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INFECTIOUS DISEASE

BACTERIOLOGY IMMUNOLOGY MYCOLOGY PARASITOLOGY VIROLOGY

TURKISH

 

VIROLOGY - CHAPTER  SEVEN 

PART EIGHT

HUMAN IMMUNODEFICIENCY VIRUS AND AIDS  

LATENCY OF HIV

Dr Richard Hunt
Professor
Department of Pathology, Microbiology and Immunology
University of South Carolina School of Medicine

 

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Figure 21
Dynamics of CD4 cells in HIV infection.

Figure 22
Activation of infected T4 cells

 

Figure 23
Latency

CELLULAR LATENCY

After T4 cells have been activated and proliferate in an immune response to a particular antigen, most die by apoptosis as the  response to that antigen wanes. However, some of the cells do not die and become dormant (they are sometimes referred to as resting T cells). They remain for a long time in the body so that they can respond promptly to a second exposure to the same antigen. This is called immunological memory and is why the response to the second encounter with an antigen is more rapid than the primary response. The T4 cells that become dormant are called memory T cells and can remain quiescent (non-proliferating) for decades.

If an activated T4 cell happens to be infected by HIV, it also is most likely to die by apoptosis but a few of these cells become memory cells. In their quiescent state they do not replicate the virus but still harbor it as a DNA copy integrated into the chromosomes, the provirus (figure 21). On immune stimulation of the infected memory cells, not only are genes expressed that are important in the immune response but also HIV genes are expressed leading to production of new virus particles (figure 22).

The dormancy of the virus in resting memory T cells is referred to as cellular latency and may last for a few hours or days or very much longer in a small minority of cells. It was hoped that the used of highly active anti-retroviral therapies (HAART) would eliminate the virus from the patient altogether but the memory T4 cells may provide a reservoir of integrated virus that cannot be eliminated by chemotherapy and may persist for a lifetime. 

Latency is broken when the virus starts to proliferate and this occurs when the T4 cell is stimulated during an antigenic response.

 

MECHANISM OF CELLULAR LATENCY

HIV mostly infects cells that express CD4 antigen and the appropriate co-receptors. This means that T4 lymphocytes are the primary target of the virus. However, the virus can only replicate in activated (actively dividing) cells but not in infected naīve T4 cells (those that have not been activated by antigen) or in resting memory T4 cells (those that have been activated but have not undergone apoptosis and have returned to the quiescent state). In these cells the virus is said to be latent.

In the naīve cells, most HIV is not integrated into the chromosomes. The virus has been reversed transcribed but remains as a provirus (the DNA form of the virus) in the cytoplasm. In memory T4 cells, the provirus has integrated into the host cell chromosomes where it is usually found in the introns of actively transcribed genes. Here, it remains in a latent state until the cell is reactivated on contact with antigen.

So why is the provirus only replicated in activated T4 cells? There have been several suggestions:

  • Quiescent T4 cells may lack sufficient small molecules (for example, nucleotides) needed to make RNA.

  • For complete transcription of the HIV genome into RNA, the presence of a small viral protein, Trans-Activator of Transcription (TAT) is required. In the absence of TAT, transcription terminates prematurely.

  • There could also be a lack of necessary host cell-provided transcription factors in resting T4 cells or the presence of host cell-encoded transcription terminators.

  • The integrated provirus may not be accessible to the transcription machinery of the resting cell. This would seem unlikely, however, since, as noted above, proviruses are often found in the introns of actively transcribed genes.

Possibly, the provirus is continually transcribed in memory cells but the viral RNA cannot get out of the nucleus because of the need for splicing prior to export. Normally, nuclear export of unspliced HIV RNA depends on expression of another small HIV encoded protein called REV (Regulator of Virion protein expression) which may be lacking in quiescent T4 cells.

Two forms of HIV cellular latency have been suggested. In pre-integration latency, the virus enters the naīve resting cell but, after reverse transcription, mostly remains in the cytoplasm as a full length provirus, probably because the low ATP levels preclude the energy-dependent import of the pre-integration complex. ATP levels rise when a T4 cell is activated and nuclear import is followed by integration and transcription. Some HIV may enter the nucleus of the naīve cell but it is only slowly transcribed because the necessary nucleotides are in short supply. Many of these transcripts are never completed and are degraded by the cell. Pre-integration latency is probably not very important clinically.

Post-integration latency is clinically very important since it is characteristic of long lived memory T4 cells. These are the cells that have been activated and reverted to the resting state. Again, little virus is produced in these cells even though the virus integrates into the introns of genes that are actively transcribed. It had been thought that HIV might integrate into regions of the chromosomes that are preferentially repressed in resting cells but this seems not to be the case. Lack of HIV transcription might result from the phenomenon of transcriptional interference in which the transcription of an active gene is initiated at its promoter and the polymerase reads through the integrated HIV sequence (see reference 1). The HIV sequence is transcribed into the primary transcript but is degraded along with the rest of the intron after splicing. In addition, the downstream HIV promoter (in the LTR) may be suppressed by the active upstream promoter. Perhaps the polymerase reading through the HIV promoter may disrupt the latter’s ability to bind the correct transcription factors. This would be overcome when the levels of these factors increases in activated T4 cells.

As noted above, the transcription factors needed for HIV transcription, such as NFkB (nuclear factor kappa B) and NFAT (nuclear factor of activated T cells), may be lacking or restricted to the cytoplasm in resting cells. Many of the factors that bind to the HIV LTR and increase HIV gene transcription are also required for transcription of specific genes in an uninfected activated T4 cell, including NFkB and NFAT. Normally, these factors are cytoplasmic because they are bound to cytoplasmic retention proteins but they dissociate and the transcription factors enter the nucleus when the T4 cell is activated. The lack of NFkB and NFAT in the nucleus does not completely inhibit HIV transcription but in the absence of TAT, the transcripts are prematurely terminated.

TAT is an HIV-encoded transcription factor but, unlike cellular transcription factors, it can bind to the DNA promoter of the integrated provirus and to the RNA transcribed from it. The latter may be the most important. In contrast to cellular DNA-binding transcription factors, TAT acts at the level of elongation of the RNA rather than RNA initiation. It binds to a specific secondary structure in the RNA call the TAT-Responsive element (TAR). After TAT binds to the TAR, a specific kinase associates with TAT (TAT-associated kinase or TAK) which consists of two cellular proteins. One of these proteins (called CDK9) phosphorylates two important targets in the HIV-infected cell. One is RNA polymerase II, allowing the polymerase to continue elongation of the RNA. The other is a negative regulatory protein that, on phosphorylation, dissociates from the TAR. TAT also associates with a variety of other proteins that enhance HIV RNA transcription.

In the absence of TAT, short transcripts (about 100 nucleotides) are initiated in the HIV-infected cells but the polymerase usually does not proceed past the TAR. These short transcripts are found in infected patients who are being treated with anti-HIV drug cocktails. Some full length HIV RNA molecules are found but TAT and REV probably do not increase enough to promote high levels of unspliced HIV RNA in the cytoplasm.

 

CLINICAL LATENCY

Cellular latency is different  from clinical latency which refers to fact that symptoms of HIV infection do not manifest themselves as AIDS for many years (figure 23). 

Reference 1:  Lassen K, Han Y, Zhou Y, Siliciano J, Siliciano RF. The multifactorial nature of HIV-1 latency.
Trends Mol Med. 2004, 10: 525-31.

 
 


 

OTHER SECTIONS ON HIV

PART I HUMAN IMMUNODEFICIENCY VIRUS AND AIDS

PART II HIV AND AIDS, THE DISEASE

PART III COURSE OF THE DISEASE

PART IV PROGRESSION AND COFACTORS

PART V STATISTICS

PART VI  SUBTYPES AND CO-RECEPTORS

PART VII  COMPONENTS AND LIFE CYCLE OF HIV

PART VIII  LATENCY OF HIV

PART IX GENOME OF HIV

PART X  LOSS OF CD4 CELLS

PART XI   POPULATION POLYMORPHISM

APPENDIX I  ANTI-HIV VACCINES

APPENDIX II  DOES HIV CAUSE AIDS?

APPENDIX III  ANTI-HIV CHEMOTHERAPY

 

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