Novel Peptides Expressed in HIV Could Drive Treatment

Genetic sequencing of peptides in rebound virus in individuals with HIV who had analytic treatment interruptions (ATIs) confirmed the peptides’ expression in HIV-1 infection, according to data presented at the International AIDS Society Conference on HIV Science. 

Previous research has shown that HIV-specific CD8 T-cell responses directed against five genetically conserved HIV-1 protein regions (Gag, Pol, Vif, Vpr, and Env) are associated with viral control, wrote Josefina Marín-Rojas, PhD, Faculty of Medicine and Health, University of Sydney, Sydney, Australia, and colleagues in their abstract.

However, data on whether these peptides are expressed in rebound virus among individuals with HIV who experienced ATI are limited, they wrote.

The researchers applied an immunoinformatics analysis pipeline (IMAP) to select 182 peptides (IMAP-peptides) from structurally important and mutation-intolerant regions of HIV-1 proteins, said senior author Sarah Palmer, PhD, co-director of the Centre for Virus Research at the Westmead Institute for Medical Research and professor in the Faculty of Medicine and Health at the University of Sydney, in an interview.

“Our studies indicate if the immune system targets these structurally important and mutation-intolerant regions of HIV-1 proteins, this can contribute to virological control in the absence of HIV-1 therapy,” she explained.

The researchers reviewed data from the PULSE clinical trial, which included 68 men who have sex with men living with HIV in Australia. The study participants underwent three consecutive ATIs. A total of seven participants’ transiently controlled HIV rebound during the third ATI. The researchers examined whether the IMAP peptides were present in the HIV-1 RNA sequences of the rebound virus in four noncontrollers (patients who had viral rebound in all three ATIs) and five of the seven transient controllers who showed viral control during the third ATI.

The technique of near full-length HIV-1 RNA sequencing of rebound virus from three noncontrollers and two transient controllers identified the Gag, Pol, Vif, Vpr, and Env IMAP-peptides in 52%-100% of the viral sequences obtained from these participants across three ATI timepoints.

“We assumed that cells from people living with HIV that experience virological control after treatment interruption would have the immune response to our IMAP-peptides that we observed; however, we are amazed and encouraged by the level and extent of this immune response,” Palmer told Medscape Medical News.

The researchers also compared CD8 T-cell response between the IMAP peptides and a control peptide pool without the IMAP peptides.

The CD8 T-cells from three transient controllers had a 15- to 53-fold higher effector response to the IMAP-peptides than the CD8 T-cells from two noncontrollers, the researchers wrote in their abstract. The relative response to the IMAP-peptides in noncontrollers was 20 times lower than that to the control peptides, but the IMAP-peptide response in transient controllers group was similar to that in the control group, the authors noted.

The results highlight the potential of IMAP in developing treatment strategies. Although the results are too preliminary to impact clinical practice at this time, the findings from the current study could lead to the development of an mRNA vaccine to clear HIV-infected cells from people living with HIV, Palmer told Medscape Medical News.

“Our next steps include developing and testing mRNA vaccine constructs that contain our IMAP-peptides to assess the immune response of cells from people living with HIV to these vaccines,” Palmer told Medscape Medical News. “From there we will conduct studies of the most promising mRNA vaccine constructs in a humanized mouse model,” she said.

Data Enhance Understanding of Immunity

The current study may provide information that can significantly impact understanding of the immune responses to HIV, said David J. Cennimo, MD, associate professor of medicine & pediatrics in the Division of Infectious Disease at Rutgers New Jersey Medical School, Newark, New Jersey, in an interview.

“The investigators looked at highly conserved regions of multiple HIV proteins,” said Cennimo, who was not involved in the study. “Conserved regions and antibody responses to them may play a role in controlling HIV viral replication and rebound,” Cennimo told Medscape Medical News. “The investigators showed these regions were present in rebounding viremia, and individuals that exhibited greater immune recognition of these regions suppressed rebound viremia longer, and perhaps targeting these regions could impact HIV prevention or cure strategies,” he said.

Secondarily, the study showed the success of the novel technique (IMAP) to identify conserved peptides, said Cennimo. The technique could potentially be applied to other viruses that mutate to escape host response, he said.

The study was funded by the US National Institutes of Health, the Foundation for AIDS Research, the Australian National Health and Medical Research Council, and Sandra and David Ansley. 

The researchers disclosed no financial conflicts of interest. 

Cennimo had no financial conflicts to disclose.