIV-1-infected patients.

This study will attempt to determine if transfusion causes activation of HIV-1 and cytomegalovirus in HIV-1-infected persons and will evaluate the role of donor lymphocytes in producing this activation. The effectiveness of filters that remove lymphocytes from transfused blood and gamma irradiation will also be examined. In addition, this study will examine the persistence of donor lymphocytes and/or evidence for the activation of latent viruses in this population.

This study is being support from 1995 to 1998.

N01 HB57115 - Michael Lederman - Case Western Reserve University, Cleveland, OH
N01 HB57116 - Princy Kumar - Georgetown University, Washington, DC
N01 HB57117 - Timothy Flanigan - Miriam Hospital, Providence, RI
N01 HB57118 - Henry Sacks - Mount Sinai School of Medicine, New York, NY
N01 HB57119 - Michael Para - Ohio State University, Columbus, OH

N01 HB57120 - Thomas Lane - University of California, San Diego, CA
N01 HB57121 - Edward Murphy - University of California, San Francisco, CA
N01 HB57122 - Charles van der Horst - University of North Carolina, Chapel Hill, NC
N01 HB57123 - John Mellors - University of Pittsburgh, Pittsburgh, PA
N01 HB57124 - Richard Pollard - University of Texas, Galveston, TX

N01 HB57125 - Ann Collier - Puget Sound Blood Centers, Seattle, WA
N01 HB57126 - Michael Busch - Irwin Memorial Blood Center, San Francisco, CA
N01 HB57127 - Leslie Kalsih - New England Research Institute, Boston, MA

Recent Progress

The study has been initiated and it is a multi center randomized clinical trial including approximately 640 HIV-1-infected patients. Patients scheduled for transfusion enter the study at the time of their first transfusion and are randomized to one of two arms: unmanipulated (i.e., non-leukoreduced and non-irradiated) red blood cells or filter-leukoreduced red blood cells. Treatment assignment is blinded to study staff and to patients. Therefore, data is not available at this point in time.

HIV and Thrombotic Thrombocytopenic Purpura (95-07)

Thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia, hemolytic anemia, fluctuating neurological signs, renal dysfunction, fever and other signs of organ failure. It has been reported with increasing frequency in persons with HIV-1 infection. The etiology of this disorder and its relation to HIV are not well understood.

The objectives of this initiative are 1) to support studies on the pathogenesis of TTP and 2) to stimulate development of new approaches for determining predisposition, early diagnosis and treatment of TTP associated with HIV infection.

R01 HL55556 - Jerome Gottschall -Blood Center of Southeastern Wisconsin, Milwaukee, WI
R01 HL55605 - Patricio Ray - Children's National Medical Center, Washington, DC
R01 HL55646 - Jeffrey Laurence - Cornell University Medical Center, New York, NY
R01 HL55660 - Gerald Keusch - New England Medical Center, Boston, MA
R01 HL55674 - Gerd Walz - Beth Israel Hospital, Boston, MA

Recent Progress

TTP is manifested by localized microvascular endothelial cell (EC) proliferation, with detachment of EC, without an inflammatory response. There appears to be some tissue specificity in EC susceptibility to apoptosis exposed to plasma from TTP patients, both HIV seronegative or seropositive. EC from glomerular, cerebral or tonsilar are more susceptible than EC from hepatic or pulmonary source. The Fas ligand is involved in this process.

Initial data suggest that HIV infection increases microvascular injury in children with TTP / HUS. These children also show renal tubular damage and 3. rapidly progresses to end stage renal disease.

The HIV envelop protein gp120 may be associated with thrombotic microangiopathy in TTP. Several expression plasmids with gp120 sequences from patient isolates have been generated and stabilized. These systems are likely to be useful in endothelial cell studies.

Effects of Cytokines on Hematopoiesis in AIDS Animal Models (95-09)

It is anticipated that the study of animal models of human acquired immunodeficiency disease (AIDS) will increase our understanding of the clinical consequences and/or efficacy of hematopoietic factors used in HIV-1 infected persons. The complexity of AIDS makes it difficult to assess cytokine effects exclusively in humans and thus the research focus of this program emphasizes animal models. However, focused cytokine studies in HIV-1 infected persons are supported under this program. A total of five grants listed below were funded in FY 95.

R01 HL55175 - Alice Tarathal - University of California, Davis, CA
R01 HL55176 - Christopher Hillyer - Emory University School of Med., Atlanta, GA
R01 HL55187 - Jerome Groopman - New England Deaconess Hospital, Boston, MA
R01 HL55193 - Osami Kanagawa - Washington University, St. Louis, MO
R01 HL55205 - Jerome Zack - University of California, Los Angeles, CA

Recent Progress

Initial studies in SIV-infected macaques have demonstrated that granulocyte-colony stimulating factor administered during pregnancy has no adverse effects on the fetus. Early data from another investigator, again using SIV-infected rhesus macaques demonstrated that these animals have the capacity to expand and mobilize their primitive bone marrow progenitor cells in response to GCSF, erythropoietin, and thrombopoietin without increased viral load.

Another investigator has examined the effect of IL-4 deficiency on the susceptibility of cells to HIV. Using IL-4 deficient mice, they demonstrated that the relative resistance of IL-4 deficient mice to MAIDS was related to suppressed lymphoproliferation, due to lack of IL-4 driven B cell proliferation.

Other investigators have identified a unique population of T cells which express TCR beta chain and CD3 complex in the absence of known beta chain associating molecules. This population is still capable of responding to MAIDS superantigen and may play a critical role in the development of disease. Further studies involve understanding the nature of superantigen activity produced by MAIDS virus transformed B cell line. Elucidation of the T cell-MAIDS superantigen interaction and the mechanisms by which such interaction induces strong IL-4 production and T cell anergy is necessary to understand the pathogenesis of retrovirus induced immunosuppression.

Lung-Specific Drug Delivery Systems for Enhanced TB Treatment (HL-95-12)

The spread of TB has re-emerged as an urgent health problem. Rates for this disease have been increasing since the mid-1980s in association with the HIV epidemic.

The development of targeted drug delivery to the lungs for TB treatment is desirable for several reasons. The lung is the major portal of entry for Mycobacterium tuberculosis and, thereby, the site of initial immune response as well as the site of the most frequently recognized pathogenic effect. Technology is now at the point where aerosols alone and aerosols combined with liposomes and, possibly, time-release treatment may offer advantages for more effective treatment and prevention of TB. It is thought that lowered systemic toxicity provided by these approaches would permit much more flexibility for treatment regimens such that smaller, more effective, doses may be employed. In addition, because a drug can be delivered directly to the site of disease, it might be possible to increase drug concentration in the lung, thus reducing the length of treatment. Perhaps the combination of new anti-tuberculosis drugs with time-release technology will reduce the frequency of dose delivery. This would provide a major benefit in treating the populations hardest hit by TB who often have poor access to sustained medical care and for whom it is hard to maintain effective compliance with treatment.

The objective of this initiative is to encourage research on novel approaches for therapy and prophylaxis of tuberculosis using the lung as the site of drug delivery.

This program supports five grants and will continue through 2000.

R01 HL55776 - Clifford Lyons - University of New Mexico, Albuquerque, NM
R01 HL55789 - Anthony Hickey - University of North Carolina, Chapel Hill, NC
R01 HL55791 - Neil Schluger - New York University Medical Center, New York, NY
R01 HL55794 - William Martin, II - Indiana University, Indianapolis, IN
R29 HL55779 - Jeffrey Hughes - University of Florida, Gainesville, FL

Recent Progress

A pilot study of aerosolized interferon gamma (IFN-gamma) as an adjunct to traditional therapy for multidrug-resistant tuberculosis shows that aerosolized recombinant human IFN-gamma is well tolerated and effective, but the effects are short-lived. The findings are important because of the severe symptoms and high mortality rates associated with multidrug-resistant tuberculosis. The study confirms that 500µg of aerosolized IFN-gamma can successfully reach infected lung tissue and stimulate the macrophages to allow the patients to control the infection. All five patients were moderately to severely ill with smear and culture positive multidrug resistant tuberculosis. All showed bodyweight stabilization or weight gain, all smears became negative, and lung cavities decreased in size after the patients inhaled aerosolized IFN-gamma three times a week for one month. Unfortunately, one to five months after the treatment was discontinued all the sputum smears reverted to being positive. The likely mechanism by which IFN-gamma acts is by increasing the intracellular killing ability of alveolar macrophages, by enhancing their capacity for making reactive nitrogen species, e.g., NO. The findings suggest that a longer course of treatment might be required to cure the patients. No serious adverse reactions occurred, but several patients experienced mild bronchospasm (>15 percent drop in FEV₁) which responded to bronchodilator therapy. The major problem with long-term therapy is the high cost of IFN-gamma.

Surfactant protein A (SP-A) acts as a ligand in the attachment of M. tuberculosis (Mtb) to alveolar macrophages. Attachment is the first step needed for entry of Mtb into the macrophages where it will either survive and grow or be killed. There is now preliminary data suggesting that SP-A binding may help Mtb escape the reactive nitrogen intermediates which play a role in killing mycobacteria.

Cell/Life Cycle Regulation in Microbial Pathogens of the Lung (HL-95-013)

Tuberculosis re-emerged as an urgent health problem in the 1980s in conjunction with the AIDS epidemic, although other factors such as homelessness and immigration from areas with high incidence of TB contribute to the current increase in TB cases. Recent projections of TB rates made by the CDC suggest that the current high rate of new TB cases, worldwide, is likely to increase over the next ten years.

The goal of this initiative is to elucidate the molecular basis of cell/life cycle regulation in the lung pathogenic and opportunistic microorganisms (e.g., Mycobacterium tuberculosis, Pneumocystis carinii, Histoplasma capsulatum and Coccidioides immitis) that may be associated with HIV infection. This program supports 7 grants and will continue through 2000.

R01 HL55934 - Andrew Limper - Mayo Foundation, Rochester, MN
R01 HL55936 - David Russell - Washington University, St. Louis, MO
R01 HL55948 - Simon Newman - University of Cincinnati, Cincinnati, OH
R01 HL55949 - Jon Woods - University of Wisconsin, Madison, WI
R01 HL55960 - George Kobayashi - Washington University, St. Louis, MO
R01 HL55965 - Henry Boom - Case Western Reserve University, Cleveland, OH
R01 HL55977 - Virginia SheperdVanderbilt University, Nashville, TN

Recent Progress

IL-6 was found to be produced by macrophages infected with mycobacterium species and suppress T cell responses. The large amount of IL-6 secreted by the infected cells has an immunosuppressive effect on the infected macrophages, other antigen presenting cells, and may affect T-cell activation. These effects may help mycobacteria escape the host immune response. Under this program as well as HL-95-012 other investigators report that Mycobacteria survive in macrophages by preventing the intracellular phagosomes that contain them from maturing into acidified lysosomal compartments conducive to microbial killing. The role of surfactant protein A (SP-A) in enhancing the uptake of mycobacteria by macrophages is being examined.

Other studies are aimed at understanding how Pneumocystis carinii (P. carinii) interferes with lung cell division and growth. Attachment of P. carinii to type I lung cells seems to be necessary for growth of the organisms, but how P. carinii grows and divides is just beginning to be understood. In other plant and animal cells, the cell cycle is regulated by expression and activation of cell division cycle (cdc) proteins. One of these proteins is a kinase closely related to a protein kinase found in P. carinii. The protein kinase activity is elevated in P. carinii that attaches to lung cells and grows and divides in the lungs. Furthermore, studies in mink lung cells show that the P. carinii protein kinase appears to disrupt the growth of the lung cells by interfering with their cell kinases. The mechanisms are being investigated and should give insight into abnormal lung cell function during P. carinii pneumonia. Surfactant protein D(SP-D) appears to be important in the clumping of P. carinii and the uptake and degradation of these organisms by macrophages.

Behavioral Interventions for Control of Tuberculosis (95-03)

Tuberculosis was on the decline from the 1950s until the mid 1980s; however, the United States is now experiencing a resurgence of tuberculosis. In 1992, approximately 27,000 new cases were reported, an increase of about 20 percent from 1985 to 1992. Not only are tuberculosis cases on the increase, but a serious aspect of the problem is the recent occurrence of outbreaks of multidrug resistant tuberculosis, which poses an urgent public health problem and requires rapid intervention.

The goal of this initiative is to seek ways of controlling the spread of tuberculosis through behavioral interventions. Studies may focus on the community at large or upon specific population groups.

This program supports 6 grants and will continue through 2000.

R01 HL55729 - Andrew Moss - University of California, San Francisco, CA
R01 HL55738 - Melbourne Hovell - San Diego State University, San Diego, CA
R01 HL55751 - Wafaa El-Sadr - Columbia University, New York, NY
R01 HL55752 - William Bailey - University of Alabama, Birmingham, AL
R01 HL55760 - Mary O'Brien - University of Illinois, Chicago, IL
R01 HL55770 - Donald Morisky - University of California, Los Angeles, CA

Recent Progress

Investigators funded under this program met for the first time in October 1996 to exchange information on their programs. One of the six programs is aimed at promoting adherence to tuberculosis regimens in Latino adolescents. The program is based in San Diego County where adolescent tuberculosis cases account for approximately one third of the 50 active pediatric tuberculosis cases in the community. The program is primarily aimed at insuring that Latino teens with latent tuberculosis (they are infected by the TB bacillus, but not clinically ill) complete the many months of prophylactic treatment needed to prevent active disease. The investigators are testing an innovative approach for motivating the teenagers to complete therapy. It relies heavily on peer counselors, who themselves are specially trained teenagers, who have successfully completed tuberculosis treatment. Other investigators are employing creative programs to promote compliance with tuberculosis drug regimens among injection drug users and the homeless.