FREDERICK, Md. -- Recent scientific papers co-authored by researchers at the Frederick National Laboratory for Cancer Research present novel discoveries about HIV and one similar infection from three fields of inquiry about the virus, all with the potential to further discoveries leading to prevention or treatment of HIV infection.
The papers reveal a deeper understanding of the genetic influencers of HIV, use high-resolution imaging to depict locations in the body where HIV hides from antiretroviral treatment, and report on a modified version of an effective vaccine against an HIV-like infection in monkeys that has a superior safety profile.
Scientists conducting research in FNL’s AIDS and Cancer Virus and Basic Science Programs are experts in a range of fields studying the science of HIV and AIDS. Summaries of their recent articles are below.
Modified Vaccine is Effective – and Safe – in Clearing HIV-Like Virus in Monkeys
A safer adaptation of an investigational HIV vaccine that has shown promising results in an animal model may be the ticket to moving the human-specific version into clinical trials. Results of a study published in Science Translational Medicine on July 17 show the modified vaccine remained effective, even after modifications to eliminate potentially serious side effects.
Jeffrey D. Lifson, M.D., director of the AIDS and Cancer Virus Program, and his long-time collaborator Louis J. Picker, M.D. at the Oregon Health and Science University’s Vaccine and Gene Therapy Institute developed the novel vaccine based on simian immunodeficiency virus (SIV), an HIV-like virus that infects monkeys.
Picker and Lifson previously established that the investigational vaccine composed of SIV genes inserted into monkey cytomegalovirus (CMV – a herpesvirus) protected animals against infection when challenged with SIV.
Though effective, and blunted compared to the typical form of CMV, the original CMV-based vaccine has the potential to cause disease in immunocompromised animals. CMV infection in utero can result in mental retardation, hearing loss or even death of the fetus.
To reduce the risk, Picker and OHSU colleague Klaus Frueh, Ph.D. deleted part of the Rh110 gene, further hampering the ability of the CMV to replicate, spread within a vaccinated host, or be shed, potentially exposing others.
The effectiveness of the original vaccine remained. Of the rhesus macaques vaccinated with the modified delta-Rh110 RhCMV/SIV vectors who were then exposed to SIV, 59 percent experienced control and eventual clearance of the virus. The persistence of vaccine-induced protection is an important feature in evaluating vaccine candidates. When exposed to SIV again three years later, nine of the 12 animals vaccinated with the new vaccine controlled the infection.
“These promising results and the improved safety profile demonstrated in the new study could facilitate regulatory approval for clinical testing of the human version of the vaccine with the same attenuating modifications,” Lifson said.
HIV Finds Places to Hide from Treatment, Preventing Full Clearance from the Body
Claire Deleage, Ph.D., head of the Tissue Analysis Core of the AIDS and Cancer Virus Program at the Frederick National Laboratory for Cancer Research, and her colleagues conducted some of the imaging for a study that showed how HIV remains in the body, even when it can’t be detected in the blood.
If antiretroviral treatment is stopped, the virus rebounds. This is one of the greatest challenges facing HIV researchers today – the virus finds ways to persist despite long-term treatment, in part by “hiding” in places that immune responses and anti-HIV drugs are not able to effectively reach.
HIV hiding places in the body include the central nervous system, male and female genital tracts, peripheral lymph nodes, and gut-associated lymphoid tissue (GALT). Results of a study led by Angela D.M. Kashuba, Ph.D. and Corbin G. Thompson, Ph.D. from the University of North Carolina in Science Translational Medicine on July 3 begin to show just how that happens in GALT.
Samples from the gut tissue of humans with HIV and from animal models with and without SHIV infection (engineered combination of simian and human virus), all treated with six antiretroviral drugs, were analyzed with two modes of powerful imaging.
FNL’s Tissue Analysis Core provided viral RNA images of the tissues obtained from next-generation in situ hybridization: RNAscope approach, Deleage said. This highly sensitive and specific approach rapidly detects the viral RNA and viral DNA in single cells and single molecules, demonstrating both latent and active HIV persistence.
These images were merged with mass spectrometry imaging that localized the distribution of antiretroviral drugs in the tissue.
The combined images provided data that showed antiretroviral drugs did not penetrate all regions of the gut. There were areas of tissue that showed HIV RNA expression but had low concentrations of antiretroviral drugs, which could indicate locations where the virus was actively replicating. This was true in humans and in the animal models.
These data suggest that some regions in the gut have little or no exposure to antiretroviral drugs which may result in low-level replication of HIV, contributing to the virus persisting in the body.
Long-Coding RNA CCR5AS Exposed as a Driver of Major Gene That Influences HIV Infection
People who inherited a genetic mutation known as CCR5-delta-32 from both parents are immune to infection by the most common strains of HIV. CCR5 is an HIV co-receptor – a molecule displayed on the surface of cells that helps HIV to get into susceptible target cells. The mutant form CCR5-delta-32 is not displayed on the cell surface and does not allow HIV to enter cells. But the mutation is rare – only 1 percent of people descended from Northern Europeans has the mutation.
However, CCR5 is expressed in varying levels in people from a variety of ethnic groups. They may be more or less susceptible to HIV infection, depending on how much CCR5 is expressed on their cells. A study published on June 17 in Nature Immunology by Mary Carrington, Ph.D., director of the FNL Basic Science Program and Smita Kulkarni, Ph.D. of the Texas Biomedical Research Institute points to a long-coding RNA called CCR5AS as a factor that influences the level of CCR5 expression.
Genomic DNA from various groups including Hispanics, African Americans and Japanese was tested in the lab with HIV and CD4+ T cells, the primary target cells for HIV infection. When CCR5AS was inhibited, CCR5 expression was also diminished and led to diminished HIV infection of CD+4 T cells. Enhancing CCR5AS increased CCR5 expression, and the cells were more susceptible to HIV infection.
Carrington and Kulkarni are excited about the findings, as the data show how the level of HIV infection and disease progression is tied to the expression of a long non-coding RNA. It’s rare to make this kind of direct connection, Carrington said.
By Mary Ellen Hackett, staff writer. HIV image courtesy National Institute of Allergy and Infectious Diseases.Tagged: