HIV Control Mechanisms; Lessons into manipulation
October 18, 2013 05:45 PM
A new mechanism for HIV control?
Some people infected with HIV can keep the level of virus in
their blood in check without any treatment. In part, that’s because these so-called HV controllers carry specific variants of genes for HLA class I proteins, which are involved in the process by which virally infected cells tell specialized immune cells that they should be destroyed. Infected cells use these proteins to present HIV peptides to CD8+ T cells, and it appears that CD8+ T cells kill infected cells more efficiently when they are engaged by the protective variants, which are named B27 and B57. Some researchers believe that another reason for the better control of HIV infection is that when the virus mutates to escape the vigorous CD8+ T-cell attack induced by these variants, it pays a price: It doesn’t replicate very well anymore.
Now, researchers led by Richard D’Aquila, a virologist and infectious disease clinician at Northwestern University Feinberg School of Medicine in Chicago, have found another possible explanation for what might weaken the virus in controllers (PLoS One 8, e76002, 2013): Their resting memory CD4+ T cells—the ones that harbor the reservoir of integrated HIV DNA in their chromosomes—seem to have higher levels of an anti-HIV factor called APOBEC 3G (A3G). A3G is a host cell protein that is packaged into newly produced HIV particles that keeps HIV from copying its RNA genome into DNA and integrating it into the target cell genome. HIV counteracts its effect by producing a protein called Vif, which causes A3G degradation.
In their study, D’Aquila and colleagues compared A3G levels in resting memory CD4+ T cells of seven viremic controllers (who can keep their viral load below 2,000 viruses per ml of blood without treatment) and 11 non-controllers on long-term highly active antiretroviral therapy (HAART).
They found that in the viremic controllers, these cells contained about twice as much A3G protein, and about half as much integrated proviral HIV DNA, than in the non-controllers. In fact, the more A3G these cells contained, the less integrated provirus they had. The researchers also showed that the higher A3G levels in the controllers weakened the virus: When they activated CD4+ T cells from the non-controllers or from uninfected people, the cells with more A3G made virus that contained more A3G and was less infectious than virus made this way by cells with less A3G. This suggests that A3G levels in the controllers were high enough that the HIV Vif protein could not completely degrade A3G.
D’Aquila believes that the A3G mechanism is independent of the protective B57 and B27 alleles. But this remains to be seen, because all of the viremic controllers in the study had one of these protective variants. It’s also unclear whether elite controllers—who can control their virus even better and keep viral levels below 50 copies per ml of blood—also have higher A3G levels.
Still, the observed higher A3G levels could explain, at least in part, why the virus doesn’t rebound in controllers in the absence of treatment, D’Aquila says. The vigorous CD8+ T cell response in controllers in the first few months after infection results in less virus and, therefore, less Vif to degrade A3G. This, in turn, preserves high A3G levels in the long run, which can then better inhibit HIV replication and integration. “We think this might be one way to explain why there is a second line of defense that keeps HIV under control even after it has mutated away to evade that first line of [the CD8+ T cell] defense,” he says.
Higher A3G levels due to low levels of HIV early after infection might also explain why some people who start antiretroviral therapy (ART) early, in the first few weeks or months after infection, become so-called post treatment controllers, who can control their infection even after they stop ART. To test if that could be the case, D’Aquila now plans to compare cellular A3G levels soon after infection and later, and check if early ART preserves higher A3G levels and correlates with the ability to control the virus after treatment is stopped one or two years later.
D’Aquila is also looking for compounds that can elevate A3G levels in cultured cells. Such A3G boosters could be used as drugs together with ART even in people who started ART later. “Maybe that’s going to do just as much good as starting ART in the first few months after infection,” he says. “We have some very early but promising leads. We are very excited about that.”
their blood in check without any treatment. In part, that’s because these so-called HV controllers carry specific variants of genes for HLA class I proteins, which are involved in the process by which virally infected cells tell specialized immune cells that they should be destroyed. Infected cells use these proteins to present HIV peptides to CD8+ T cells, and it appears that CD8+ T cells kill infected cells more efficiently when they are engaged by the protective variants, which are named B27 and B57. Some researchers believe that another reason for the better control of HIV infection is that when the virus mutates to escape the vigorous CD8+ T-cell attack induced by these variants, it pays a price: It doesn’t replicate very well anymore.Now, researchers led by Richard D’Aquila, a virologist and infectious disease clinician at Northwestern University Feinberg School of Medicine in Chicago, have found another possible explanation for what might weaken the virus in controllers (PLoS One 8, e76002, 2013): Their resting memory CD4+ T cells—the ones that harbor the reservoir of integrated HIV DNA in their chromosomes—seem to have higher levels of an anti-HIV factor called APOBEC 3G (A3G). A3G is a host cell protein that is packaged into newly produced HIV particles that keeps HIV from copying its RNA genome into DNA and integrating it into the target cell genome. HIV counteracts its effect by producing a protein called Vif, which causes A3G degradation.
In their study, D’Aquila and colleagues compared A3G levels in resting memory CD4+ T cells of seven viremic controllers (who can keep their viral load below 2,000 viruses per ml of blood without treatment) and 11 non-controllers on long-term highly active antiretroviral therapy (HAART).
They found that in the viremic controllers, these cells contained about twice as much A3G protein, and about half as much integrated proviral HIV DNA, than in the non-controllers. In fact, the more A3G these cells contained, the less integrated provirus they had. The researchers also showed that the higher A3G levels in the controllers weakened the virus: When they activated CD4+ T cells from the non-controllers or from uninfected people, the cells with more A3G made virus that contained more A3G and was less infectious than virus made this way by cells with less A3G. This suggests that A3G levels in the controllers were high enough that the HIV Vif protein could not completely degrade A3G.
D’Aquila believes that the A3G mechanism is independent of the protective B57 and B27 alleles. But this remains to be seen, because all of the viremic controllers in the study had one of these protective variants. It’s also unclear whether elite controllers—who can control their virus even better and keep viral levels below 50 copies per ml of blood—also have higher A3G levels.
Still, the observed higher A3G levels could explain, at least in part, why the virus doesn’t rebound in controllers in the absence of treatment, D’Aquila says. The vigorous CD8+ T cell response in controllers in the first few months after infection results in less virus and, therefore, less Vif to degrade A3G. This, in turn, preserves high A3G levels in the long run, which can then better inhibit HIV replication and integration. “We think this might be one way to explain why there is a second line of defense that keeps HIV under control even after it has mutated away to evade that first line of [the CD8+ T cell] defense,” he says.
Higher A3G levels due to low levels of HIV early after infection might also explain why some people who start antiretroviral therapy (ART) early, in the first few weeks or months after infection, become so-called post treatment controllers, who can control their infection even after they stop ART. To test if that could be the case, D’Aquila now plans to compare cellular A3G levels soon after infection and later, and check if early ART preserves higher A3G levels and correlates with the ability to control the virus after treatment is stopped one or two years later.
D’Aquila is also looking for compounds that can elevate A3G levels in cultured cells. Such A3G boosters could be used as drugs together with ART even in people who started ART later. “Maybe that’s going to do just as much good as starting ART in the first few months after infection,” he says. “We have some very early but promising leads. We are very excited about that.”
Comments
Post a Comment