HIV Propagation on ART PDF Print E-mail
Written by Alain Lafeuillade   
Thursday, 18 August 2011 12:15

Cell-to-cell Spread of HIV Permits Ongoing Replication

lymphoTA novel model for ongoing HIV replication in the face of ART is described in Nature by researchers at the California Institute of Technology (1). The persistence of HIV reservoirs could be explained by cell-to-cell spread of the virus that overwhelms drug concentrations in cells.

 

L
 atency and ongoing replication have both been proposed to explain the HIV reservoir, which is insensitive to ART. The reservoirs might be long-lived latently infected cells, ongoing cycles of viral replication, or a combination of sources.

How ongoing replication might take place in the presence of ART has remained unclear.

 

In this model, multiple infections per cell lead to reduced sensitivity to drugs without requiring drug-resistance mutations.

 

Multiple infections of one cell may propagate at drug concentrations where infection by single particles would die out. If more virions are transmitted per cell, the probability that at least one of the virions escapes the drug is increased (Figure, adapted from {1}). This was tested in the highly infection permissive MT-4 cell line with cell-free HIV at low and high infectious units in the presence of Tenofovir.


 

 

cellcell


Figure adapted from Ref. 1


 

M
  ultiple infections occur in vivo and in vitro and are thought to be associated with cell-to-cell spread, a direct transmission mode that minimizes the number of virus particles failing to reach the target cell.

The authors therefore used a co-culture system with infected cells to generate cell-to-cell spread, in the absence or presence of Tenofovir.

Co-culture dramatically decreased sensitivity to drug: Tenofovir decreased cell-free infection 30 fold but caused less than a twofold decrease of coculture infection.

They also used a combination of Tenofovir and Efavirenz and found that cell-free infection was efficiently prevented by these drugs. But infections occuring by cell-to-cell transfer was much less affected by the drugs: at highest drug concentrations, transmission rate was 6 times higher than that of cell-free infection.

 

T
o investigate whether cell-to-cell spread can lead to HIV replication through multiple virus cycles with ART, the authors measured the replication ratio (R) in the absence of drug, with 100 mcM Tenofovir, or with a combination of Tenofovir, FTC and Efavirenz at their clinical maximum plasma concentrations. Ratios obtained by co-culture were significantly higher than predicted cell-free ratios.


Once infection became established as a result of cell-to-cell spread, the number of infected cells in the experiment kept growing despire ARV concentrations similar to those achieved in the clinic.

 

The authors also demonstrated that replication is intermittent.

 

T
hese data indicate that cell-to-cell spread is a likely source of intermittent ongoing replication in the presence of ART, and that it is a consequence of some cell-to-cell infections transmitting virus numbers much in excess of what is required to infect a cell in the absence of ART. The large transmitted dose strongly decreases the probability that every transmitted virus will be inhibited by the drugs and therefore greatly weakens their effect.

 

This replication may adversely affect the immune system, increasing activation and cell death, and could potentially contribute to the maintenance of an HIV reservoir in locations such as lymphoid tissue where cell-to-cell spread occurs

the authors added.

 

Reference

{1} Sigal A, Kim JT, Balazs AB, Dekel E, Mayo A, Milo R & Baltimore D. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature 2011; Epub ahead of print August 17; doi: 10.1038/nature10347 


 



Key words: HIV cure, HIV ongoing replication, HIV persistence, HIV reservoirs, towards an HIV cure
Last Updated on Wednesday, 07 September 2011 14:13
 

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