HIV Targets T Cells During Infection in the Brain

Author:

J Victor Garcia-Martinez, PhD

University of North Carolina

Citation:

Garcia-Martinez JV. How HIV infects the brain [published online January 16, 2019]. Infectious Diseases Consultant.

The human brain is a very important cite of HIV replication and persistence, particularly during antiretroviral therapy. However, the study of HIV infection in the brain in otherwise healthy individuals is clearly not feasible. Therefore, we have to study HIV infection in the brain using animal models.

The T-Cell Discovery

To analyze how HIV infects the brain, my team and I studied how the virus infects the brains of mice, evaluating the pathology as well as possible therapeutic interventions. We found that, in addition to other cell types that have been very well described as infected in the brain, human T cells are also targets for HIV infection in the brain. So, HIV can very rapidly penetrate the brain, establish infection, and deplete the pool of CD4-positive T cells in the brain. And in the absence of any therapeutic intervention, it can completely reduce the levels of T cells, creating a deficit in hemostasis.

However, if the mice were treated with currently used antiretroviral therapy, the levels of T cells returned to normal, the levels of viremia decreased to almost undetectable levels, and homeostasis was restored.

What These Groundbreaking Results Mean

The findings are very important because they highlight a new cell type infected in the brain that has received very little to no attention in the past. In the past, the dogma was that the cells infected in the brain were either macrophages or microglia, but certainly not human T cells. This study shows that T cells—which are perhaps the most important cell type in the body when it comes to HIV infection and persistence—are also infected in the brain; that is new information that has very significant implications to the field.

If you do not know who the enemy is, it is very difficult to combat it. But now that we know T cells are actually infected in the brain, the therapeutic interventions will have to target that particular cell type. When we look at inhibitors of antiretroviral replication or at the type of viruses that are going to be infecting the brain, we will have to keep in mind that they are actually infecting human T cells.

The investigation of systemic HIV replication is of fundamental importance not only for therapy, but also because it is central to our ability to eventually eradicate the virus and find a cure for HIV/AIDS. The human brain is a very important site of HIV infection, where the virus can replicate and possibly seed long-lasting reservoirs. But our studies indicate that both T cells and macrophages can be successfully and independently infected in this organ, so the notion that macrophages alone are responsible for seeding HIV infection in the brain is not supported by the presence of T-cell tropic viruses both in the cerebrospinal fluid of patients or in the brains of mice, like in our study.

And even though infection of the brain can take place shortly after exposure, the fact that therapy dramatically reduces viremia is consistent with the significant benefits of early treatment interventions.

But one issue that remains to be addressed is whether HIV-infected cells in the brain represent persistent reservoirs capable of reigniting infection upon reactivation of virus within the central nervous system. As such, they should be targeted by future cure approaches, so in the future we will be to leverage these observations into treatment and into approaches to eradicate the virus from patients.

Next Steps

What I would like to see by the end of my career—and hopefully even sooner—is an approach to eradicate HIV from the body. Some peripheral tissues like lymph nodes and the spleen can be biopsied, and we can see the effect of eradication therapy. But the brain is the final frontier. And so, learning more about how HIV infection of the brain is established, which cells are infected, and how we are able to target them for eradication is a very lofty goal that we hope to achieve.

Further, we have been waiting more than 30 years for an HIV vaccine. We now have vaccines; they are not very efficacious, but progress using alternative types of vaccines, some of which are based on other viruses, have shown significant promise—not so much for prevention, but perhaps for eradication, which actually would be a great benefit to humanity.

J Victor Garcia-Martinez, PhD, is an Oliver Smithies Investigator, a professor of Medicine, and a member of the University of North Carolina (UNC) Institute for Global Health and Infectious Diseases, the UNC Center for AIDS Research, and the UNC Lineberger Comprehensive Cancer Center.