Dr. Diaz-Griffero studies the early events of HIV infection. A native of Chile, he earned a master’s in plant virology by pursuing a combined program between the Pontifical Catholic University of Chile and the Max Planck Institute for Plant Molecular Physiology in Germany, followed by a Ph.D. in retrovirology at Einstein. He later completed postdoctoral fellowships at NYU School of Medicine and the Dana Farber Cancer Institute at Harvard Medical School. Dr. Diaz-Griffero joined the Einstein faculty in 2010, where he is professor of microbiology & immunology, the Elsie Wachtel Faculty Scholar, and a member of the Einstein-Rockefeller-CUNY Center for AIDS Research. He now leads two National Institutes of Health–funded studies into cell proteins that keep viral replication in check.

Felipe Diaz-Griffero, Ph.D.Faculty ProfileResearch Profile

When did you first become interested in HIV?

In high school, in the late 1990s. I was doing volunteer work in a hospital in La Paz, Bolivia and heard about an HIV patient who was placed in quarantine because everyone was afraid, and nobody knew what to do. I asked the infectious disease specialist how I could help. He welcomed me into his lab and trained me how to do ELISAs [assays for detecting viruses and other substances in the blood].

Thanks to antiretroviral therapy (ART), most people with HIV have near-normal lifespans. What else is needed in terms of treatment?

The problem is that ART can have many side effects, from fatigue to cognitive issues to liver damage. Not surprisingly, many patients don’t comply with treatment—with disastrous consequences. ART suppresses viral replication, but since the virus integrates into the genome of host cells, it never goes away. If you stop taking the drugs, the infection comes roaring back and you risk infecting others. Another issue with ART is that some HIV strains are developing resistance to one or more components of the ART drug cocktail. So while we’ve made great progress in treating HIV, it’s not enough.

Is the only solution a therapy that eliminates HIV altogether from our cells?

Or at least a therapy that allows people to live with HIV symptom free—a so-called functional cure. Perhaps we can learn from our fellow primates, like African green monkeys, who have found a way to co-exist with viruses similar to HIV. The virus in infected green monkeys does not get out of control, and they don’t develop symptoms.

Is there any benefit to co-existing with retroviruses?

In evolutionary terms, yes. Retroviruses drive primate evolution by introducing regulatory sequences into the genome, some of which can be beneficial. For the most part, primates have learned how to control these pathogens rather than eliminate them. One way cells control retroviruses is with host-cell proteins called restriction factors, which I started studying as a postdoc. When HIV or other viruses infect cells, restriction factors are the cells’ first line of defense against viral replication. Unfortunately, in the case of HIV, our restriction factors aren’t very good at keeping the virus in check. Most ARTs developed so far do not target this early part of the HIV life cycle.

What aspects of HIV do you study?

My lab’s ultimate goal is to find novel therapeutic targets for HIV, which requires a basic understanding of how the virus replicates. We’re particularly interested in the steps that occur early in infection—just after HIV enters a cell—which include the processes known as uncoating and reverse transcription. In uncoating, the virus’s genetic material is released from its protective coat, or capsid. In reverse transcription, the virus’s single-stranded RNA is transcribed into double-stranded DNA, which is then integrated into the host cell’s genome, where new copies of the virus’s RNA are made. Restriction factors oppose these early-HIV-infection processes, and we hope to exploit them to develop an effective HIV cure.

Tell us about some of your findings. What have you learned about capsid uncoating?

Scientists had assumed that capsid uncoating occurs in the host cell’s cytoplasm. We’ve shown that uncoating and other early HIV replication steps actually take place in the host-cell nucleus. This fundamentally changes our understanding of HIV infection and gives us a better idea of where to target interventions.

In another capsid-related study, we discovered exactly how the drug lenacapavir works. It’s a long-acting antiretroviral drug for patients with HIV whose infections have developed resistance to other ARTs. Unlike most other ARTs, lenacapavir is a capsid inhibitor. We found that lenacapavir binds to the capsid protein and stabilizes it, preventing it from opening and releasing the virus’s genetic material. In short, lenacapavir mimics the way the human immune system naturally works to prevent retroviruses from replicating.

My lab's ultimate goal is to find novel therapeutic targets for HIV, which requires a basic understanding of how the virus replicates.

Felipe Diaz-Griffero, Ph.D.

And what have you learned about restriction factors?

One of our projects focuses on a restriction factor called TRIM5α. In monkeys it’s very good at blocking HIV infection, but human TRIM5α doesn’t help very much. We found we can activate TRIM5α in human cells with a non-immunosuppressive form of the drug cyclosporine, which—in its standard form—is typically used to prevent the immune system from attacking and rejecting transplanted organs. Once activated by non-immunosuppressive cyclosporine, human TRIM5α binds to HIV’s protein shell and potently blocks HIV from replicating in human cells. Non-immunosuppressive cyclosporine is not toxic to human cells and could potentially be combined with other therapies to prevent HIV from spreading to uninfected cells or even to eliminate HIV from infected patients.

One of your NIH grants focuses on SAMHD1. What does it do?

SAMHD1 is a restriction factor that combats HIV infection by preventing reverse transcription from occurring. Some evidence suggested this effect stems from SAMHD1’s enzymatic activity. But we’ve shown that SAMHD1 works by interfering directly with nucleic acids in the HIV genome. An interesting tangent of this work is that mutations to the SAMHD1 gene cause Aicardi-Goutières syndrome [AGS], a rare childhood inflammatory disorder that affects the brain and skin. Understanding how SAMDH1 works may help us to identify novel anti-HIV targets and also develop new therapies for AGS.

During the pandemic, you turned your attention, at least in part, to SARS-CoV-2, the virus that causes COVID-19. What has come of that research?

Early in the pandemic, it became apparent COVID-19 infection was less severe among Asians than among other ethnic groups. A lot of researchers were looking at whether variants of the virus’s spike protein might underlie differences in infectivity and disease severity. To cause infection, the coronavirus responsible for COVID-19 must first latch onto proteins called ACE2 receptors on the surface of cells—and there was little information on variants of ACE2 that might influence the virus’s ability to infect cells. Our study showed that ACE2 variants that protect against infection are found almost exclusively in Asian populations. Some ACE2 variants found in people in the U.S. and Europe were associated with a two- or three-fold increase in infectivity. This may explain the lower mortality rates seen in Asian countries. Our study’s take-home message is that the search for COVID-19 treatments should include looking at the ACE2 receptor as a potential therapeutic target.