CYTOMEGALOVIRUS &CYTOKINES--COFACTORS IN HIV ACTIVATION

University Of California Davis, Davis CA

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Abstract

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in AIDS patients and is causes significant pulmonary pathology in HIV-infected individuals. Epidemiological and molecular data indicate the CMV may be an important cofactor for AIDS pathogenesis. The molecular interactions between CMV and HIV within a coinfected individual are not known. Clinical data indicate that the interstitial pneumonia that develops in transplant recipients may be caused by a CMV-induced immunopathological response to CMV antigens. It is hypothesized that HIV is activated directly and/or indirectly in the lungs of AIDS patients by cytokines synthesized by T- cells responsive to cytomegalovirus antigens. According to this hypothesis, expression of CMV antigens gradually increases in lungs cells of individuals coinfected with both HIV-CMV, activating T-cells primed to CMV epitopes. T-cell activation induces the release of cytokines which up- regulate HIV gene expression within cells harboring an HIB provirus. In this model, the cytokines also stimulate expression of endothelial adhesion molecules, facilitating emigration of HIV-infected peripheral blood mononuclear cells into the lungs. This sequence of pathogenic events would compromise pulmonary defenses against opportunistic infections, leading to lung pathology. The experimental design of this proposal will utilize rhesus macaques coinfected with rhesus cytomegalovirus *RhCMV) and simian immunodeficiency virus (SIV) to demonstrate in the lungs whether there is a relationship between: (1) RhCMV expression and cytokine production by activated T cells, (2) cytokine production by T cells and increased SIV gene expression, (3) cytokine production by T cells and increased expression of adhesion molecules by endothelial cells, and (4) expression of adhesion molecules and increased SIV viral load. This will be accomplished through the following Specific Aims: (I) To establish a model for acute infection of macaques with (i SIV, (ii) RhCMV, or (iii)SIV + RhCMV, (II To analyze the cellular location of SIV and RhCMV ina the lungs of acutely infected macaques, (III) To examine expression of immunoregulatory molecules ina the lungs of infected macaques, (IV) To develop a model for chronic infection of macaques with (i) SIV, (ii) RhCMV, or (iii) SIV +RhCMV. These studies utilize the strength of the SIV/rhesus macaque AIDS model to prospectively examine the complex interactions between CMV and immunodeficiency retroviruses in the lungs and to evaluate roles for cellular activation in potentiating the pathologic effects resulting form a pulmonary infection with both viruses.