Enhanced HIV infectivity and changes in GP120 conformation associated withviral incorporation of human leucocyte antigen class I molecules

Background: Assembly of human immunodeficiency virus type 1 (HIV-1) occurs at the level of the plasma membrane of the host cell. During this process H IV incorporates significant quantities of cell surface-derived molecules in to its lipid bilayer including human leucocyte antigen (HLA) class I and II , intercellular adhesion molecule-1 and lymphocyte function antigen-1. Seve ral studies indicate that virion-bound host-cell-derived molecules are func tional and affect the biological properties of HIV-1. Virion-associated HLA class II and intercellular adhesion molecule-1 enhance the infectivity of T-cell line-adapted (TCLA) viruses. No role for virion-associated HLA class I molecules has yet been identified. Objective: To investigate the role of HLA class I molecules in HIV replicat ion and infectivity Methods: HLA class I negative human cells lines transfected with the HLA Cw 4 gene were infected with different TCLA viruses as well as primary X4 isol ates. The infectivity of HLA Cw4 positive and negative viruses was determin ed on indicator cell lines and on phytohaemagglutinin-activated peripheral blood mononuclear cells. An entry polymerase chain reaction assay was used to determine differences in entry-competence of Cw4 positive and negative v iruses. The expression of selected gp120 epitopes on native Env molecules d erived from Cw4 positive and negative viruses was determined by a monoclona l antibody-based enzyme-linked immunosorbent assay. Immunoprecipitation exp eriments were performed to investigate the presence of gpl20/HLA Cw4 comple xes. Neutralization assays determined the differences in susceptibility to neutralization between HLA Cw4 negative and positive viruses. Results and conclusions: The infectivity of primary HIV-1 X4 isolates and o f TCLA viruses is increased upon viral incorporation of HLA Cw4 molecules. This effect is associated with changes in viral envelope proteins conformat ion including an enhanced expression of the V3 loop of gp120, and of epitop es that are exposed upon CD4 binding. The gp120 conformational changes are consistent with the formation of a multimolecular complex between HLA class I and gp120/160. HLA Cw4 incorporation is also associated to a lower susce ptibility to antibody neutralization. These findings have important implica tions for understanding the immune response to cryptic and conformational e pitopes of the viral envelope. (C) 1999 Lippincott Williams & Wilkins.