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HIV-1 infecting a T-cellWIKIMEDIA, NIH

HIV’s Stealth RevealedHIV-1 evades the immune system with a protein shield, which can be lifted.

By Ed Yong | November 21, 2013

HIV-1, the virus that causes AIDS, is renowned for

its ability to escape the immune system. A new

study shows that its sneaky talents depend on

the capsid protein that makes up the virus’s outer

coat.

Xavier Lahaye and Takeshi Satoh from the Institut

Curie in Paris showed that HIV-1 uses its capsid

to cloak its DNA from dendritic cells—sentries that

detect incoming threats and mobilize the immune

system. The researchers also managed to lift this

immunity cloak by mutating the capsid.

“By playing with the capsid, we made an HIV-1

that does not replicate but can stimulate an immune response,” said Nicolas Manel, who led the

study. “We could imagine modifying the virus and using it as a vaccine.” The results are published

today in Immunity.

“It’s a very nice piece of work,” said Greg Towers from University College London, who was not

involved in the study but recently published similar results. “I think we’re all on the same page, and

there’s a paradigm shift in our understanding of how HIV interacts with the immune system. We used

to think that the capsid came off the virus when it entered the cell, and its job was done. It turns out

that it also protects the virus’s DNA from being seen.”

Dendritic cells can recognize viruses that infect them with a range of sensor molecules, and they

instruct other parts of the immune system to target these threats. “They are the key orchestrators

of the immune response,” said Manel. “They’re first to detect pathogens and direct what happens

after that.”

Back in 2010, Manel’s team showed that dendritic cells can detect HIV-1 under some circumstances,

although this is atypical because the virus does not usually infect the cells efficiently. By contrast, a

related virus called HIV-2 does fully infect dendritic cells and triggers a strong immune response. This

partly explains why HIV-1 can evade the immune system and cause AIDS, while HIV-2 often does

not.

The team wanted to find out how the dendritic cells were detecting the viruses, and which parts they

were sensing. They began by tweaking HIV-2’s capsid, and found that changing a single amino acid

produced a virus that cannot infect dendritic cells but can still be detected by them. This implied that

detection takes place at an early part of the virus’s life cycle, before it has a chance to make copies

of itself.

Once HIV-1 and HIV-2 enter cells, they copy their RNA genome into a DNA molecule that is integrated

into the genetic material of their host. The team found that this DNA is what the dendritic cells

detect. “You need synthesis of DNA for detection, but you don’t need the steps after,” said Manel.

The team also identified the sensor molecule—a protein called cGAS, which was discovered by

investigators at University of Texas Southwestern Medical Center in Dallas this year. When cGAS

detects viral DNA in dendritic cells, it triggers a chain of molecular signals that marshals an immune

response.

That explains HIV-2, but how does HIV-1 evade detection? The team showed that the capsid

somehow masks the viral DNA, preventing cGAS from sensing it. This allows the DNA to integrate into

the host’s genome, be copied, and produce new virus particles.

The team managed to peel back this invisibility cloak by mutating the capsid, leaving HIV-1’s DNA

exposed and visible to the cGAS sensors. This suggested that similar modified viruses may, after

much development, form the basis of a vaccine. This modification happens naturally to an extent—

people who are infected with HIV-1 live longer if they had previously been infected with HIV-2, and

are less likely to proceed to develop AIDS.

Alternatively, “we can think about small chemical compounds that stimulate this pathway and mimic

the immune response,” said Manel.

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“The study highlights the importance of studying HIV-2 [to increase] our understanding of underlying

mechanisms important for HIV-1 pathogenesis,” added Joakim Esbjörnsson from Lund University in

an e-mail.

X. Lahaye et al., “The capsids of HIV-1 and HIV-2 determine immune detection of the viral cDNA

by the innate sensor cGAS in dendritic cells,” Immunity, doi:10.1016/j.immuni.2013.11.002,

2013.

Editor's Note (December 4): For the sake of clarity, we've added the word "often" to the sentence in the

sixth paragraph describing immune detection of HIV-1 and HIV-2.

Tagsvirology, immunology and HIV

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Comments

November 26, 2013

HIV-2 most definitely does cause AIDS! I haven't read the journal article

yet, but the explanation provided in this article is just plain wrong.

Please rewrite your article with a corrected (or at least plausible)

explanation, whatever that explanation is. If the explanation given

here is the one preferred by the authors, that brings into question

whether their experiment exists, and whether it worked as described in

their article. Perhaps there is some misunderstanding between the

science journalist and X. Layaye et al. perhaps not.

http://www.ncbi.nlm.nih.gov/pubmed/17255738

Is HIV-2- induced AIDS different from HIV-1-associated AIDS? Data from

a West African clinic.

RESULTS: Three hundred and forty-one AIDS patients with HIV-1 and 87 with

HIV-2 infection were enrolled. The most common AIDS-defining events in both

infections were the wasting syndrome and pulmonary tuberculosis. The

median CD4 cell count at AIDS was 109 cells/microl in HIV-1 and 176 in HIV-2

(P = 0.01) and remained significantly higher in HIV-2 after adjustment for age

and sex (P = 0.03). The median time to death was 6.3 months in HIV-1 and

12.6 months in HIV-2-infected patients (P = 0.03). In a multivariable analysis

adjusting for age, sex and CD4 cell count, the mortality rates of HIV-1 and

HIV-2-infected patients were similar (P = 0.25). The median CD4 cell count

near time of death was 62 and 120 cells/microl in HIV-1 and HIV-2-infected

patients, respectively (P = 0.02).

CONCLUSIONS: HIV-2 patients have a higher CD4 cell count at the time of

AIDS, and a longer survival after AIDS. The mortality after an AIDS diagnosis is

more influenced by CD4 cell count than HIV type.

Ewald has been discussing HIV-1 vs HIV-2 as variants evolved by

differing levels of promiscuity for a long time. Both progress to mortality,

but HIV-2 progresses more slowly, so it can transmit on a much longer

cycle.

http://www.ncbi.nlm.nih.gov/pubmed/15081500

See: http://www.pophealth.wisc.edu/PopHealth/files/file/Weekly%20Update/WU%20-

%2003_03_10/Ewald-03_18_10.pdf

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Replied to a comment from Ellen Hunt made on November 26, 2013

December 4, 2013

Hi Ellen,

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Thanks for reading and your comment. We understand how the

sentence to which you are referring could easily be misunderstood, and

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