Molecular Understanding of HIV-1 Latency

Abstract

The introduction of highly active antiretroviral therapy (HAART) has been an important breakthrough in the treatment of HIV-1 infection and has also a powerful tool to upset the equilibrium of viral production and HIV-1 pathogenesis. Despite the advent of potent combinations of this therapy, the long-lived HIV-1 reservoirs like cells from monocyte-macrophage lineage and resting memory CD4+ T cells which are established early during primary infection constitute a major obstacle to virus eradication. Further HAART interruption leads to immediate rebound viremia from latent reservoirs. This paper focuses on the essentials of the molecular mechanisms for the establishment of HIV-1 latency with special concern to present and future possible treatment strategies to completely purge and target viral persistence in the reservoirs.

Figure 1

Schematic representation of HIV-1 life cycle and latency with current and possible targets for antiviral intervention. The HIV-1 life cycle begins with the attachment of virus to the receptor (CD4) and coreceptor (CXCR4 or CCR5), followed by fusion with target cell membrane. After virus entry, the viral nucleocapsid enter the cytoplasm, undergoes reverse transcription and then uses cytoplasmic dynein to move towards the nuclear pore complex. The preintegration complex is transported into nucleus through NPC, and then dscDNA either circulizes as one or two LTR containing circle or is integrated into a host cell chromosome. After integration the provirus remains quiescent in post integration latent state. On activation the viral genome is transcribed by cellular transcription factors, spliced mRNA are transported into cytoplasm where viral mRNA translated into regulatory and structural viral proteins. New virions assemble and bud through cell membrane, maturing through the activity of viral protease. The different classes of antiretroviral drugs are available. Fusion or HIV co-receptor inhibitors inhibit the entry of virions into a new target cell. The step of reverse transcriptase can be targeted, using nucleoside analogues or non-nucleoside reverse transcriptase inhibitors (NRTI and NNRTI, resp.). The HIV-1 integrase inhibitors inhibit the strand transfer reaction in the integration process, a crucial step in the stable maintenance of the viral genome, as well as efficient viral gene expression and replication. The class of protease inhibitors interferes with the last stage of viral life cycle which results in the production of noninfectious viral particles. The HIV maturation inhibitors disrupt a late step in HIV-1 Gag processing.