Talking About Three Decades of HIV Science

It was 30 years ago this month that researchers from the Pasteur Institute reported in Science the isolation of a new retrovirus from the lymphoid tissue of a gay Caucasian that appeared to be associated with AIDS-related syndromes. 

The virus would eventually come to be called HIV for human immunodeficiency virus and found to be responsible for what Anthony Fauci, the longtime director of the US National Institute of Allergy and Infectious Diseases, considers one of the five worst pandemics in human history. 

Fittingly, Fauci was on hand this week at the Paris-based institute to kick off “Thirty Years of HIV Science: Imagine the Future,” a three-day meeting that opened May 21 on the storied campus named for the pioneering microbiologist. The meeting brought together about 500 researchers and people on the AIDS policy front—including Françoise Barré-Sinoussi, one of the Pasteur scientists who isolated the virus and earned a Nobel Prize for that feat in 2008.

Her co-discoverer, Luc Montaigner, was slated to give one of the talks at a fancy dinner Wednesday night at the Le Théâtre du Merveilleux, but canceled at the last minute. Scientist Robert Gallo, whose laboratory reported in 1984 the isolation of a retrovirus that was later determined to be HIV, delivered the other talk. 

The meeting was held to focus on the critical challenges and the future priorities in HIV research, after of 30 years of remarkable scientific achievement.  

The conference literature actually used the word “fantastic achievements,” and as one strolls past color photographs of HIV and other pathogens that adorn the stone wall around the Pasteur Institute, one couldn’t help but imagine what it was like back then, as researchers sought the culprit responsible for a mysterious new disease. 

Fauci touched on the history, the research milestones and the challenges that remain both for proven interventions such as antiretroviral therapy and adult male circumcisions, and those interventions still in development, such as AIDS vaccines and the search for a cure. 

“It’s too soon for a victory lap,” said Fauci, addressing proclamations that the world now has the tools in hand to usher in an AIDS-free generation.  “There is still much to do.” 

Indeed, in a series of talks the following day that dealt mostly with the molecular arms race between the virus and the host, a growing library of data on some of the most basic biological questions related to HIV revealed some potentially new and unexpected chinks  in the armor of HIV and its close cousin, the simian immunodeficiency virus (SIV).

In a development that could have implications for the development of an AIDS vaccine that targets gp41, one of the glycoproteins that comprises HIV’s surface protein known as the Envelope, Ashley Haase, a primate researcher at the University of Minnesota, presented new data collected from rhesus macaques immunized intravenously with a nef-deficient live-attenuated virus (LAV) before they were challenged vaginally with a high-dose of SIV. 

The vaccine regimen itself might appear odd, given its checkered history.  In 1992, rhesus macaques vaccinated with a LAV were found to be protected, but four years later hopes were dashed when the attenuated strain of SIV used in the vaccine regimen led to disease and death in fetal macaques. This outcome dashed hopes that a LAV vaccine candidate might one day be tested in humans, and LAV candidates have all but disappeared from the To Do lists of AIDS vaccinologists. 

In fact, Haase is not interested in developing LAV for clinical testing.  Rather his motivation was to use the macaque model to study mucosal transmission, the most common mode of transmission, by sampling tissue in a synchronized fashion directly after viral challenge.  One of the goals of the study was to pinpoint potential correlates of protection, he said. 

Haase said despite seeing substantial protection among the vaccinated macaques within 20 weeks after vaccination, and sterilizing immunity by week 50, the T cell responses were underwhelming. But when they searched for antibodies in the vaginal tissue of the macaques they found a striking five-fold increase in Immunoglobulin G (IgG) antibodies to the oligomeric forms of gp41. This region of the virus’ Envelope is considered something of a wasteland for vaccine targets.  While two broadly neutralizing antibodies (bNAbs) are known to target gp41’s membrane proximal external region (MPER) of the Envelope, scientists haven’t been able to induce similar antibodies through immunization. They also tend to yield weak immune responses. 

In Haase’s study, the vaccine candidate contained a soluble form of gp41 that had the MPER sliced off.  With a potential immunogen in hand, Haase said his group wants to next try to replicate these local effects in macaques. He also wants to test different methods of vaccination, including intranasal vaccination, to measure systemic responses. 

While a LAV vaccine candidate probably wouldn’t survive regulatory review for human evaluation, Haase said the information they are gleaning from this monkey model could possibly be a step forward for the field. “It may be possible to figure out new rules by which the mucosal immune system concentrates its resources where they are needed.” 

Notably, the identification of such rules is a key objective of the search for an AIDS vaccine.