Title: Mechanisms of Defective Natural Killer Cytotoxicity

R01 HL43388 - Joan Stein-Streilein - University of Miami, Miami, FL

This researcher looked at the cytotoxic mechanism of natural killer (NK) cells in normal and immunodeficient patients with defective NK activity. Studies used both bronchoalveolar lavage cells and peripheral blood lymphocytes.

This grant was funded from 1990 to 1994.

Achievements

It appears that both NK and T lymphocytes have a defect in the pathways that signal release of factors such as Interleukin-2 (IL-2), but the defect in each may be different. For example, NK cells can be induced to release lytic factors by non-specific activators but T cells cannot be. Molecular techniques are being used to determine if activators induce an increase in mRNA from cell surface activation markers such as IL-2R. The absence of a secreted or membrane protein may be due to a lack of transcription, increased instability of the message or a block in translation. Complementary DNA probes for IL2, IL2R, IL4, TNF-alpha, TNF-beta, granzyme A and perforin are being used in hybridization studies to investigate these possibilities.

Title: HIV Lung Disease and Macrophages -- Molecular Cell Biology

K11 HL02358 - Ronald Collman - University of Pennsylvania, Philadelphia, PA

This project was a carefully supervised training program that provided the trainee with research skills and experience in viral pathogenesis relevant to the lung. The focus was on studying the biology of HIV-1 infection of monocytes and macrophages.

This grant was supported from 1989 to 1994.

Achievements

A macrophage-tropic isolate of HIV-1 has been obtained and cloned. The current effort is directed at characterizing the isolate biologically and molecularly. Its DNA sequence has been determined and entered into GenBank and the HIV Database. The isolate appears to be an intermediate strain, or "transitional isolate," with respect to its tropism. That is, it has the unique combination of being both macrophage-tropic and highly cytopathic for lymphocytes. Previous clinical studies have shown that asymptomatic HIV-infected individuals usually harbor macrophage-tropic strains of HIV-1 that are noncytopathic; individuals with disease, however, usually harbor strains that are cytopathic and nonmacrophage-tropic. This isolate may thus prove useful in ongoing studies on the relationships that exist between the various types of HIV isolates and their ability to produce symptoms.

Prospective Study of the Pulmonary Complications of HIV Infection (PACS) (HR-87-09 and 10)

This program started on 9/30/87 and was funded under the contract mechanism through 5/14/93. The study was then extended as a cooperative agreement which is active through 5/31/96. There is a Coordinating Center and six Clinical Centers. Focusses on prospective, longitudinal follow-up of pulmonary complications in 1,130 HIV-infected adults representative of the AIDS epidemic in the US and 167 HIV-negative controls.

Clinical Coordinating Center:

HL048779 - Kenneth Poole - Research Triangle Inst., Research Triangle Park, NC

Clinical Centers:

U01 HL048534 - Jeffrey Glassroth - The Medical College of Pennsylvania & Hahnemann                         University, Philadelphia, PA
U01 HL048501 - Philip Hopewell - University of California, San Francisco, CA
U01 HL048511 - Paul Kvale - Henry Ford Hospital, Detroit, MI
U01 HL048518 - Mark Rosen - Mount Sinai School of Medicine, New York, NY
U01 HL048500 - Lee Richman -Univ. of Medicine and Dentistry of NJ, Newark, NJ
U01 HL048516 - Jeanne Wallace - University of California, Los Angeles, CA

Achievements

Patients with HIV infection are at increased risk for bacterial pneumonia in addition to opportunistic infections. The risk is highest in those with CD4+ counts below 200 and among injection drug users. In the group with the low CD4+ cell count there was an increased rate of bacterial pneumonia among cigarette smokers. This study confirms a reduced incidence of bacterial pneumonia among patients on Trimethoprim-sulfametoxazole prophylaxis for P. carnii pneumonia, for which it appears to be the most effective agent. Thus, Trimethoprim-sulfametoxazole prophylaxis for P. carnii is encouraged and smoking cessation, is encouraged, especially for patients who are injection drug users.

The investigators continue to analyze and publish study data. The effects of pulmonary infections on viral load are now being studied using stored sera.

Title: Pulmonary-Parasite Interactions--Pneumocystis

K08 HL01916 - Jay Fishman - Massachusetts General Hospital, Boston, MA

In this training program, the trainee studied the interaction of alveolar Type I and II cells with P. carinii at the cellular and molecular levels. The research program address the morphology of binding of cultured alveolar epithelial cells to P. carinii, the identification of these glycoproteins and antigens of rat and human P. carinii, and attempts were made to clone the major surface antigens of P. carinii in a lambda bacteriophage.

This grant was supported from 1987 to 1992.