Interesting Article On Hiv Caused Cd4 T Cell Death

[jeff238]

Found this interesting article from THE SCIENTIST magazine. published Dec, 2013.
I never heard of these studies and their findings before now.

They suggest that there may be an accessible and inexpensive treatment to HIV caused CD4 T cell
mass death.

A few excerpts, since the article is quite long.

"...HIV leads to AIDS primarily because the virus destroys essential immune cells called CD4 T cells,
but precisely how these cells are killed has not been clear. Two papers published simultaneously
today (December 19) in Nature and Science reveal the molecular mechanisms that cause the death of
most CD4 T cells in lymphoid tissues, the main reservoir for such cells, during infection.

...The death of CD4 T cells during HIV infection has generally been attributed to plain old apoptosis,
or programmed cell death. Problem is, most studies have focused on active cells in the blood, which
are “productively infected” by HIV, meaning that the virus has integrated with host-cell genome and
can make copies of itself. In a 2010 study, Greene and his colleagues showed that 95 percent of
CD4 T cells in lymphoid tissue, by contrast, are bystander cells that are “abortively infected”—the
virus penetrates but can’t integrate or replicate. To better understand HIV pathogenesis, Greene
sought to figure out how this particular population of immune cells dies during HIV infection.

...For the study published in Nature, the team looked at human spleen and tonsil tissue cultured in
the lab and spiked with HIV. The researchers found that when the virus productively infects the few
permissive CD4 T cells present, death occurs through apoptosis mediated by an enzyme called caspase-3.
But when HIV abortively infects nonpermissive CD4 T cells, death occurs by pyroptosis, which depends
on the activation of caspase-1. It turns out that the vast majority—roughly 95 percent—of CD4 T cell
death in lymphoid tissues is driven by caspase-1-mediated pyroptosis.

...In bacterial infection, the release of inflammatory signals is thought to promote clearance by
attracting more immune cells to help. In a pathogenic inflammation scenario like HIV infection,
however, the strategy backfires. Instead of clearing the infection, proinflammatory signals released
by pyroptosis attract more cells into the infected tissue to die and, in turn, produce more
inflammation. “The cavalry come riding in and fall victim to this same form of fiery cell death,
turning their rifles on themselves,” says Greene.

...The discoveries could help researchers come up with new treatments that restrain the hosts’
destructive response to HIV rather than the virus itself. The authors showed in the Nature study
that an existing caspase-1 inhibitor—a drug already shown to be safe in humans—suppressed CD4 T-cell
death and inflammation in cell culture. They are now planning a Phase II clinical trial to test its
capacity to block pyroptosis in HIV-infected patients.

 Fauci said such an approach would not replace antiretrovirals (ARVs), which suppress HIV replication
and halt disease progression. But it could be used in combination in people who are dealing with
highly resistant HIV strains to reduce the destruction of CD4 T cells and inflammation. “One of the
things about blocking the host response is that it's very difficult for the virus to mutate to
counteract it,” added Fauci.

Greene pointed out that a caspase-1 inhibitor might also provide a bridge therapy for the millions
of people without access to ARVs. He added that such drugs might even prevent expansion of the
reservoir of latent virus that lies low in memory CD4 T cells, which has so far precluded a cure
for HIV/AIDS.

The dysregulated action of cytokines during chronic inflammation might stimulate the homeostatic
proliferation of memory CD4 T cells. “If we get rid of chronic inflammation, will we stop the
homeostatic proliferation and degrade the latent reservoir?” asked Greene. “That’s something we can
test. If it does, caspase-1 inhibitors might—and I emphasize might—become a component of a curative
cocktail.”

  So naturally I looked to see what caspase inhibitor they might be talking about. There is really only
one. CrmA, derived from the cow pox virus, inhibits caspase 1,8,10.

All very interesting stuff. A study, just using the anti-inflamitory caspase inhibitor could actually
arrest the progression of HIV infection. The person would still be a carrier, but would show little to
no symptoms, by way of letting productively infected cells (5%) die, while saving the other 95% from
pyroptosis. At least that's my take on it.
 

[BBCream]

I hope, the invention will pass all stages of clinical trials and take place in therapy.