HIV latency @ a glance

Greetings

     More often than said, HIV is one of the topics that I keep coming back to blog about. The hallmark ability of HIV virus, that has baffled and trimmed our ability to fight HIV is the ability of HIV to integrate stably into the host genome. Though there are some new strategies that are specifically designed to attack the HIV such as ZFN (Zinc finger nuclease) based proviral attack and bnAb (Link), most of the research is still focused on understanding the HIV latency. The promise of vorinostat (Link), to attack the latency has brought in certain revived interest in the old strategy. This blog post concentrates on the basic biology of HIV latency.

Fig 1: Typical course of HIV infection

Source

     The term "HIV latency"  was first used to describe, the clinical long asymptomatic period initial infection and the development of AIDS. The term is often misleading, since it is known that the HIV replication occurs throughout the course of infection. However, HIV can also be present in dormant condition, as integrated DNA in T cells. For all the discussion purpose, HIV dormancy is referred here as latency. HIV readily infects active T cells and destroys most of them via cytopathic effect or host immune response. However, a small subset of cells that return to resting state and become memory cells harbor the virus have latent genomes. The HIV genome expression in its initial stages is dependent on the cellular activity and NF-kB activity. This latency makes it impossible to attack the virus through anti-retrovirals or immune system.Classically, HIV resides in dormant T cells. However, it also resides in macrophages and dendritic cells (DCs).

      The cellular latency can be defined under two broad groups- Pre-integration latency, which represents a block in viral life cycle and Post-integration latency where the proviral genome is reversibly silenced after integration into the host cell genome. Pre- integration latency is often used as a surrogate marker for recent infection, and doesn't correlate well with the clinical symptoms. Often in literature, Post integration latency is simply stated as latency.

     Though latency is a multi-factorial phenomenon, the mechanisms cited as the common causes of latency includes- Chromatin remodeling and DNA methylation. Chromatin remodeling involves more of a cellular based approach. Though DNA methylation (epigenetic modification) is controlled by the host cell, the HIV can remove or add the methyl group at will and hence is more a virus mediated latency control. Chromatin remodeling mechanisms include- SWI/SNF remodeling and post translational remodeling (Acetylation, Methylation, Ubiqutination, Phosphorylation and SUMOylation). Each individual mechanism has its own value. Perhaps, of all these the most studied is the role of HDACs (Histone deacetylase). HDAC-1 is activated by HIV LTR (Long terminal repeats), and efficiently interacts with multiple DNA binding proteins with subsequent effects. The use of Vorinostat or valporic acid (inhibitors of HDAC), causes effective remodeling of Nuc-1 and enhances the viral transcription, overcoming latency which can then be attacked. One of the best cellular combat method to suppress a genetic information is by methylation of specific DNA sequences. DNA methylation is known to suppress the promoter activity of the HIV-1 LTR. However, The demethylation signals at 5’-LTR can  induced by the TNF-α, thus posing no problem to the HIV expression, since this can be achieved at will.

Fig 2: Model for the activation of RNA polymerase II

by Tat and cellular co-factors. Source

   A yet another mechanism that is discussed commonly is the dependence on RNA pol II expression. Positive transcription elongation factor (P-TEFb), plays an essential role in the regulation of transcription by RNA polymerase II (Pol II) in eukaryotes. As shown in the figure 2, The TAT-TAR complex that is formed in TAT dependent phase of replication, mediates a serine phosphorylation, of CTD of Pol II which then induces a chain elongation as a result of overcoming the block. The P-TEFb complex which consists of Cyclin T1 and CDK9, is involved in the process. P-TEFb can be used by the TAT to induce high level Pol II elongation. This forms another level of control. There are 2 transcriptional blocks- NELF (Negative elongation factor) and DRB sensitivity inducing factor (DSIF). The P-TEFb can phosphorylate NELF thereby overcoming the block. See fig 3

Fig 3: Importance of TAT in regulating latency

      A recent paper published in BMC- Retrovirology by Sherrill-Mix et al, compared chromosomal environment of integrated proviruses has been proposed to influence HIV latency based on five different in vitro models of latency based on primary human T cells. The studied showed that probably the site of DNA integration (which differs in different cell systems authors studied) dictates the mode of molecular latency.


Abbas W, & Herbein G (2012). Molecular Understanding of HIV-1 Latency. Advances in virology, 2012 PMID: 22548060

Sherrill-Mix S, Lewinski MK, Famiglietti M, Bosque A, Malani N, Ocwieja KE, Berry CC, Looney D, Shan L, Agosto LM, Pace MJ, Siliciano RF, O'Doherty U, Guatelli J, Planelles V, & Bushman FD (2013). HIV latency and integration site placement in five cell-based models. Retrovirology, 10 (1) PMID: 23953889

Coleman CM, & Wu L (2009). HIV interactions with monocytes and dendritic cells: viral latency and reservoirs. Retrovirology, 6 PMID: 19486514

Mbonye UR, Gokulrangan G, Datt M, Dobrowolski C, Cooper M, Chance MR, & Karn J (2013). Phosphorylation of CDK9 at Ser175 enhances HIV transcription and is a marker of activated P-TEFb in CD4(+) T lymphocytes. PLoS pathogens, 9 (5) PMID: 23658523