Monday, June 27, 2016

HIV nuclear entry


HIV or Human immunodeficiency virus is a topic that I have blogged multiple times. Every week I see so many publications about HIV. It is one of the absolutely highly researched topics in infectious diseases and yet we neither have a cure nor have a vaccine. Retroviruses in comparison to other groups of viruses have one special property. They are made up of RNA, gets converted to DNA and then integrate with the genome. But what is special to HIV is the way it does it. Simple lentiviral members like MLV (Murine Leukemia Virus) rely on cell division process to integrate their genome to the host. During the cell division process, the nucleus opens and virus gains entrance to the nuclear material. But HIV simply makes its way in through nuclear transport.

Fig 1: HIV Life Cycle.
Nuclear transport of HIV is a well-studied phenomenon. The Reverse transcriptase has three domains: thumb, palm, finger and RNAaseH. This enzyme uses one RNA copy from the HIV genome to make single stranded DNA by reverse transcription and then double-stranded DNA from it. The RNA is degraded by RNAaseH. The presence of 2 copies of RNA facilitates floppy replication and enhances replication errors. The formation of dsDNA continues in the Reverse Transcriptase Complex (RTC), simultaneously migrating towards the nucleus using microtubule network with a cellular dynein-dependent motor complex. On the formation of DNA, the complex is referred to as the Pre-Integration Complex (PIC).

Fig 2: Structure of Nuclear Pore.
PIC interacts with several different factors that influence its nuclear import. It is currently not clear as to what are the factors important for nuclear factors. Though many of them have been identified which includes TNPO3, NUP358, NUP153, Integrase, LEDGF, CypA, CPSF6 and much more. There is one fundamental problem in understanding the nuclear import of HIV in all the studies. HIV is transported to nucleus through nuclear import factors by passing through the pore. However, the nuclear pore is much smaller than the HIV PIC. So how does it still manage to pass? 

Let me digress a little bit. The nucleus of a cell is not accessible to chemicals for direct communication. The Nucleus is well guarded and specific channels are provided in the membrane called as Pores. The nuclear pore is a protein-lined channel in the nuclear envelope that regulates the transportation of molecules between the nucleus and the cytoplasm.

Fig 3: Model of KIF5B mediated
nuclear import of HIV-1. Source
In a study published by Edward et al; they looked into this question. In the first part of the study, they found that depletion of KIF5B (Kinesin Family Member 5B) and Nup358 (nucleoporin 358) led to the accumulation of viral cores around the nucleus, with a reduction in nuclear import. This is consistent with previous reports indicating that these are required for nuclear import of HIV. Subsequent investigation showed that HIV-1 induces NUP358 relocalization in a KIF5B dependent manner. The last part of the experiments yielded that KIF5B transported Nup358 away from nucleus thus making the pore wide enough for HIV to pass through. It is essentially tearing of the nuclear membrane. A model of how KIF5B is involved in HIV nuclear import is shown in Fig 3. The authors also noted based on previous studies that failing to import (which means the HIV is staying in the cytoplasm for a longer time), activate cytoplasmic host cell sensors and initiate interferon response.

Based on the study it has been suggested that blocking KIF5B-HIV interaction should be able to block the nuclear import and thus give more time for the cell to sense and develop a response. As one of the author states, "It's like making a bank vault harder to break into. In addition to making the money more secure, it would increase the chance of sounding the alarm and catching the burglars."

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