Mechanisms associated with the generation of biologically active human immunodeficiency virus type 1 particles from defective proviruses.

Abstract

The human immunodeficiency virus (HIV) is the etiological agent of acquired immunodeficiency syndrome (AIDS). HIV exhibits extensive genetic diversity and it is apparent that an infected individual contains different populations of distinct viral strains, a large proportion of which has been found surprisingly to be defective for replication. A similar phenomenon has also been observed with some cell lines that are known to produce infectious viral particles but harbor defective proviral genomes. Here, we investigated the molecular basis of this phenomenon by cloning proviral genomes of HIV from a cell line that was capable of producing high titers of biologically active HIV particles that readily induced syncytia with CD4+ cell lines and peripheral blood lymphocytes. This cell line was found to contain five proviral genomes, all of which, when tested individually, failed to produce replication-competent viruses upon transfection into human cells. However, when a specific combination of two proviral genomes was used in such transfection studies, it was possible to obtain biologically active, replication-competent viral particles that infected and replicated in CD4+ cell lines and induced syncytia characteristic of HIV. Such a result may be due to homologous recombination between proviral DNAs occurring in cells after transfection and/or complementation of replication-defective proviral DNAs. The diploid nature of the viral RNA genome present in the viral particle may enable the persistence of defective HIV genomes.

Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase

“…A chronic HIV-1 producer cell line A1953 [45] was pretreated for 24 h using 100 and 1,000 nM GSK002, 100 and 1,000 nM GSK1264, or diluent control (DMSO). The cells were washed with 1 x PBS and incubated with fresh medium containing inhibitor or DMSO.…”

Defective Virus Drives Human Immunodeficiency Virus Infection, Persistence, and Pathogenesis

“…The continuous evolution of HIV, deemed useful for "immunological escape," is sustained by a high rate of mutation and a high rate of replication. The high mutation rate is driven by the error-prone process of reverse transcription (5)(6)(7)63) and by recombination (34,35,94). The end result is the generation of the large range of viral diversity and a predominance of defective virus.…”

Multidrug‐Resistant Variants of HIV Type 1 (HIV‐1) Can Exist in Cells as Defective Quasispecies and Be Rescued by Superinfection with Other Defective HIV‐1 Variants

“…For example, it has been reported that most infected spleen cells in vivo have 11 HIV copy; a single cell can contain up to seven different copies of HIV-1 DNA [11]. It has also been shown that cells harboring 5 copies of defective provirus were able to produce highly infectious viral progeny [12].…”