Advertisement
Advertisement


News

HIV Latency: Trapped in Transition, Lurking in Treg

November 29, 2017

The question of how HIV latency is typically established in long-lived memory CD4 T cells has yet to be fully resolved. One theory is that latency occurs when HIV infects a CD4 T cell that is in the process of transitioning from an activated state to a resting state, but direct evidence has been lacking. A new paper from the research group of Robert Siliciano, published in the journal Immunity, provides experimental support for this model of HIV latency initiation.

For background, HIV preferentially targets activated CD4 T cells because their genetic code (the genome) is very busy transcribing the proteins required to for the cell to go about its work, and the virus is able to hijack this process by integrating its own DNA into the cell's DNA in order to generate new virions (which can then go on to infect other cells). Resting CD4 T cells are less amenable to HIV replication because their genome is largely shut down, and the virus has difficulty coopting it for the production of new viruses.

Siliciano's research offers evidence that HIV latency occurs when the virus's DNA essentially becomes entrapped in the genome of an activated CD4 T cell as it is in the process of shutting down, due to the transition of the cell into a resting state. An example of when these transitions normally occur is after a CD4 T cell has responded to an infection -- when the responsible pathogen is cleared or controlled, a proportion of the activated responding CD4 T cells return to a resting memory state, ready to react again should the same pathogen cause further trouble.

Advertisement
The experiments described in the new paper mimicked the transition process in the laboratory by activating CD4 T cells (modified with a gene, Bcl-2, that enhances their survival in the lab dish) and then allowing them to return to rest. A key finding was that latent infection occurred most frequently when activated CD4 T cells were infected with HIV at a time when analyses showed the transcriptional activity of their genome was shutting down -- on days 6, 9 or 15 after receiving an activating stimulus. Studies of CCR5 co-receptor expression found that, at these timepoints, the CD4 T cells were displaying enough CCR5 on their surface to facilitate infection by R5-tropic HIV.

The results contrasted with those obtained when CD4 T cells were infected with R5-tropic HIV immediately after activation, or when they were already in a resting state. In these experiments, essentially no establishment of viral latency could be detected.

The researchers found that X4-tropic HIV was more promiscuous in its ability to cause latent infection in CD4 T cells -- whether activated, resting, or in transition -- which they note is "probably due to the universal expression pattern of CXCR4 on CD4 T cells." However, analyses of latently infected CD4 T cells isolated directly from HIV-positive individuals on ART demonstrated that the majority contained R5-tropic virus, implying that the mechanism involving infection of activated CD4 T cells transitioning to a resting state is predominant in creating the latent reservoir.

Interestingly, the laboratory studies revealed that while most of the activated CD4 T cells downregulated CCR5 expression as they transitioned into a resting state, a subset continued to display the molecule. Subsequent assessments of samples from the individuals on ART found that levels of HIV DNA were 10- to 100-fold higher in these CCR5-expressing resting memory CD4 T cells compared to CCR5-negative subsets. The CCR5-expressing resting memory CD4 T cells also harbored a greater proportion of replication-competent HIV, suggesting that CCR5 should be included among the candidate biomarkers for identifying latently infected cells.

In a final set of experiments, the researchers showed that functional HIV-specific CD8 T cells have the potential to recognize and destroy virus-infected activated CD4 T cells that are transitioning to a resting state, thereby reducing the frequency of latent infection. These results indicate that effective HIV-specific CD8 T cell responses have the potential to inhibit the formation of the latent reservoir.

The model of HIV latency described by Siliciano and colleagues differs from some other proposed scenarios. For example, a recent paper identifying CD32a as a biomarker of latently infected CD4 T cells reported that the finding was consistent with direct HIV infection of resting memory CD4 T cells as the initiator of latency. The research group of Sharon Lewin in Australia has also demonstrated that certain chemokines and myeloid dendritic cells can facilitate HIV infection of resting memory CD4 T cells and generate latently infected cells.

Evidence in support of the in vivo relevance of Siciliano's results may come from studies of the specific locations in the genome of CD4 T cells into which HIV commonly integrates -- at the IAS 2017 meeting earlier this year, Jori Symons from Sharon Lewin's laboratory noted that HIV DNA is more commonly found integrated into cellular genes that would be predicted to be active in activated CD4 T cells (a video of the presentation is available, and the slides can be downloaded).

It may not be an either-or proposition, as both mechanisms might conceivably contribute to the formation of the latent HIV reservoir.

Another recent theory to explain HIV latency involves the virus having specifically evolved the strategy in order to facilitate crossing the mucosal barrier at the time of initial infection. In the discussion section of their paper, Siliciano and colleagues argue that their data supports a simpler explanation: "latency results from infection of cells in a narrow time window after activation when cells are permissive for infection but not for prolonged HIV-1 gene expression."


Treg and Latent HIV

In the same issue of Immunity, Colleen S. McGary and colleagues report that a previously obscure subset of memory CD4 T cells that express the immune checkpoint receptor CTLA-4, but not PD-1, contribute significantly to the latent virus reservoir. The findings are largely derived from SIV-infected macaques but the researchers also documented the presence of these cells in lymphoid tissue samples from HIV-positive individuals on ART. The majority of the CTLA-4+PD-1- CD4 T cells were found to be of a regulatory (Treg) phenotype, a subset typically involved in dampening down immune activation. Several previous studies have reported that Treg can harbor latent HIV (e.g. Jiao YM et al and Tran TA et al), and a cellular gene that has been identified as a common HIV integration site -- BACH2 -- is known to be involved in Treg differentiation.

The researchers suggest that immune checkpoint inhibitors that target CTLA-4, such as the licensed anticancer antibody ipilimumab, may be able to reverse HIV latency in the CTLA-4+PD-1- CD4 T cell population; in support of this suggestion, they cite a published case report regarding an HIV-positive individual receiving ipilimumab for the treatment of cancer, which documented an increase in cell-associated HIV-1 RNA. Further exploration of this possibility is likely to focus on the SIV/macaque model, at least initially, because ipilimumab has a number of potentially serious side effects.

[Note from TheBodyPRO.com: This article was originally published by Treatment Action Group on Nov. 16, 2017. We have cross-posted it with their permission.]


Related Stories

Locking Down Latent HIV
Estimating the Total Size of the HIV Reservoir
Flagging the HIV Reservoir: A Potential New Marker for CD4 Cells Hiding HIV
No Proof of New HIV Cure, Despite Headlines -- Here's What We Know
The Only Cases of HIV Cure or Remission
Beyond the Berlin Patient: How Researchers Are Now Trying to Cure More HIV-Positive People (Video)
What Would an HIV Cure Mean for You?



 

No comments have been made.
 

Add Your Comment:
(Please note: Your name and comment will be public, and may even show up in
Internet search results. Be careful when providing personal information! Before
adding your comment, please read TheBody.com's Comment Policy.)

Your Name:


Your Location:

(ex: San Francisco, CA)

Your Comment:

Characters remaining:

Advertisement

The content on this page is free of advertiser influence and was produced by our editorial team. See our content and advertising policies.