Nature Microbiology: How HIV sneaks around drugs and immune escape

Researchers at Duke Health report that an immune response that may have evolved to help fight infection appears to be the mechanism that drives the human immunodeficiency virus (HIV) into a latent state, lurks in cells, and then flares.

The research team, published Nov.
14 in the journal Nature Microbiology, provides new insights into this troubling process that makes HIV particularly stealthy but may also play a role
in other viral infections.

Senior author Bryan R.
Cullen, Ph.
D.
, professor in the Department of Molecular Genetics and Microbiology at Duke University School of Medicine, said: "HIV has been shown to be incurable because there are a small number of latent HIV-infected T cells that are not affected
by antiviral drugs and immune responses.
"

"These long-lived cells can emerge spontaneously from the incubation period and even start producing HIV years after infection, requiring lifelong use of antiretroviral drugs
.
" "Despite great efforts, the source of these potentially infected cells remains unknown
.
"

The findings by Cullen and colleagues provide important insights, pointing to a protein complex called SMC5/6, which is involved
in chromosomal function and repair in host cells.

The HIV virus enters the body, infects CD4+ T cells of the immune system, and then makes a genome-length DNA molecule that integrates into the host cell's chromosomes, and then replicates to produce viral RNA and proteins
.

If this so-called DNA provirus cannot fit into the DNA of the host cell, for example by a drug that blocks this process, then it cannot make any viral RNA and proteins and becomes inert.

In contrast, DNA proviruses that can integrate are often able to drive prolific HIV infection
.

Cullen and his team found that in a small subset of infected cells, the SMC5/6 protein complex initiates
a process that silences DNA proviruses before they integrate into the host cell chromosomes.
Even after integration, these proviruses remain indolent and cause latent infection, which lurks low until an outbreak is suggested
.

"Our study shows that the delay does not come from any intrinsic property of HIV infection, but from the unfortunate side effect of the cell's innate immune response, which may have evolved to inhibit the invasion of foreign DNA
," Cullen said.

The researchers found that a molecule that shuts down the silencing effect of SMC5/6 showed good results as a potential therapeutic strategy because it inhibited the formation
of latent HIV infection.
Reactivated proviruses are susceptible to natural immune system responses and antiretroviral drugs
.

"Although antiretroviral therapy can reduce the viral load in AIDS patients to undetectable levels, these drugs do not eradicate HIV-1
.
Considerable efforts have been made to develop therapies that can activate latent HIV-1 virus and help antiretroviral therapy clear infectious viruses from the body, but this effort has so far failed to find drugs
that are both effective and non-toxic.
Our research represents a possible important step
towards achieving this goal.
”

"It's clear that understanding the mechanisms that cause the HIV-1 latency may give us an idea of how the latent HIV-1 provirus is reactivated and then destroyed
," Cullen said.

Original:

Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency