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HIV vaccine

For HIV, Treatment is Prevention

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U=U

For almost four decades, researchers have worked tirelessly to find a cure for the human immunodeficiency virus (HIV), which causes AIDS. There’s still more work to do, but a recent commentary published in JAMA [1] by Anthony Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases, and his colleagues serves as a reminder of just how far we’ve come. Today, thanks to scientific advances, especially the development of effective antiretroviral therapy (ART), most people living with HIV can live full and productive lives. These developments have started to change how our society views HIV infection.

In their commentary, the NIH scientists describe the painstaking research that has now firmly established that people who take ART daily as prescribed, and who achieve and maintain an undetectable viral load (the amount of HIV in the blood), cannot sexually transmit the virus to others. To put it simply: Undetectable = Untransmittable (U=U).

The U=U message was introduced in 2016 by the Prevention Access Campaign, an international health equity initiative that aims to help end the HIV epidemic and HIV-related social stigma. The major breakthrough in combination ART regimens, which successfully reduced viral loads for many HIV patients, came over 20 years ago. But their importance for HIV prevention wasn’t immediately apparent.

There’d been some hints of U=U, but it was the results of the NIH-funded HIV Prevention Trials Network (HPTN) 052, published in The New England Journal of Medicine [2] in 2011, that offered the first rigorous clinical evidence. Among heterosexual couples in the randomized clinical trial, no HIV transmissions to an uninfected partner were observed when ART consistently, durably suppressed the virus in the partner living with HIV.

The data provided convincing evidence that ART not only treats HIV but also prevents the sexual transmission of HIV infection. The public health implications of what’s sometimes referred to as “treatment as prevention” were obvious and exciting. In fact, the discovery made Science’s 2011 list of top 10 Breakthroughs of the Year .

Three subsequent studies, known as PARTNER 1 and 2 and Opposites Attract, confirmed and extended the findings of the HPTN 052 study. All three showed that people with HIV taking ART, who had undetectable HIV levels in their blood, had essentially no risk of passing the virus on to their HIV-negative partners.

Of course, the success of U=U depends on people with HIV having the needed access to health care and taking their medications as prescribed every day of their lives [3]. ART works by preventing the virus from making more copies of itself. It’s important to note that achieving an undetectable viral load with treatment can take time—up to 6 months. Viral load testing should be performed on a regular basis to ensure that the virus remains at undetectable levels. If treatment is stopped, the virus typically rebounds within a matter of weeks. So, strict adherence to ART over the long term is absolutely essential.

Practically speaking, though, ART alone won’t be enough to end the spread of HIV, and other methods of HIV prevention are still needed. In fact, we’re now at a critical juncture in HIV research as work continues on preventive vaccines that could one day bring about a durable end to the pandemic.

But for now, there are more than 35 million people worldwide who are HIV positive [4]. With currently available interventions, experts have predicted that about 50 million people around the world will become HIV positive from 2015 to 2035 [5]. Work is proceeding actively on the vaccine, and also on ways to totally eradicate the virus from infected individuals (a “cure”), but that is proving to be extremely challenging.

Meanwhile, with continued advances, including improved accessibility to testing, adherence to existing medications, and use of pre-exposure prophylaxis (PrEP) in high risk individuals, the goal is to reduce greatly the number of new cases of HIV/AIDS.

References:

[1] HIV Viral Load and Transmissibility of HIV Infection: Undetectable Equals Untransmittable. Eisinger RW, Dieffenbach CW, Fauci AS. JAMA. 2019 Jan 10.

[2] Prevention of HIV-1 infection with early antiretroviral therapy. Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, Hakim JG, Kumwenda J, Grinsztejn B, Pilotto JH, Godbole SV, Mehendale S, Chariyalertsak S, Santos BR, Mayer KH, Hoffman IF, Eshleman SH, Piwowar-Manning E, Wang L, Makhema J, Mills LA, de Bruyn G, Sanne I, Eron J, Gallant J, Havlir D, Swindells S, Ribaudo H, Elharrar V, Burns D, Taha TE, Nielsen-Saines K, Celentano D, Essex M, Fleming TR; HPTN 052 Study Team. N Engl J Med. 2011 Aug 11;365(6):493-505.

[3] HIV Treatment (U.S. Department of Health and Human Services)

[4] HIV/AIDS (World Health Organization)

[5] Effectiveness of UNAIDS targets and HIV vaccination across 127 countries. Medlock J, Pandey A, Parpia AS, Tang A, Skrip LA, Galvani AP. Proc Natl Acad Sci U S A. 2017 Apr 11;114(15):4017-4022.

Links:

HIV/AIDS (National Institute of Allergy and Infectious Diseases/NIH)

Treatment as HIV Prevention (NIAID)

Prevention Access Campaign

Anthony S. Fauci (NIAID)

HIV Prevention Trials Network (Durham, NC)


Simplifying HIV Treatment: A Surprising New Lead

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CD4+ cells in the gut

Caption: PET/CT imaging reveals a surprisingly high concentration (yellow, light green) of key immune cells called CD4 T cells in the colon (left) of an SIV-infected animal that received antibody infusions along with antiviral treatment. Fewer immune cells were found in the small intestine (right), while the liver (lower left) shows a high level of non-specific signal (orange).
Credit: Byrareddy et al., Science (2016).

The surprising results of an animal study are raising hopes for a far simpler treatment regimen for people infected with the AIDS-causing human immunodeficiency virus (HIV). Currently, HIV-infected individuals can live a near normal life span if, every day, they take a complex combination of drugs called antiretroviral therapy (ART). The bad news is if they stop ART, the small amounts of HIV that still lurk in their bodies can bounce back and infect key immune cells, called CD4 T cells, resulting in life-threatening suppression of their immune systems.

Now, a study of rhesus macaques infected with a close relative of HIV, the simian immunodeficiency virus (SIV), suggests there might be a new therapeutic option that works by a mechanism that has researchers both excited and baffled [1]. By teaming ART with a designer antibody used to treat people with severe bowel disease, NIH-funded researchers report that they have been able to keep SIV in check in macaques for at least two years after ART is stopped. More research is needed to figure out exactly how the new strategy works, and whether it would also work for humans infected with HIV. However, the findings suggest there may be a way to achieve lasting remission from HIV without the risks, costs, and inconvenience associated with a daily regimen of drugs.


AIDS Vaccine Research: Better By Design?

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OD-GT8 60mer

Caption: eOD-GT8 60mer nanoparticle based on the engineered protein eOD-GT8. Yellow shows where eOD-GT8 binds antibodies; white is the protein surface outside the binding site; light blue indicates the sugars attached to the protein; dark blue is the nanoparticle core to which eOD-GT8 has been fused.
Credit: Sergey Menis and William Schief, The Scripps Research Institute

A while ago, I highlighted a promising new approach for designing a vaccine against the human immunodeficiency virus (HIV), the cause of AIDS. This strategy would “take the immune system to school” and teach it a series of lessons using several vaccine injections—each consisting of a different HIV proteins designed to push the immune system, step by step, toward the production of protective antibodies capable of fending off virtually all HIV strains. But a big unanswered question was whether most people actually possess the specific type of precursor immune cells that that can be taught to produce antibodies that kill HIV.

Now, we may have the answer [1]. In a study published in the journal Science, a research team, partly supported by NIH, found that the majority of people do indeed have these precursor cells. While the total number of these cells in each person may be low, this may be all that’s needed for the immune system to recognize a vaccine. Based in part on these findings, researchers plan to launch a Phase 1 clinical trial in human volunteers to see if their latest engineered protein can find these precursor cells and begin coaxing them through the complicated process of producing protective antibodies.


Vaccine Research: New Tactics for Tackling HIV

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HIV-infected Immune Cell

Caption: Scanning electron micrograph of an HIV-infected immune cell.
Credit: National Institute of Allergy and Infectious Diseases, NIH

For many of the viruses that make people sick—think measles, smallpox, or polio—vaccines that deliver weakened or killed virus encourage the immune system to produce antibodies that afford near complete protection in the event of an exposure. But that simple and straightforward approach doesn’t work in the case of human immunodeficiency virus (HIV), the virus that causes AIDS. In part, that’s because our immune system is poorly equipped to recognize HIV and mount an attack against the infection. To make matters worse, HIV has a habit of quickly mutating as it multiplies.That means, in order for an HIV vaccine to be effective, it must induce antibodies capable of fighting against a wide range of HIV strains. For all these reasons, the three decades of effort to develop an HIV vaccine have turned out to be enormously challenging and frustrating.

But now I’m pleased to report that NIH-funded scientists have taken some encouraging strides down this path. In two papers published in Science [1, 2] and one in Cell [3], researchers presented results of animal studies that support what most vaccine experts have come to suspect: the immune system is in fact capable of producing the kind of antibodies that should be protective against HIV, but it takes more than one step to get there. In effect, a successful vaccine strategy has to “take the immune system to school,” and it requires more than one lesson to pass the final exam. Specifically, what’s needed seems to be a series of shots—each consisting of a different engineered protein designed to push the immune system, step by step, toward the production of protective antibodies that will work against virtually all HIV strains.