Approximately 40 million people in the world are HIV-positive, and though antiretroviral medications suppress viral replication and are clinically effective, not everyone can get or afford them. So long as the virus is out there unchecked, HIV remains a threat.

To address that threat, researchers at the Icahn School of Medicine at Mount Sinai are exploring everything from HIV cellular physiology to translational clinical strategies.

The laboratory of Benjamin K. Chen, MD, PhD, Irene and Dr. Arthur M. Fishberg Professor of Medicine and Vice Chair for Research in the Department of Medicine at Icahn Mount Sinai, has been focused on the pathogenesis of human immunodeficiency virus type 1 (HIV-1) infection, including a deep dive into cell-cell interactions.

“Cell-cell interactions are very important in how they allow HIV to spread efficiently,” explains Dr. Chen, who is also a Professor of Microbiology, and Pharmacological Sciences. “We have been developing models to observe and accurately measure different steps in the lifecycle of the virus by engineering either fluorescent viruses or viruses that turn on genetic switches.”

Bioengineered viruses that carry fluorescent proteins can be used to visualize cell-cell interactions that support HIV infection. This live imaging technique has revealed that when HIV-infected cells are co-cultured with uninfected cells, durable cell-cell interactions form adhesive contacts, called virological synapses, which in turn promote immune evasion. Dr. Chen and co-authors have explained how the dynamic movements of the HIV Env protein support virological synapse formation in a study published in Viruses, and an emerging view of how these cell-cell infections affect the Env on the surface of cells and allow the virus to evade immune responses, published in mBio.

“This approach has helped us understand how the virus spreads and how it evades immune responses,” Dr. Chen notes. “We have been focused on trying to understand how the major protein on the surface of the virus, the envelope glycoprotein—which is also the main target of vaccines—enables it to spread from cell to cell, and how it is different on the surface of cells than it is on the surface of viruses.”

An active area of HIV research has focused on stimulating a patient’s own immune system to recognize and eliminate cells that are infected with the virus. This line of inquiry was prompted by the identification of individual antibodies isolated from patients that can neutralize a variety of different HIV strains, so-called broadly neutralizing antibodies (bNAbs). These bNAbs are being tested clinically as a new immune-modulating therapeutic strategy. Thus far, however, this strategy by itself has not been shown to be capable of suppressing the virus in the long term. In addition, which patients with HIV should be given which bNAb or bNAb combinations has yet to be elucidated.

Dr. Chen and his lab have recently received a National Institutes of Health grant to develop assays to test the sensitivity of HIV to bNAbs. “We have found that bNAbs are really potent blockers of HIV infection,” Dr. Chen says. “These are much better at blocking cell-free virus infections than they are at blocking at the virological synapse. We are trying to better define this and use it as a clue to identify antigens or vaccines that would block cell-cell infections and cell-free virus infections.”

The Quest for a Therapeutic Vaccine

The work on virological synapses and bNAbs by Dr. Chen and his lab colleagues has informed the fight for new drugs and vaccines against HIV infection.

That fight has been taken up by, among others, Francesca Cossarini, MD, an Assistant Professor of Medicine (Infectious Diseases) at Icahn Mount Sinai and an Infectious Diseases attending physician at The Mount Sinai Hospital. As Dr. Chen explains, “Our research relates to Dr. Cossarini’s clinical trials, because these same bNAbs are being tested as drugs to help recruit the immune system to clean up infected cells in ways that the normal immune response cannot.”

Dr. Cossarini notes that in the controlled phase of HIV infection, even as patients take antiretroviral therapy, the virus hides, persisting in long-lived immune cell subsets called the viral reservoir. “I have focused on the gastrointestinal (GI) tract, which is the major lymphoid tissue in the body,” Dr. Cossarini explains. “I started off by working on how to better define the responses to the interaction of the GI immune cells with HIV and some of the environmental factors in the intestinal mucosa, specifically the intestinal microbiome.”

Dr. Cossarini has begun a clinical trial that will focus on the effects of proposed treatments for HIV on the gastrointestinal immune system—one of the sites of the lymphoid viral reservoir. The study will track a small group of patients as they are treated with experimental HIV treatments. Via colonoscopy, GI tissue will be collected and the effect of the treatments on the GI tract’s viral reservoir will be ascertained. The findings should help gauge the therapeutic efficacy of different approaches.

Both Drs. Chen and Cossarini note that the hunt for an HIV-preventive vaccine has failed after more than 40 years of effort. The problem, as Dr. Chen explains, is that “all the vaccines are targeting the glycoprotein, which is on the surface of virus particles. But glycoprotein is also on the surface of cells mediating spread, where we think it assumes very different conformational states.” The diversity of HIV, which mutates readily, is a challenge for creating a preventive vaccine.

More promising, in their view, is to use bNAbs or other molecules as HIV therapies to recruit the immune system to clear the latent viral reservoir. “I would venture to guess that we might obtain a therapeutic strategy that is able to eliminate most of the residual virus before we have an effective preventive vaccine,” Dr. Cossarini says.