Exposure of genital and intestinal tract mucosal tissues to HIV-infected body fluids is the leading mode of HIV transmission worldwide, as these tissues are rich in activated CD4+ T cells, which are the primary targets of the virus. Additionally, the gut contains about half of all CD4+ T cells in the body, making it a major site of viral growth, regardless of how the person was infected. Two teams of amfAR-funded scientists have delved deeper into the interaction between HIV and gut tissues, making important contributions to treatment and therapeutic vaccine strategies.
First, writing in the February issue of the online journal PLOS ONE, Dr. Peter Anton and associates at the University of California, Los Angeles, describe different immune responses to an experimental HIV vaccine when it was administered in the shoulder muscle (the standard route of delivery) or into the skin overlying a lymph node in the groin. Twelve people received a genetically engineered canarypox vaccine containing proteins from the envelope, core, and protease of HIV, and six received a placebo. Canarypox proteins are harmless to humans, but can boost a vaccine response to HIV. The vaccine is being developed by Sanofi Pasteur in France.
The research team found that targeting the vaccine to the bloodstream (via a muscle injection) versus to the gut (injecting skin overlying a groin node) produced very different immune responses. In the gut mucosa, HIV-specific killer T cells developed within 10 days following groin injections, but were not detectable until 24 to 180 days after muscle injections. The results underline the potential implications of vaccine administration route, and indicate that measurements of immunity in blood may not reliably reflect mucosal immunity. Dr. Anton and colleagues concluded that this "highlight[s] the importance of not only evaluating early blood responses to HIV-1 vaccines but also mucosal responses over time."
In a second study, reported in the Journal of Acquired Immune Deficiency Syndrome, amfAR grantees Drs. Steven Deeks and Joseph McCune, and colleagues from the University of California, San Francisco, along with collaborators at Case Western Reserve University and GlaxoSmithKline, looked at differences in inflammation -- an over-activity of the immune system -- in the blood versus the gut of individuals taking antiretroviral therapy (ART). They compared blood and intestinal biopsy tissues from patients with viral suppression for at least two years whose T cell counts remain below 350 cells/mm3 (immunologic nonresponders), with those whose T cells exceeded 500 cells/mm3 (immunologic responders) -- a more normalized level during such therapy. Persistent signs of inflammation in the blood are known to be associated with failure to regulate CD4+ T cell counts despite years of highly suppressive ART.
As expected, Deeks, McCune, and associates found that those who had not responded optimally to therapy had elevated levels of inflammatory indicators in blood, but not in colon biopsies compared to responders. The research team concluded that, "interventions that diminish inflammation may improve CD4+ T cell recovery during ART ... and improve the expected lifespan among treated patients. [Such interventions] might be most conveniently and accurately assessed in the blood."
Dr. Laurence is amfAR's senior scientific consultant.