A demonstrator holds up paper dolls, which were usedas message boards for people to write their thoughts on female condoms during the 19th International AIDS Conference in Washington, DC on July 24.

 

In Pursuit of an “AIDS-Free Generation”

Published Tuesday, July 10, 2012  on AMFAR.org

CLICK HERE to read original article.

 

 CLICK HERE to read original article on USAToday.com

WASHINGTON, D.C. – There are no scientific reasons the world can’t chart a path, albeit a difficult one, toward the world’s first AIDS-free generation, a top federal health official said Sunday.

 

“There is no excuse scientifically to say we cannot do it,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, speaking to the media at AIDS 2012, an international AIDS conference, which began here Sunday. “What we need now is the political and organizational will to implement what science has given us.”

The challenges of the AIDS pandemic are great, Fauci said. Worldwide, the disease has claimed more than 30 million lives, and 34 million people today are infected withHIV, the virus that causes the disease. About 2.5 million people worldwide still die each year, Fauci said.

• STORY: Begin HIV treatment sooner, experts say

Yet scientists are talking enthusiastically about recent discoveries that, when combined, have the potential to dramatically curtail new infections. Last week, leading researchers called for a new push to cure the disease. In another landmark finding that Fauci described as a “slam-dunk, out of the ballpark,” researchers last year showed that getting an HIV-positive patient’s virus under control makes that person virtually non-contagious.

 

That suggests that getting proper treatment to more people with HIV — 20% of whom don’t know they are infected — could be a powerful tool to stop the spread of the disease, Fauci said. Most new infections are spread by people who do not realize they have the disease, he said.

Turning the tide “is not going to happen spontaneously,” Fauci said. “It’s going to require purpose and commitment.”

Bill Gates, co-founder of the Bill & Melinda Gates Foundation, a major funder of AIDS research, is more skeptical. “We don’t have the tools” to end the AIDS pandemic today, Gates said at the conference Monday. While he’s impressed with research toward a vaccine, he said the best prevention strategy available today is voluntary, medical male circumcision, which can reduce a man’s risk of infection by 60%.

His foundation also has funded research into microbicide gels for women to use before sex. And he said he was enthusiastic about microbicidal rings, which could potentially provide long-lasting protection.

A mantra among AIDS advocates now is “seek, test, treat and retain,” said Nora Volkow, director of the National Institute on Drug Abuse. Public health officials want to test undiagnosed patients for HIV, treat their disease and retain them in care.

And while those challenges are daunting, Fauci noted that the USA has always led in the fight against AIDS. The National Institutes of Health has spent $50 billion on AIDS since 1982.

And the USA has succeeded in other difficult circumstances before — such as providing AIDS drugs to Africa. Fauci noted that “naysayers” were doubtful about PEPFAR, the President’s Emergency Plan for AIDS Relief, a $15 billion effort launched in 2003 byGeorge W. Bush, after consultation from Fauci.

At that time, only 50,000 people in the developing world had access to anti-retroviral therapy, the drug cocktails credited with transforming AIDS from a death sentence into a chronic disease. Since then, PEPFAR — which received an additional $48 billion in funding in 2008 — has provided AIDS therapy to nearly 4 million people. The program also is credited with preventing HIV infection in 200,000 babies by providing drugs to 660,000 HIV-infected mothers.

PEPFAR must be reauthorized by Congress next year. And while many are focused on cutting the federal budget, Fauci said PEPFAR has always had support from both Republicans and Democrats. “I can’t imagine not authorizing an overwhelming success,” Fauci said.

 Called segment of population most in need of prevention, treatment help

CLICK HERE to read the full article on WashingtonTimes.com

Black men who are gay or bisexual are “at the center” of the U.S. HIV/AIDS epidemic and should be a primary focus of testing, service and treatment efforts, a federal official and advocates said Wednesday.

Black men who have sex with men (MSM) account for one in four new HIV infections, even though they represent only one in 500 Americans, the Black AIDS Institute said in its new report, “Back of the Line: The State of AIDS Among Black Gay Men in America 2012.”

This infection rate climbs quickly with age for these men: The odds of a black MSM becoming infected with HIV is about 8 percent at age 20 and nearly 60 percent by age 40.

Moreover, unless they receive treatment, black MSM “are significantly less likely to be alive three years after testing HIV-positive,” when compared to white MSM, said the report.

Black MSM “continue to be first in line when it comes to need, but remain at the back of the line when it comes to assistance,” said Phill Wilson, founder and executive director of the Black AIDS Institute.

Black MSM “are not simply a fringe group in the fight against HIV/AIDS,” said Dr. Fenton. “They are, in fact, at the center of the nation’s epidemic, and we cannot achieve an AIDS-free generation, or the end of AIDS in the United States, unless we make major inroads in the fight against HIV among black gay men.”

Panelists talked about stigma, homophobia and other heightened risk factors for black MSM.

Research indicates that black MSM “are no more likely to engage in HIV-related risk behaviors than other MSM,” said Ernest Hopkins, chairman of the National Black Gay Men’s Advocacy Coalition and director of legislative affairs at the San Franciso AIDS Foundation.

But they are associated with risk factors such as early sexual experience, having older sex partners, being molested as a child, being incarcerated, growing up in poverty, homelessness and suffering discrimination, saidMr. Hopkins.

The U.S. Food and Drug Administration (FDA) announced it has approved the drug combination of 300 mg tenofovir and 200 mg emtricitabine (TDF/FTC; brand name Truvada) for daily use by uninfected adults to help prevent the sexual acquisition of HIV. TDF/FTC has been commercially available as an HIV treatment since 2004. This is the first time any drugs have been approved for the prevention of sexually acquired HIV infection.

Below is a statement for attribution to Dr. Kevin Fenton, Director, CDC National Center for HIV/AIDS, Viral Hepatitis, STD & TB Prevention:

 

With 50,000 new HIV infections in the United States each year, additional prevention methods are urgently needed. The Centers for Disease Control and Prevention applauds the U.S. Food and Drug Administration’s decision to approve the use of Truvada (a combination of 300 milligrams of tenofovir and 200 milligrams of emtricitabine) to reduce the risk of acquiring HIV. We believe this is an important step that should help ensure that physicians and patients receive the detailed information and educational materials needed to most effectively use this prevention strategy.

If delivered effectively and targeted to those at highest risk, pre-exposure prophylaxis (PrEP) could play an important role in our response to the HIV epidemic. Strong research evidence indicates that PrEP, when used consistently, is safe and effective at reducing the risk of acquiring HIV sexually. Last year, the Centers for Disease Control and Prevention provided interim guidance for gay and bisexual men who may be considering the use of PrEP, and soon will publish similar guidance for heterosexual men and women. Key considerations for the use of PrEP include:

• PrEP will not be right for everyone, but for some individuals at high risk for HIV infection, it may provide an important additional prevention tool.
• PrEP must be used consistently to be effective, as the level of protection has been shown to be closely related to levels of medication adherence.
• PrEP should not be thought of a stand-alone solution. It should be provided as part of a comprehensive package of prevention services, including counseling regarding risk reduction and the importance of adherence to daily doses of PrEP medication, ready access to condoms, and diagnosis and treatment of sexually transmitted infections.
• Individuals using PrEP must receive initial and regular HIV testing to confirm they do not have HIV infection, and be monitored for potential side effects.

CDC is also leading the development of more detailed U.S. Public Health Service guidelines on the use of PrEP as part of comprehensive HIV prevention programs, which we anticipate will be published later this year.

Let’s Stop HIV Together, the Centers for Disease Control and Prevention’s (CDC) new HIV awareness and anti-stigma campaign launching nationwide today.

The campaign gives voice to people living with HIV from all walks of life, alongside their friends and family members. As part of the campaign, these individuals share their personal stories and call on everyone to join the fight against the disease. Let’s Stop HIV Together highlights the fact that HIV touches every corner of American society and that people with the infection are part of the fabric of our families and valued members of our communities. Click here to watch the campaign video:  http://www.youtube.com/watch?v=FRF5p96JD9k&feature=youtu.be.  Please also visit www.ActAgainstAIDS.org to download all campaign materials, view and share the campaign videos and PSAs, and share your personal stories about how you, your friends, and your colleagues are stopping HIV together.

Let’s Stop HIV Together encourages everyone to:

• Get the facts – Learn the basics of HIV transmission and prevention.
• Get tested – CDC recommends that every adult and adolescent get tested at least once in his or her lifetime, and those at increased risk (for example, men who have sex with men, and individuals with new or multiple sexual partners) get tested at least once a year.
• Get involved – Encourage friends and loved ones to get tested and speak out against the stigma and complacency that help fuel the spread of HIV.

More than three decades after the first reported AIDS cases, HIV is still a crisis in the United States.  Approximately 50,000 Americans become newly infected each year, and an estimated 1.1 million people are now living with HIV. Yet, nearly one in five of these individuals does not know that they are infected.

The new campaign will appear in national print and online ads, television and radio public service announcements (PSAs), billboards and other outdoor advertising venues, and will be the focus of a national media relations effort to generate print and broadcast news stories.

Outlined below are several ways you – as a partner in HIV prevention – can help support this important campaign. Your efforts can help CDC extend the reach of these important campaign messages through your organization’s communication channels online and in your community.

Online
Support the campaign online:

• Like the Act Against AIDS Facebook page, sharing or responding to our posts, and directing your followers to check out our page and our website.
• Here’s an example Facebook post your organization can use:
• Check out CDC’s new national HIV awareness campaign, “Let’s Stop HIV Together.” The campaign features stories of people living with HIV supported by their loved ones and friends. Share your thoughts on CDC’s Act Against AIDS Facebook page, www.facebook.com/ActAgainstAIDS.
• Share your story online about how you or your organization is working to fight HIV (www.ActAgainstAIDS.org).

• Post about it.  Share the news about the new campaign throughout your network via an e-mail or posting on your organization’s website.
• Download digital banner ads and badges from our campaign website to add to your organization’s website.
• Tweet about it.  Spread the word about the campaign through Twitter by using the campaign hashtag #StopHIVTogether and by visiting us on the Act Against AIDS Twitter page @TalkHIV.
• Example campaign tweets:
• CDC is launching a new national #HIV campaign to raise awareness and fight stigma. http://bit.ly/aoS6eS #StopHIVTogether

In your community
Support the campaign in your community:

• Use the campaign materials in your local area.  Request printed posters, palm cards and brochures from CDC to distribute at community events and to provide to local venues in your city by sending an e-mail request to ActAgainstAIDS@cdc.gov.
• CDC will provide a limited quantity of already printed materials; additional items can be downloaded and printed from www.ActAgainstAIDS.org.
• Co-brand the campaign materials or advertisements with your organization’s logo. For more information about cobranding, please send an email to ActAgainstAIDS@cdc.gov.
• Incorporate Let’s Stop HIV Together messages into community events and educational presentations, underscoring the importance of fighting stigma and increasing awareness about HIV and how to prevent infection.
• Talk about Let’s Stop HIV Together and the importance of HIV prevention with your colleagues, family and friends.

Please visit www.ActAgainstAIDS.org to download all campaign materials, view and share the campaign videos and PSAs, and share your personal stories about how you, your friends, and your colleagues are stopping HIV together.

How have recent data on the antiretroviral drug Truvada and its possible approval as an HIV prevention drug affected the design of AIDS vaccine trials?

Several novel strategies have in recent years shown promise in preventing HIV infection (see VAX July 2011Spotlight article, An Antiretroviral Renaissance). Among these is pre-exposure prophylaxis, or PrEP—the administration of antiretrovirals (ARVs) either orally or topically to HIV-uninfected individuals.

One of those studies, known as iPrEx, revealed that Truvada—a combination of the ARVs tenofovir and emtricitabine—was 44% effective in preventing HIV infection among nearly 2,500 men and transgendered women who have sex with men. The study, which was conducted in six countries including the US, prompted Truvada’s maker, Gilead Sciences, to apply for regulatory approval from the US Food and Drug Administration (FDA) to expand the use of ARV as a therapy to prevent HIV acquisition, making it the first antiretroviral drug to be considered for such use.

In June, an FDA advisory panel voted in favor of using Truvada as a preventive measure for HIV-uninfected men, the uninfected partners of those with HIV, and other at-risk individuals. The FDA is expected to rule on Gilead’s application in September.

Truvada could undoubtedly help some high-risk communities curb HIV transmission. Yet its approval could also present significant challenges to current and future studies evaluating other novel HIV prevention tools, not least AIDS vaccines. Even before the FDA took up Gilead’s application, AIDS vaccine researchers were discussing how best to deal with the ethical and scientific conundrums kicked up by the successes of PrEP.

In fact, those successes have had immediate implications for the AIDS vaccine trial known as HVTN505. This trial is currently enrolling 2,200 men who have sex with men (MSM) in the US who are circumcised and who have not been previously exposed to a common cold virus known as adenovirus serotype 5 (Ad5), a modified version of which is being used as the vector that delivers the active ingredients of the vaccine under evaluation (see VAX Sep. 2011 Global News). The Phase II trial has already signed up about 1,800 MSM and should meet its enrollment target soon. It is designed to determine if a DNA vaccine candidate followed by an Ad5 vector-based vaccine candidate in a prime-boost regimen is effective in either blocking HIV acquisition or lowering viral load among individuals who become HIV-infected through natural exposure despite vaccination.

When the results of the iPrEx study were unveiled in November 2010, the Seattle-based HIV Vaccine Trials Network (HVTN)—which is conducting the trial—consulted nearly 800 trial participants, scientists, community leaders, and other stakeholders to determine whether PrEP should be offered to some or all of the enrollees and, if the drug were offered, how participants should be monitored during and after the trial.

While studying the effect of the vaccine candidate remains the main focus of the study, trial organizers, after consultations with stakeholders, are providing volunteers information about PrEP in periodic risk-reduction counseling sessions that are standard in HIV prevention trials. They are also monitoring PrEP use among trial participants in two different ways. Trial participants who voluntarily choose to use PrEP are now being asked to report their PrEP use on a regular basis. To supplement this self-reporting tool, trial sites will also be analyzing the blood plasma levels of volunteers in order to obtain additional data on PrEP use among participants.

Should the FDA approve Truvada for the prevention of HIV—and the PrEP drug become a standard of care in some high-risk populations—it could further impact the design of AIDS vaccine trials.

Vaccine vs. PrEP

Not all the questions regarding the impact of PrEP have to do with ethics. For instance, if the HVTN505 trial shows that the vaccine regimen being evaluated is effective in reducing HIV transmission, it could raise questions about what part of the observed protection was due solely to the vaccine. This in turn could complicate efforts to determine the true efficacy of the vaccine. But researchers do not believe that PrEP use will cloud their results, since only a small percentage of trial participants are thought to be using Truvada and they are spread randomly between the vaccinated and placebo arms of the trial. The assumption could therefore be fairly made that any protective effect observed in the study can be attributed to the vaccine.

Researchers say the emergence of PrEP regimens, such as Truvada, will also likely mean that future AIDS vaccine trials will need to be larger and more expensive, particularly if a vaccine is studied in concert with PrEP. For instance, should a trial seek to evaluate the efficacy of a partially effective vaccine candidate combined with oral PrEP, it would require multiple arms to determine whether the overall efficacy of this combination strategy is greater than that of PrEP alone, the vaccine candidate alone, or a placebo (see VAX Sep. 2011 Primer on Understanding the Rationale for Combination Prevention Trials). With funds for HIV prevention research in short supply these days, that may well prove to be the most disruptive effect of PrEP’s recent successes.

 

 

People diagnosed with HIV—the human immunodeficiency virus that without treatment develops into AIDS—take antiviral medications to control the infection that attacks their immune system.

 

Now, for the first time, adults who do not have HIV but are at risk of becoming infected can take a medication to reduce the risk of sexual transmission of the virus.

 

The Food and Drug Administration (FDA) has approved the new use of Truvada—to be taken once daily and used in combination with safer sex practices—to reduce the risk of sexually acquired HIV-1 infection in adults who do not have HIV but are at high risk of becoming infected. (HIV-1 is the most common form of HIV.)

 

In two large clinical trials, daily use of Truvada was shown to significantly reduce the risk of HIV infection

 

• by 42 percent in a study sponsored by the National Institutes of Health (NIH) of about 2,500 HIV-negative gay and bisexual men and transgender women, and
• by 75 percent in a study sponsored by the University of Washington of about 4,800 heterosexual couples in which one partner was HIV positive and the other was not.

 

Debra Birnkrant, M.D., director of the Division of Antiviral Products at FDA, explains that Truvada works to prevent HIV from establishing itself and multiplying in the body. She notes that while this is a new approved use, Truvada is not a new product. It was approved by FDA in 2004 for use in combination with other medications to treat HIV-infected adults and children over 12 years old.

 

“In the 80s and early 90s, HIV was viewed as a life-threatening disease; in some parts of the world it still is. Medical advances, along with the availability of close to 30 approved individual HIV drugs, have enabled us to treat it as a chronic disease most of the time,” Birnkrant says.

 

“But it is still better to prevent HIV than to treat a life-long infection of HIV,” she says.

 

Birnkrant stresses that Truvada is meant to be used as part of a comprehensive HIV prevention plan that includes consistent and correct condom use, risk reduction counseling, regular HIV testing, and treatment of any other sexually-transmitted infections. Truvada is not a substitute for safer sex practices, she says.

 

CLICK HERE to read an article about the approval from CBS.com

 

 

 

 

 

• Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana

http://natap.org/2012/HIV/071212_05.htm

• 3 Newly Published PrEP Studies: Preexposure Prophylaxis for HIV Infection among African Women

http://natap.org/2012/HIV/071212_04.htm

• Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women 

http://natap.org/2012/HIV/071212_03.htm

• Preexposure Prophylaxis Case Studies for HIV Prevention

http://natap.org/2012/HIV/071212_02.htm

• Preexposure Prophylaxis for HIV (PrEP)- Where Do We Go from Here? Editorial 

http://natap.org/2012/HIV/071212_01.htm

 

Potential cause of HIV-associated dementia revealed
	“HIV decreases BDNF in WIHS women……BDNF is critical for neuronal survival……recent data have shown a relationship between BDNF in blood and Alzheimer’s disease [20] and age-related cognitive impairment…….The research team found that even though HIV does not infect neurons, it tries to stop the brain from producing a protein growth factor – mature brain derived neurotrophic factor (mature BDNF)……acts like “food” for brain neurons. Reduced mature BDNF results in the shortening of the axons and their branches that neurons use to connect to each other, and when they lose this communication, the neurons die…….serum BDNF could be a predictor of risk for the development of neurological signs in HIV-positive individuals. Our findings…….provide initial evidence in support of this hypothesis and suggest this neurotrophin (BDNF) as a possible biomarker for HIV dementia…..Mocchetti believes that HIV stops production of mature BDNF because that protein interferes with the ability of the virus to attack other brain cells. It does this through the potent gp120 envelope protein that sticks out from the viral shell – the same protein that hooks on to brain macrophages and microglial cells to infect them. “In earlier experiments, when we dumped gp120 into neuronal tissue culture, there was a 30-40 percent loss of neurons overnight. That makes gp120 a remarkable neurotoxin.”” “The findings suggest a possible therapeutic intervention…….to use a small molecule to block the p75NTR receptor that proBDNF uses to kill neurons. A small molecule like that could get through the blood-brain barrier…….”If this works in HIV-dementia, it may also work in other brain issues caused by proBDNF, such as aging” How HIV Affects the Brain-new study: Human Immunodeficiency Virus Type 1 Alters Brain-Derived Neurotrophic Factor Processing in Neurons – (07/12/12) Journal of Neuroscience paper WASHINGTON – Researchers at Georgetown University Medical Center appear to have solved the mystery of why some patients infected with HIV, who are using antiretroviral therapy and show no signs of AIDS, develop serious depression as well as profound problems with memory, learning, and motor function. The finding might also provide a way to test people with HIV to determine their risk for developing dementia. They say the answer, published in the July 11 issue of the Journal of Neuroscience, may ultimately lead to a therapeutic solution that helps these patients as well as others suffering from brain ailments that appear to develop through the same pathway, including those that occur in the aged. “We believe we have discovered a general mechanism of neuronal decline that even explains what happens in some elderly folks,” says the study’s lead investigator, Italo Mocchetti, Ph.D., professor and vice chair of the department of neuroscience at Georgetown University Medical Center. “The HIV-infected patients who develop this syndrome are usually quite young, but their brains act old.” The research team found that even though HIV does not infect neurons, it tries to stop the brain from producing a protein growth factor – mature brain derived neurotrophic factor (mature BDNF) – that Mocchetti says acts like “food” for brain neurons. Reduced mature BDNF results in the shortening of the axons and their branches that neurons use to connect to each other, and when they lose this communication, the neurons die. “The loss of neurons and their connections is profound in these patients,” Mocchetti says. HIV-associated dementia occurs in two to three percent of HIV-infected patients using retroviral therapies, all of who appear to be otherwise healthy, and in 30 percent of HIV-positive patients who are not on medication. Mocchetti believes that HIV stops production of mature BDNF because that protein interferes with the ability of the virus to attack other brain cells. It does this through the potent gp120 envelope protein that sticks out from the viral shell – the same protein that hooks on to brain macrophages and microglial cells to infect them. “In earlier experiments, when we dumped gp120 into neuronal tissue culture, there was a 30-40 percent loss of neurons overnight. That makes gp120 a remarkable neurotoxin.” This study is the product of years of work that has resulted in a string of publications. It began when Mocchetti and his colleagues were given a grant from the National Institutes on Drug Abuse to determine whether there was a connection between the use of cocaine and morphine, and dementia. (A substantial number of HIV-positive patients have been or currently are intravenous drugs users.) They found that it was the virus that was responsible for the dementia, not the drugs, and so they set out to discover how the virus was altering neuronal function. Their scientific break came when the researchers were able to study the blood of 130 women who were enrolled in the 17 year-old, nationwide WIHS (Women’s Interagency HIV Study, directed at Georgetown by Mary Young, M.D.), which has focused on the effects of HIV in infected females. In one seminal discovery, Mocchetti and colleagues found that when there was less BDNF in the blood, patients were at risk of developing brain abnormalities. He published this finding in 2011 in the May 15 issue of AIDS (below). In this study, Mocchetti, Alessia Bachis, Ph.D., and their colleagues studied the brains of HIV-positive patients who had died, and who had developed HIV-associated dementia. They also found that neurons had shrunk, and that mature BDNF had substantially decreased. He and his colleagues then worked out the mechanism responsible for this destruction of neurons. Normally, neurons release a long form of BDNF known as proBDNF, and then certain enzymes, including one called furin, cleave proBDNF to produce mature BDNF, which then nurtures brain neurons. When uncut, proBDNF is toxic, leading to “synaptic simplification”, or the shortening of axons. It does this by binding to a receptor, p75NTR, that contains a death domain. “HIV interferes with that normal process of cleaving proBDNF, resulting in neurons primarily secreting a toxic form of BDNF,” Mocchetti says. The same imbalance between mature BDNF and proBDNF occurs as we age, he says, although no one knows how that happens. “The link between depression and lack of mature BDNF is also known, as is the link to issues of learning and memory. That’s why I say HIV-associated dementia resembles the aging brain.” Loss of mature BDNF has also been suggested to be a risk factor in chronic diseases such as Parkinson’s and Huntington’s diseases, Mocchetti says. The findings suggest a possible therapeutic intervention, he adds. “One way would be to use a small molecule to block the p75NTR receptor that proBDNF uses to kill neurons. A small molecule like that could get through the blood-brain barrier. “If this works in HIV-dementia, it may also work in other brain issues caused by proBDNF, such as aging,” Mocchetti adds. The finding also suggests that measuring proBDNF in HIV-positive patients may provide a biomarker of risk for development of dementia, he adds. “This finding is extremely important for both basic scientists and physicians, because it suggests a new avenue to understand, and treat, a fairly widespread cause of dementia,” Mocchetti says. —————– AIDS: 15 May 2011 HIV-1 decreases the levels of neurotrophins in human lymphocytes: “Serum levels of brain-derived neurotrophic factor (BDNF) were measured by an enzyme-linked immunosorbent assay in human samples collected between 1994 and 2007 at the Washington, District of Columbia site of the Women’s Interagency HIV Study…….Our main finding is that the serum of HIV-positive women is characterized by reduced levels of BDNF……This was confirmed by direct evidence that both R5 and X4 HIV-1 strains downregulate BDNF mRNA levels in T cells……recent data have shown a relationship between BDNF in blood and Alzheimer’s disease [20] and age-related cognitive impairment…….serum BDNF could be a predictor of risk for the development of neurological signs in HIV-positive individuals…….Our findings of an association between HIV infection and serum BDNF levels, and of lowered BDNF mRNA levels in infected T cells, provide initial evidence in support of this hypothesis and suggest this neurotrophin as a possible biomarker for HIV dementia. Additional studies are needed to validate our results and extend them to both sexes, as we examined a relatively small cohort of women individuals. Also, a link between BDNF and cognitive performance needs to be established.” aDepartment of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA bDepartment of Microbiology and Immunology, Institute of Human Virology, University of Maryland, Baltimore, USA cLaboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke/National Institute of Health, Bethesda, Maryland, USA dDepartments of Psychiatry and Psychology, University of Illinois at Chicago, Chicago, Illinois, USA eDepartment of Neurology, USA fDepartment of Medicine, Georgetown University Medical Center, Washington, District of Columbia, USA. Abstract Neurotrophins control cell survival. Therefore, we examined whether HIV-1 reduces neurotrophin levels. Serum of HIV-positive individuals exhibited lower concentrations of brain-derived neurotrophic factor (BDNF), but not of other neurotrophins, than HIV-negative individuals. In addition, R5 and X4 strains of HIV-1 decreased BDNF expression in T cells. Our results support the hypothesis that reduced levels of BDNF may be a ris Neurotrophins [1,2] are produced by immune organs and immunocompetent cells, including T cells [3] and macrophages [4], and are believed to play a role in various functions of the immune system, including lymphocyte proliferation [5,6]. Little is known about the effect of HIV-1 on neurotrophin levels. Loss of neurotrophin expression may impair the immune system and promote AIDS. In this study, we investigated whether HIV-1 reduces serum concentration of the neurotrophins and sought to establish a correlation between HIV infection and neurotrophin expression in T cells. Serum levels of brain-derived neurotrophic factor (BDNF) were measured by an enzyme-linked immunosorbent assay in human samples collected between 1994 and 2007 at the Washington, District of Columbia site of the Women’s Interagency HIV Study [7,8]. Because approximately 50% of these individuals were polydrug abusers, mainly cocaine, methamphetamine and heroin, a two-way analysis of variance (ANOVA) was used to examine a potential interaction between HIV-1 and drug use and to examine each factor independently. HIV-positive individuals exhibited significantly lower levels of BDNF compared with HIV-negative controls (Fig. 1a). Drug use significantly affected BDNF levels such that the amount of BDNF in the serum of HIV-positive drug users were higher than in HIV-positive nondrug users (Fig. 1a), suggesting that polydrug use may affect serum BDNF levels in HIV-1-positive individuals. There was no interaction between drug use and serostatus on BDNF levels (P > 0.33). Drugs of abuse [9] or HIV-1 may influence the expression of other neurotrophins. To test this hypothesis, we measured nerve growth factor (NGF) and neurotrophin-3 (NT-3) levels in the same samples. The two-way ANOVAs analyzing associations of HIV status and drug use on NGF (P = 0.516) and NT-3 (P = 0.382) were not statistically significant, and no evidence of interaction between HIV and drug use was observed for either outcome. Although we found a tendency toward lower average NGF levels in the serum of HIV-positive individuals compared with controls, the effect was not significant (P = 0.89) nor did polydrug use affect NGF levels (data not shown). Results for NT-3 levels were similarly not statistically significant (data not shown). The reduction of BDNF observed in HIV-1-positive individuals could be due to single nucleotide polymorphisms (SNPs) that alter intracellular packaging and secretion of BDNF [10]. rs6265 is a polymorphism in the BDNF gene that produces an amino acid substitution of valine to methionine in codon 66 (Val66Met); rs56164415 is located in the fifth of the seven noncoding exons of the BDNF gene [11] and appears to be moderately associated with substance abuse [12]. Therefore, these SNPs, either alone or in combination, might lead to a reduction in serum BDNF levels. To test this hypothesis, we examined the frequency of these polymorphisms in the same cohort, using DNA from the same sample of individuals. There was no significant difference in frequency of alleles in HIV individuals as compared with HIV-negative controls (rs6265, P = 0.83; rs56164415, P = 0.72). Therefore, mutation of the BDNF gene does not appear to account for difference in the levels of BDNF in these individuals. Contributing factors that may account for the decrease in serum BDNF in HIV-positive individuals are not easily defined. BDNF and other neurotrophins are produced by immune organs and immunocompetent cells [13], as well as platelets [14]. Thus, a decrease in the number of platelets may explain the lower levels of BDNF in HIV-1-positive individuals. To determine whether BDNF from platelets constitutes a significant fraction of serum BDNF, we examined which blood cell type expresses BDNF. We found that platelets and T cells exhibited comparable levels of BDNF expression (Fig. 1b). Thus, platelets account for only for a fraction of serum BDNF. Nevertheless, to more directly examine the effect of HIV-1 on BDNF, we examined the ability of HIV-1 to decrease BDNF expression in T cells. T lymphocytes were prepared from healthy donors and were infected with X4 (IIIB) or R5 (BaL) HIVs. BDNF mRNA levels were then quantified 24 h after the infection. We observed an approximately 50% decrease in BDNF mRNA levels by both HIV-1 strains (Fig. 1c), further suggesting that HIV-1 is capable of reducing the expression of this neurotrophin in T cells. Our main finding is that the serum of HIV-positive women is characterized by reduced levels of BDNF, but not of NGF or NT-3, irrespective of drug use status, suggesting that HIV-1 influences the expression of selected neurotrophins. This was confirmed by direct evidence that both R5 and X4 HIV-1 strains downregulate BDNF mRNA levels in T cells. These results may contribute new insights into our understanding of the immune dysregulation of AIDS. In fact, given the well known antiapoptotic effect of the neurotrophins for T cells [6,13], we may speculate that a decrease in BDNF could be among the mechanisms employed by HIV-1 to induce apoptosis of T cells. On the contrary, experimental evidence has shown an inverse correlation between levels of BDNF and CXCR4 [15] and CCR5 [16] expression. These coreceptors are crucial for HIV-1 infection [17]. Therefore, reduced levels of BDNF may be a risk factor for increasing HIV infection. HIV-1 also causes axonal injury, neuronal loss and dementia [18]. BDNF is critical for neuronal survival [19]. Blood neurotrophin levels have been used to investigate the role of the neurotrophins in the pathogenesis of various neurodegenerative diseases. In fact, recent data have shown a relationship between BDNF in blood and Alzheimer’s disease [20] and age-related cognitive impairment [21]. Therefore, serum BDNF could be a predictor of risk for the development of neurological signs in HIV-positive individuals. Our findings of an association between HIV infection and serum BDNF levels, and of lowered BDNF mRNA levels in infected T cells, provide initial evidence in support of this hypothesis and suggest this neurotrophin as a possible biomarker for HIV dementia. Additional studies are needed to validate our results and extend them to both sexes, as we examined a relatively small cohort of women individuals. Also, a link between BDNF and cognitive performance needs to be established.