Gut microbes linked to immune activation, HIV disease progress, may explain long-term CD4 loss

Leakage of microbes from the gut as a result of HIV-related damage to the wall of the gut may be one of the major causes of the systemic immune activation that drives the HIV disease process, according to a United States-led research group reporting in Nature Medicine. Their findings provide further evidence that the lymphoid tissue of the gut is the chief site of the struggle between HIV and its host, and that early HIV treatment must be targeted to this battleground.

The normal gut lining transports antigens associated with microbes and food to immune cells located in clusters beneath its surface, called Peyer’s patches. The majority of the body’s immune cells are located here, and they provide the early warning system that decides which microbes need to be eliminated or blocked from accessing the circulating blood.

The normal gut is host to vast quantities of `friendly` bacteria that actually protect the surface of the gut from inflammation and unwelcome microbes.

However, when the gut lining is damaged these bacteria and food antigens can leak through the tight junctions that normally present them to immune cells, and find their way into the circulation, where they trigger a generalised activation of immune cells. This is known to happen during immunosuppressive treatment for transplantation, and leads to exacerbation of graft-versus-host disease. This phenomenon is called translocation.

In HIV disease, major injury to the gut immune environment begins to occur immediately after infection. Extensive depletion of CD4+ memory cells occurs in the gut lymphoid tissue within 4-6 weeks of infection, while HIV itself damages the lining of the gut, making the lining permeable.

Meanwhile, generalised immune activation causes the population of activated CD4 cells to grow, and since these are the target cells for HIV infection, a higher level of immune activation leads to a faster progression of HIV disease.

In order to prove that translocation of microbes contributes to the systemic immune system activation that drives HIV disease progression, scientists at the Vaccine Research Center of the US National Institutes of Allergy and Infectious Diseases and colleagues studied HIV-positive individuals (n=205), uninfected human controls (n=47), primates infected with simian immunodeficiency virus and uninfected primate controls.

They tested all subjects for plasma levels of lipopolysaccharide (LPS), a component of gram-negative bacterial cell walls that is a proven predictor of gastrointestinal permeability.

LPS levels were significantly higher than the control group in HIV-positive individuals with chronic HIV infection, but not in the 50 HIV-positive individuals tested less than four weeks after seroconversion.

Using SIV-infected macaques, the group then demonstrated that gut bacteria were the source of LPS by monitoring LPS levels before and after treatment with an antibiotic regimen designed to eliminate gut bacteria. LPS levels rose after SIV infection, then declined markedly after one week of antibiotic treatment, concomitant with a substantial decrease in faecal bacteria.

In HIV-infected individuals, antiretroviral therapy reduced LPS levels when viral load was undetectable in 24 of 28 patients after 48 weeks on treatment, and there was an inverse correlation between the reduction in LPS and the increase in CD4 cell count on treatment (r=0.463, p=0.015).

In individuals classified as `elite controllers` - those who control HIV below the limit of detection without treatment – LPS levels were elevated compared to the control group, but there was significantly less immune activation than in HIV-positive individuals with detectable viremia, suggesting that the immunmostimulatory effects of LPS are neutralised in some HIV-positive individuals by higher levels of endotoxin-core antibodies, which clear LPS from the circulation.

“These data point to a central role for HIV itself in perpetuating microbial translocation, such that ongoing infection and depletion of CD4 T cells throughout the chronic phase of the disease prevents the re-establishment of competent immunological control of microbial translocation. The complement to such events would be that microbial translocation in its turn perpetuates viral replication through the provision and activation of target T-cells for HIV.”

This month another research group showed that the early loss of CD4 cells in the gut lymphoid tissue is rarely repaired by antiretroviral therapy, despite long periods of viral suppression. Is there a link between this finding and the NIAID finding that microbial translocation is causing immune activation?

Daniel Douek of the Vaccine Research Center told aidsmap: “The link could be that local immune activation in the gut is associated with the same microbial translocation that causes systemic immune activation. The lack of immune reconstitution would prevent restoration of the mucosal barrier. Also – the immune activation could prevent immune reconstitution and drive viral replication. So it’s a vicious circle.”

Taken together the researchers say that the findings suggest the need for new interventions which can “prevent or reduce the propagation of HIV at mucosal surfaces, restore the immunological and epithelial integrity of the mucosal barrier, and to block the cellular and molecular pathways through which microbial products cause systemic immune activation.”