HIV-1 latency: From acquaintance to confidant

Abstract

Antiretroviral therapy (ART) has transformed HIV from a fatal disease into manageable circumstance. However, the HIV reservoirs remain a main barrier to complete cure. This review emphasized when, where and how the latency is established, with focus on various host factors and viral proteins. We highlight the importance of Tat and Rev in facilitating the export and stability of HIV latency. We discuss how transcription factors such as NFκB, NFAT, and Sp1 regulate HIV gene expression during T cell activation, while other factors like MRTFB, BACH2, FOXO1, HMGB1, SAMHD1, APOBEC3, TRIM5, Wnt/β-catenin and LEDGF/p75 also contribute to the persistence of reservoirs. Recent studies have also identified novel restriction and immune regulatory factors such as, LAPTM5, KRT72, and CARD8, directly or indirectly influencing HIV 1 latency. The advancements in CRISPR screening technology have also identified novel host factors, such as FBXO34, FTSJ3, TMEM178A, NICN1, PEBP1, ZNF304 and ORC1, that are associated with HIV-1 latency. These findings underscore the multifaceted nature of viral latency and ongoing need for research to develop effective strategies for viral eradication.

Keywords: CRISPR screening; HIV-1 latency; Reservoir; Viral eradication; Viral persistence.

Fig. 1

Where, when and how is the latency established. The CNS, peripheral blood, GALT and reproductive tracts are the potential anatomical target for latency, consists of different subsets of immune cells. The HIV reservoir can be established shortly after infection. Administering antiretroviral therapy within 72 h can protect patients from productive infection; however, this intervention does not prevent viral rebound upon cessation of treatment, highlighting the swift establishment of the viral reservoir. Factors such as the integration site of the provirus, homeostatic mechanisms, and the regulation of certain cytokines and antigen presentation play significant roles in the maintenance and expansion of the viral reservoirs.

Fig. 2

Factors related to both the virus and the host are implicated in the maintenance and activation of reservoirs. Upon entering host cells, the viral RNA undergoes reverse transcription to form double-stranded complementary DNA (cDNA), referred to as provirus. The HIV provirus can integrate into the host genome and remain in a quiescent state. Upon activation, the viral genome is transcribed, leading to the production of mature viral particles. Various viral and host molecules may play a role at different stages of the HIV life cycle, influencing the maintenance or activation of the reservoirs.