Mechanisms of the host cell effect on human immunodeficiency virus type 1 neutralization sensitivity

• Main Author: Sawyer, Lynette Susan Walker
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-1996
• Subjects: Immunology; Microbiology; Public health
• ISBN: 9780591095050; 059109505X

Neutralizing antibody responses in vitro are a primary marker of host immunity and resistance to viral infection in vivo. However, studies of in vitro neutralization of human immunodeficiency virus type I have generated widely variable results and questionable association with disease progression. For example, HIV-1 propagated in continuous T-cell lines is more sensitive to neutralization by a variety of antibody preparations and soluble forms of its receptor (CD4) than is HIV-1 propagated in primary peripheral blood mononuclear cells (PBMCs). This host cell effect has become a central issue in the development and evaluation of experimental HIV vaccines. This work was therefore undertaken to elucidate the mechanisms underlying the host cell effect. Five clinical isolates and one laboratory strain of HIV-1, each propagated in both the continuous T-cell line H9 and in phytohemagglutinin-stimulated PBMCs, were used to examine potential mechanisms for this host cell effect: (1) culture methodology; (2) epigenetic factors under the control of the host cell; and (3) selection in different host cells of genetically different subpopulations of the (uncloned) stock virus. As a result of these studies differences in the following factors can be completely ruled out as the basis for the host cell effect: culture conditions, assay methodology, incorporation of cellular adhesion molecules into the virion, rate of glycoprotein 120 shedding and selection of viral subpopulations in different host cells. Glycosylation and neutralization by antibody to host cell proteins may play a minor role, but cannot entirely explain the host cell effect. In the case of the laboratory strain IIIB, the host cell effect was dependent upon the presence of complement, duration of virus/antibody incubation, and whether the viral stock was obtained from an acute or chronic infection. A fourth possible mechanism, not investigated here, is differential mutation of the virus during passage into different host cells. Future sequencing of the HIV isolates used in this study may not only determine whether mutation is the primary mechanism underlying the host cell effect, but may also clarify the interaction of mutation with some of the other mechanisms examined in this dissertation.