Researchers find tough new obstacle to HIV cure strategies

February 15, 2016 by Christopher Packham, Medical Xpress report
HIV-1 Virus. Credit: J Roberto Trujillo/Wikipedia

(Medical Xpress)—It's a good news/bad news scenario: Researchers have made a new discovery about HIV that will redirect curative strategies toward latent reservoirs of HIV—that's the good news. The bad news is that they discovered that clonally expanded, HIV-infected cells can can persist and produce new virus over many years in a patient on combination antiretroviral therapy (cART). Thus, any cure for HIV infection will have to attack these cells in order to permanently clear the virus.

The persistence and stubbornness of HIV infection is well documented. Since the 1980s, significant medical research has resulted in the transformation of HIV/AIDS from a terminal disease to a manageable condition. Modern , usually used in combination, include entry inhibitors that interfere with the binding of HIV to host cells; nucleoside reverse transcriptase inhibitors that inhibit HIV integration with DNA; integrase inhibitors that block a key HIV viral enzyme; and protease inhibitors, which block a viral protease enzyme key to the maturing of virons.

However, no vaccine, drug or therapy has emerged capable of permanently curing an infected patient. Failure to adhere to a strict regimen of combination antiretroviral drugs invariably results in the recurrence of detectable HIV. One reason is the ability of latent virus to persist in cells and re-emerge in response to imperfectly understood stimuli. In the current study, published in the Proceedings of the National Academy of Sciences, a large research collaborative has established for the first time that reservoirs of infectious HIV-1 persist in CD4+ T cells that are clonally expanded–that is, a population of many cells that have been produced by a single cell. These T cell clones contain active virus that can begin to proliferate in the event of cART cessation.

It took over a decade to reach this conclusion. The results are derived from the study of a single HIV-positive patient first diagnosed with the virus in 2000. The researchers conducted virologic, immunologic, and anatomic analyses of an African-American patient from the time that he began cART until he died 13 years later from cancer. Before the publication of the study, it was unknown whether the identical viruses found in the blood cells of patients were infectious. "This result shows that cells containing replication-competent HIV-1 proviruses can clonally expand and persist in vivo, presenting a challenge for achieving a cure of HIV infection," they write.

It remains unknown which CD4 subtypes contain viable HIV (most latent reservoirs do not contain replication-competent virus), and the researchers note that further study is required to establish the mechanisms of of HIV production during persistence and clonal expansion. Nor does the present study establish whether these expansions are the result of homeostatic proliferation or a response to an antigen.

The researchers conclude, "To develop successful curative strategies, a better understanding is needed of the fraction of the replication-competent reservoir that is composed of clonally expanded and how to specifically target and eliminate them."

Explore further: HIV is still growing, even when undetectable in the blood

More information: Francesco R. Simonetti, et al. Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo. PNAS 2016 ; published ahead of print February 8, 2016, DOI: 10.1073/pnas.1522675113

Abstract
Reservoirs of infectious HIV-1 persist despite years of combination antiretroviral therapy and make curing HIV-1 infections a major challenge. Most of the proviral DNA resides in CD4+T cells. Some of these CD4+T cells are clonally expanded; most of the proviruses are defective. It is not known if any of the clonally expanded cells carry replication-competent proviruses. We report that a highly expanded CD4+ T-cell clone contains an intact provirus. The highly expanded clone produced infectious virus that was detected as persistent plasma viremia during cART in an HIV-1–infected patient who had squamous cell cancer. Cells containing the intact provirus were widely distributed and significantly enriched in cancer metastases. These results show that clonally expanded CD4+T cells can be a reservoir of infectious HIV-1.

Related Stories

HIV is still growing, even when undetectable in the blood

January 27, 2016
A team of international scientists led by Northwestern University found that HIV is still replicating in lymphoid tissue, even when it is undetectable in the blood of patients on antiretroviral drugs.

Identification of drug combinations that reverse HIV-1 latency

March 30, 2015
There are almost 40 million people throughout the world living with HIV-1/AIDs. While current antiretroviral therapies are able to reduce the amount of virus in the blood, HIV remains present in a latent state within T cells. ...

Cellular pathway discovered that may re-energize immune cells to eliminate HIV

January 12, 2016
Researchers at the University of Hawai'i (UH) and Oregon Health Sciences University (OHSU) have revealed a novel new immune pathway that can be targeted to increase the immune system's ability to eliminate HIV, the virus ...

HIV antibodies block infection by reservoir-derived virus in laboratory study

August 26, 2014
A laboratory study led by scientists from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health (NIH), lends further weight to the potential effectiveness of passive immunotherapy ...

Targeting HIV 'reservoir' could be first step to understanding how to cure the disease

December 1, 2015
A new clinical trial will test whether it is possible to destroy hidden reservoirs of HIV virus that are a key obstacle to curing the disease.

Researchers find that antiretroviral therapy reduces HIV in the female reproductive tract

February 8, 2016
For the first time, investigators in the Division of Infectious Diseases at the University of North Carolina School of Medicine have determined how antiretroviral therapy (ART) affects the way HIV disseminates and establishes ...

Recommended for you

HIV exports viral protein in cellular packages

February 15, 2018
HIV may be able to affect cells it can't directly infect by packaging a key protein within the host's cellular mail and sending it out into the body, according to a new study out of a University of North Carolina Lineberger ...

Can gene therapy be harnessed to fight the AIDS virus?

February 13, 2018
For more than a decade, the strongest AIDS drugs could not fully control Matt Chappell's HIV infection. Now his body controls it by itself, and researchers are trying to perfect the gene editing that made this possible.

Big data methods applied to the fitness landscape of the HIV envelope protein

February 7, 2018
Despite significant advances in medicine, there is still no effective vaccine for the human immunodeficiency virus (HIV), although recent hope has emerged through the discovery of antibodies capable of neutralizing diverse ...

Scientists report big improvements in HIV vaccine production

February 5, 2018
Research on HIV over the past decade has led to many promising ideas for vaccines to prevent infection by the AIDS virus, but very few candidate vaccines have been tested in clinical trials. One reason for this is the technical ...

Microbiome research refines HIV risk for women

January 25, 2018
Drawing from data collected for years by AIDS researchers in six African nations, scientists have pinpointed seven bacterial species whose presence in high concentrations may significantly increase the risk of HIV infection ...

Researchers find latent HIV reservoirs inherently resistant to elimination by CD8+ T-cells

January 22, 2018
The latest "kick-and-kill" research to eliminate the HIV virus uncovered a potential obstacle in finding a cure. A recent study by researchers at the George Washington University (GW) found that latent HIV reservoirs show ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.