Early antiretroviral therapy may limit gut damage and immune activation

Starting antiretroviral therapy (ART) at the earliest stage of HIV infection can help prevent immune cell dysregulation that contributes to destruction of the gut lining and promotes systemic immune over-activation, according to a study presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) earlier this month in Boston.

When HIV disrupts the gut lining, bacteria can leak out – known as bacterial translocation – and trigger a systemic or whole-body inflammatory response. Persistent inflammation and excessive immune activation are thought to contribute to non-AIDS conditions such as cardiovascular disease and cognitive impairment in people with HIV.

Alexandra Schuetz from the Armed Forces Research Institute of Medical Sciences and colleagues in Thailand looked at whether early ART during acute HIV infection might limit damage to the intestinal mucosal barrier.  

In particular, they measured Th17 cells, a type of T-cell that is instrumental in maintenance of the gut epithelial barrier, the researchers explained as background. These cells produce cytokines including interleukin 17 (IL-17), which is involved in inflammatory response. Disruption of the normal balance between Th17 cells and regulatory T-cells (T-regs) that dampen the response contributes to excessive immune activation.

This analysis included 34 participants with acute HIV infection (median duration 15 days) at Fiebig stages FI (n = 13) or FIII (n = 21), identified out of nearly 53,000 screened samples. In addition, five HIV-uninfected individuals and nine treatment-naive people with chronic HIV infection (6-12 months post-infection; median 298 days) matched for age and sex served as controls. Most participants were men who have sex with men and the mean age was approximately 28 years.

Fiebig stages indicate when HIV RNA, p24 antigen and antibodies become detectable. Stage FI indicates initial ramp-up of viral replication, with peak viral load occurring during stage FIV.

Participants underwent sigmoid biopsies to obtain gut tissue samples at baseline and at 6 and 24 months after starting ART (27 and 16 people had the second and third biopsies, respectively).

At the time of diagnosis, participants at Fiebig stage FIII had a significantly lower proportion of Th17 cells in their gut mucosa compared to those at stage FI or HIV-uninfected control participants, but there was no significant difference between people at stage FI and uninfected people (median 7, 13 and 15%, respectively). People with chronic HIV infection had even further depleted Th17 cells (median 1%). People with higher colonic viral load had lower Th17 cell levels, on average.

During stage FI, Th17 cell function remained intact, as indicated by production of IL-2, Il-22 and gamma interferon. Th17 cell function declined substantially, however, in people at stage FIII. Individuals with chronic HIV infection had the poorest cell function.

Participants who started ART during stage FI were able to maintain a Th17 cell proportion similar to that of uninfected people at six months (median 14%) and 24 months (median 13%). Starting ART during stage FIII prevented further loss of Th17 cells, but did not restore them to earlier levels (median 9% at six months and 8% at 24 months). Starting ART at stage FI preserved T-cell function, but it typically remained low when treatment did not start until stage FIII.

People diagnosed at stage FI had significantly increased immune activation in the sigmoid colon and peripheral blood (as indicated by CD8 T-cell HLA-DR/CD38 markers), while those at stage FIII had much greater activation. Starting ART at stage FI "fully reversed" local and systemic immune activation, with CD8 cell activation at 6 and 24 months being similar to that of HIV-negative people. Those who were not treated until stage FIII, however, still had elevated immune activation at six and 24 months.

"Initiation of ART at Fiebig I prevents loss of mucosal Th17 cells and function," the researchers summarised. "Initiation of ART in Fiebig III cannot restore the initial loss of multifunctional mucosal Th17 cells, despite partial recovery of Th17 cells."

These findings, they concluded, "emphasise the importance of strategies to prevent loss of mucosal Th17 cell function and argue for early and aggressive treatment intervention."