Does HIV Unleash Endogenous Retroviral Elements?

Two interesting presentations on the first day of CROI related to human endogenous retroviruses (HERVs). HERVs are essentially fossil remnants of retroviruses that humans encountered many millennia ago; they can no longer replicate but rather have incorporated into human DNA and now make up a surprising 8% of our genome. Some rare HERV sequences (e.g. HERV-K) exist as full length proviruses but fragments known as human endogenous retrotransposable elements (HERE) are more common. Human cells have restriction factors like the recently discovered APOBEC proteins which suppress retroviral activity and these factors are believed to keep endogenous retroviral sequences dormant. However, it is known that HIV has evolved mechanisms (such as the viral protein Vif) which disable host restriction factors. This led researcher Brad Jones from the University of Toronto to wonder if perhaps HIV infection of CD4 cells would awaken endogenous retroviral sequences and allow them to become active.

When Jones looked at HIV-infected primary CD4 T cell lines in vitro, this is exactly what he found. These cells accumulated increasing numbers of genomic copies of the HEREs that Jones tested for (AluSX, LINE-1 and segments of HERV-K), but uninfected CD4 cells did not. To take a preliminary look at whether such events occur in vivo, Jones searched databases of HIV sequences and found a primary HIV isolate into which a HERE (LINE-1) had become inserted, strongly suggesting that HIV and LINE-1 can be active in the same cell.

Further supporting Jones's reasoning, Keith Garrison from UCSF presented a poster (#457) showing that people with HIV have higher levels of HERV-K genetic material in their blood compared to uninfected controls. Furthermore, T cell responses to HERV-K protein fragments (peptides) could be detected in individuals with primary HIV infection but not in uninfected controls.  There was even a weak but statistically significant inverse correlation between HERV-K-specific T cell responses and HIV viral load (r²=0.11, p=0.03). 

These findings may suggest novel strategies for HIV vaccines and immunotherapies. HIV's notorious ability to mutate makes it a difficult, moving target for immune responses. But endogenous retroviral proteins cannot mutate, and if they are only expressed in HIV-infected cells it is possible that triggering immune responses against these proteins with a vaccine would provide another means of targeting and eliminating HIV-infected cells.

Brad Jones's presentation will soon be available online as part of the Monday webcast of the CROI session entitled "Host-Cell Regulation of Viral Replication" (Monday Feb 26, 10:00 AM). Abstracts and PDFs of poster presentations will start becoming available online on the conference website after the meeting ends on February 28.

Comments

[Paul Simmons]

So if I correctly understand your summary, the presenters were NOT saying that these HERVs play a role in pathogenesis; but rather that they might serve as a surrogate for identifying and eliminating HIV-infected cells. Yes?

[Richard Jefferys]

Hi Paul, as far as I understand it that's correct, the endogenous viruses can't become replication-competent and do any damage themselves, but - according to these researchers - they do seem to be able to make proteins inside HIV-infected cells and thus targeting these endogenous proteins could offer the immune system an alternative way of targeting HIV-infected cells. I think a lot more work will have to be done to show if this is really possible.

[Brad Jones]

Thanks for your interest, and a very accurate summary of our work!

To address Paul and Richard's comments - we do feel that it is likely that aberrant activity of these elements in the context of natural HIV-1 infection does contribute to pathogenesis. However, further insight into their behaviour in that context is necessary before proposing any mechanisms i.e: one very important question is whether or not retrotransposition is strictly limited to HIV-1 infected cells. If so, this naturally sets limitations on any potential contribution to pathogenesis (but adds weight to the argument that these antigens can be used as surrogate markers of HIV-1 infected cells).

The inverse question which I find interesting, if a bit more abstract, is whether the retrotransposition of these elements could play a defensive role in retroviral infection i.e: the HIV-1 sequence containing the LINE-1 insertion that I pointed out in my talk, has essentially been inactivated by the LINE-1 element (as Vif, Vpr, Tat, and Rev are all deleted). Could newly inserted retroviruses potentially serve as hotspots for integration of endogenous elements - leading to distruption of the invasive virus?

[Richard Jefferys]

Thanks for the information & clarification Brad, very interesting work!

[Pat Kramme]

Great comments! Endogenous retroviruses have been characterized in many species, feline, chicken, mouse, long before HIV. While they are generally not replication competent it is possible for them to act as loci of recombination with other retorviruses. In addition, replication incompetent viruses often become replication comeptent when there is co-infection with a replication competent retroviruses, e.g., tumor causing retorviruses such as Rous sarcoma virus. Usually this occurs between closely related retroviruses with the same or similar RNA sequences that facilitate incorporation into a virion. Are human endogenous retroviruses related to lentiviruses (HIV) or are they more typical of tumor viruses (alpha, beta, gamma, or spumiviruses)?