PATHOGENESIS OF AIDS--ROLE OF CYTOMEGALOVIRUS

The overall aim of this project is to determine whether human
cytomegalovirus (HCMV) contributes to the pathogenesis of
acquired immune deficiency syndrome (AIDS) by interacting
specifically with the AIDS virus (HIV). AIDS is a disease which
has reached epidemic numbers with greater than 40,000 new cases
worldwide predicted over the next two years. Individuals with
this syndrome develop severe immunosuppression accompanied by
opportunistic infections, most commonly HCMV. Although the
precise pathogenic mechanism or this syndrome has not been
identified, the etiological agent of AIDS is the human
immunodeficiency virus (HIV). HCMV possesses many similarities
to the AIDS virus including suppression of the immune system,
spread by venereal transmission and blood transfusion, and
infection of OKT4 lymphocytes and monocytes. The ability of
HCMV to transactivate HIV and our recent co-localization of both
viruses in single cells in tissue with aberrant HCMV growth
suggests a symbiotic relationship. Therefore, the focus of this
project will be to determine the in vivo and in vitro interactions
between HCMV and HIV which may contribute to the pathogenesis
of AIDS. We will first identify the tissues and cell types from
AIDS patients infected by HIV and HCMV using in situ
hybridization and immunocytochemistry concentrating on brain,
rectal tissue, lymph node, spleen, and peripheral blood. We will
determine the extent of HCMV expression within these tissues and
using double-labeling techniques assess the frequency of HIV and
HCMV coinfection of single cells. We will also examine the
ability of the HIV to transactivate HCMV immediate-early (IE),
(E), and late (L) genes normally quiescent in lymphocyte cells in
culture, peripheral blood mononuclear (PBMN) cells, PBMN subset
populations, and endothelial cells. Specific HCMV genes
representing the three kinetic classes will be examined in these
cells coinfected with the AIDS virus by northern analysis and in
vitro nuclear runoff transcription of nuclei. We will finally
examine the ability of the AIDS virus to directly activate HCMV
IE, E, and L promoters in transient transfection assays.
Comparison of these in vivo and in vitro results will give an
insight into the pathogenesis of the disease.