The annual Conference on Retroviruses and Opportunistic Infections (CROI) is an annual gathering where advocates and researchers learn where the science on HIV is taking us. The findings can be both grand and granular. They answer questions, raise new ones or both. And not all of those questions are strictly about science. Two of AVAC’s partners have been reflecting on what they took away from the conference, insights that inform our thinking long after the sessions end and results are published.

Julie Patterson is an HIV prevention research advocate and public health professional who lives in Northeast Ohio. She is chair of the Case Western Reserve University/University Hospitals of Cleveland AIDS Clinical Trials Unit’s Community Advisory Board, a member of AVAC’s PxROAR program, and a member of the US Women and PrEP Working Group.

Recently, I had the opportunity to attend the Conference on Retroviruses and Opportunistic Infections (CROI) as a community educator scholar. It was a grand experience – a gathering of brilliant, hard-working research minds at one of the premier HIV scientific meetings that are held each year. It was truly an honor to be among them.

However, I’m not sure my presence was felt.

A cohort of us came to CROI to give voice to community needs and bring new research back to our communities. We see it as a two-way street.

On the first day of CROI, there is a workshop held for newer researchers called, “Program Committee Workshop for New Investigators and Trainees”. People awarded the Young Investigator and International Delegate Scholarship are required to attend in order to get an introductory overview of the conference, what to expect in the days ahead, and a primer on aspects of the science that may be unfamiliar. The attention is on the science and the scientists—new investigators and clinicians who are actively involved in research. The organizers encourage participants to ask questions because lab scientists aren’t always aware of the issues in epidemiologic research, virologists speak a slightly different tongue than immunologists. You get the idea.

Not surprisingly, community educators are also required to attend the workshop for new investigators. This is a great idea; the nature of these talks is more general than others at the conference, and provides a foundation for understanding key results. Unfortunately, the structure often does not allow the presence of community educators to be known. Sure, we ask questions, but mostly we are like ghosts – ethereal beings with messages from the past. Not quite real. Certainly not equals.

This year, in what I perceived as an attempt to turn this CROI norm on its head, one of the crucial lectures included in the workshop was centered on GPP—Good Participatory Practice. It was led by community activists, grounded in the lives of people living with HIV, and aimed squarely at the new investigators, and with this I agree wholeheartedly. The Martin Delaney Lecture honored his legacy and brought the attention back around to the communities who are struggling with HIV, to the people who are at the heart of this epidemic. The message: listen to community stakeholders, and you will hear what you need to know. Ignore them, and your research results will suffer. We will all suffer.

I was disappointed that this vital talk was held during lunch when many left the room to pursue other food options. Most of the awardees of the Young Investigator and International Delegate Scholarship stayed to eat a free box lunch, but the timing appeared to indicate that this lecture wasn’t as important as the others. It would have been easy to miss it and not be held accountable.

Researchers, I’m here to say that you are accountable to us. We need you on our side and to see this through to the end. Our goals are the same—we want to end this HIV epidemic, to roll out a vaccine that will prevent new infections, to find a cure that works for everyone, to lead happy, healthy and long lives full of purpose and meaning, full of love and adventure. We want to see all of it in our lifetimes, just like you.

I tend to follow HIV prevention and public health research closely, so those were the sessions that I attended. Time and again, I sensed the urgency in the tone of the presentations. For that I am grateful. We must continue to push forward. Yet I also heard something else, even from prominent scientists—a scientific expediency that can leave communities behind.

Two significant HIV prevention clinical trials that are currently being conducted under the umbrella name of the “AMP Studies”—HVTN 704/HPTN 085 and HVTN 703/HPTN 081 are a case in point. I sit on the Community Working Group for these trials that are studying the efficacy of antibody mediated prevention. The HVTN 704/HPTN 085 trial is recruiting cisgender heterosexual women at risk in South Africa. In the US, Peru, Brazil and Switzerland, HVTN 703/HPTN 081 is recruiting cisgender men and transgender people who have sex with men.

Unfortunately, on multiple occasions at CROI, when I heard researchers refer to the AMP Trial, they neglected to mention the involvement of transgender people.

This may seem like a small oversight. Surely it is acceptable to use shorthand amongst fellow researchers? Everyone knows that referring to MSM as the target population for recruitment in this situation includes transgender people, right? Wrong. Transgender and gender non-conforming (TGNC) people don’t necessarily assume it. We all need to see ourselves in HIV prevention research.

Will this study collect data in such a way that we can separately analyze findings that are specific to TGNC participants—if not,we will have lost an invaluable opportunity. Will TGNC people at risk for HIV see results from AMP as applicable to their lives? If our experience with PrEP is any indicator, the answer is no, unless the investment continues to be made in TGNC people. AMP has included TGNC stakeholders early in the research process- from choosing research questions to protocol development, from design of informed consent to rollout of marketing materials. Now advocates are watching to ensure that it continues—from interpreting results to follow-on studies and implementation, all the way to the next trial. Every step of the way. Every step.

The AMP Trial has helped to set a new standard for transgender inclusion in HIV prevention research, but it is only one example of how GPP can be utilized. There are so many more. Community stakeholders have to be involved at every step.

In the end, researchers, my message isn’t to watch your step, it’s to walk alongside us. We can’t do it without you, and you can’t do it without us. As community stakeholders, we bring information to the table that you may never know without our voices. Knowing it up front will make the science more efficient, more ethical, and better in the long run.

For over 30 years, HIV research has been on the cutting edge of engaging affected communities and working together with activists. We need to keep that momentum going. I look forward to it.

Editor’s Note: AVAC’s Stacey Hannah led the presentation during the session on Good Participatory Practice (GPP). GPP is a set of guidelines developed by AVAC and UNAIDS in 2007 to engage affected communities and all other stakeholders in the design and conduct of biomedical HIV prevention trials. GPP has been widely adopted and is instrumental to a research process that yields trusted results.

Fervid research has uncovered dozens of antibodies that shield cells from HIV. These broadly neutralizing antibodies (bNAbs) protect monkeys from SHIV, the simian-HIV hybrid. Thousand-person human trials are already dripping bNAbs into high-risk men and women to see if they prevent HIV infection. And much work suggests bNAbs hold promise as keys to HIV vaccine design or as immune therapy delivered by passive immunization or viral vectors.

So what inspired the media handstands proclaiming the discovery of yet another bNAb—one explored so far only in lab tests, inflating a bNAb class already studded with candidates that show potential based on their antiviral activity in lab studies? While human trials of bNAbs are underway, this newest next-generation candidate is years away from human trials. So, does the world need even one probably costly, hard-to-administer bNAb when as-needed PrEP taken consistently before and after sex or PrEP plus antiretroviral therapy for HIV-discordant couples virtually eliminate HIV transmission?

It appears so. All the fuss focused on a bNAb tagged N6, isolated from a volunteer whose immune system had 21 years to mold and remodel the antibody into a form that neutralized 98 percent of global HIV strains Mark Connors and colleagues threw at it—the most ever harnessed by a single bNAb. The diverse and exacting studies performed by this team from the National Institute of Allergy and Infectious Diseases (NIAID) and other centers offer tantalizing evidence that N6 is indeed something special.

Previously studied bNAbs, Connors and coauthors note, are either strong (stalling HIV at a relatively low dose) or broad (blocking a high proportion of tested HIV strains). None claims both distinctions—but N6 does. The new bNAb boasts sweeping breadth, thwarting 98 percent of HIV strains tested, compared with 80 percent to 90 percent neutralization with other bNAbs in this class, which targets the CD4 binding site. But the other CD4-homing bNAbs, observe Scripps researchers Devin Sok and Dennis Burton, wield only “modest potency” compared with N6’s robust median 50 percent inhibitory concentration (IC50) of 0.04 µg/mL. A few other bNAbs in different classes flex even more inhibitory muscle than N6 (median IC50 0.003 µg/mL for bNAb PGDM1400) but have narrower breadth than N6 (83 percent of isolates neutralized by PGDM1400).

bNAbs affix themselves to some stretch of the HIV envelope protein that the virus uses to snag CD4 cells. But the gene that encodes the HIV envelope mutates manically to shirk the embrace of antibodies (and vaccines designed to elicit or transport antibodies). At the same time, HIV shrouds its envelope in a sugar coat poorly recognized by antibodies. So a key measure of bNAb prowess is how well it copes with HIV’s shape-shifting mutations. And by this measure, N6 is a star. Only 4 of 181 HIV strains tested (2 percent) proved highly resistant to N6. Among 20 HIV strains resistant to other bNAbs in the same class as N6, the new bNAb neutralized 16 (80 percent).

To learn how N6 dodges HIV’s resistance defenses, Connors and crew performed a series of rigorous structural analyses showing precisely how N6 seizes HIV’s envelope loops. N6 grabs HIV the same way we grab things—with a hand, or at least something that looks like a hand. Connors’s team asks us to visualize N6 and other antibodies in this class as an index finger and thumb that pinch a sugar-coated shape-shifting part of the HIV envelope called the V5 loop. To resist other CD4 binding site antibodies, HIV warps V5 in a way that pushes away these antibodies to prevent them from binding. Crystal structure analysis showed that, compared with the index finger and thumb of VRC01 (the most-studied bNAb in this class), the finger and thumb of N6 are shorter and differ subtly in rotation and tilt. These subtle changes allow N6 to avoid wrinkles in V5 that cause resistance to other bNAbs in the VRC01 class.

Besides clutching V5, bNAbs in this class finger two other HIV envelope regions, the CD4-binding loop and another loop labeled D. The twist and tilt of N6 relative to other bNAbs make it rely less on V5 and more on loop D to grip HIV. Because loop D shifts shape much less than V5, the N6 hand grabs it more reliably and firmly from one HIV strain to the next.

VRC01, the bNAb now in large placebo-controlled trials to prevent HIV infection in men and women, must be dripped into a vein for 30 to 60 minutes every 8 weeks. Because N6 is 5 to 10 times more potent than VRC01, simpler subcutaneous shots may be possible and at longer intervals. Connors and colleagues suggest the durability of N6 may be further tweaked by mutational manipulation. Anything that simplifies delivery of a preventive or therapeutic agent boosts its chances of successful clinical use.

Autoreactivity (sometimes called self-reactivity) occurs when an agent produced by an organism (like humans) works against that organism. Although autoreactivity may be a defining feature of bNAbs, researchers agree that it represents an obstacle to inducing bNAbs and may account for their rarity in people with HIV. Connors and colleagues performed four binding studies indicating minimal autoreactivity with N6, a benefit that bNAb experts Sok and Burton suggest may favor N6 use for prophylaxis or treatment.

To learn how N6 evolved in their volunteer, Connors and coworkers sequenced B-cell antigen receptors at three times—2012, 2014, and 2015. Hints from these studies and from phylogenetic (evolutionary) analyses may give researchers vital clues to targeting diverse HIV strains with vaccines or immunotherapies. Discovering features shared by N6 and other bNAbs could inform the design of better vaccine and immunotherapy candidates.

Together these propitious traits inspired Sok and Burton to proclaim N6 the “best-in-class” among CD4-binding bNAbs. And given the breadth and brawn of N6, it may not be a stretch to call it the best bNAb period. But caution remains the catchword for any agent at this earliest stage of research. So far everything we know about N6 comes from a single, though exhaustive, 14-page paper, plus supplementary online data. From this point agents like N6 typically require further lab work and studies in animals like mice and monkeys before starting small human trials to assess their safety and find the right dose. Only then can researchers test efficacy in bigger human trials. But bNAb development moves fast these days. The much-vaunted VRC01 got discovered in 2010, its first human trial began only 3 years later, and the above-noted phase 2 efficacy trials are recruiting HIV-negative volunteers right now. Connors told P-Values that several pharma and biotech companies are already collaborating with academic partners to develop N6 for potential clinical use.

Will N6 and other bNAbs play a practical role in global HIV control? A lab study testing seven bNAbs found that the CD4-focused antibody NIH45-46W neutralized 91 percent of 45 global HIV strains. Adding PGT128, a bNAb directed at the V3 loop of HIV’s envelope, crippled 96 percent of tested HIV strains. Supplementing that two-pronged attack with PGT121, another V3 loop grabber, neutralized all HIV strains tested. Perhaps N6 combined with just one more bNAb would protect CD4 cells from all HIV-1 strains.

But right now that approach would prove impractical as a vaccination strategy because large and costly vats of bNAbs would have to be brewed, delivered to big target populations, and injected (as things stand now) every few months. A phase 2 trial of PrEP with cabotegravir, the long-acting integrase inhibitor, is testing intramuscular shots given every 4 or 8 weeks. A PrEP bNAb duo that works when injected at longer intervals would hold a clear convenience advantage over cabotegravir, but potential costs remain unknown, and we have already ventured far into the realm of speculation.