Research offers a new approach to improving HIV vaccines

Researchers have identified a molecule that recognizes HIV and initiates an immune response. The findings could help improve the efficacy of HIV vaccines to prevent infection, they say. 

The study shows how a protein called polyglutamine-binding protein 1 (PQBP1) acts as a front-line sensor and is critical to initiating an immune response to HIV. When the PQBP1 encounters the virus, it starts a program that triggers an overall protective environment against infection and enhances the production of virus-specific antibodies. The research, which identified PQBP1 as a target for improving HIV vaccines, was published June 4 online ahead of print in the journal Cell.
'Vaccines work by teaching the immune system to react by mimicking a natural infection,' said lead author Sunnie Yoh, Ph.D., a postdoctoral fellow in the lab of Sumit Chanda, Ph.D., director of the Immunity and Pathogenesis Program at Sanford-Burnham. 'Designing a drug that mimics the interface between HIV and PQBP1 would allow an HIV vaccine to more effectively re-create an immune environment that mirrors real infection.'
'Current approaches to HIV vaccine development have thus far yielded little fruit, partly because of the lack of an effective vaccine adjuvant. Adjuvants promote a robust immune response to vaccines and are critical to eliciting long-lasting immunity,' said Chanda. 'Our study identifies a promising new target for a vaccine adjuvant that could advance the development of HIV vaccines and prevent infection.'
How it works
Although the major target of HIV infection is CD4+ T cells, dendritic cells are one of the first cell types to encounter HIV during sexual transmission. After HIV infects cells, its DNA forms an interface with PQBP1 in sentinel dendritic cells and initiates the immune response.
Dendritic cells control the innate immune response -- a generic, non-specific defense against pathogens. These cells also activate the adaptive immune response that generates highly specific antibodies that provide protective, long-lasting immunity. Both the innate and adaptive immune systems are necessary to provide an optimal immune response to vaccines.
'PQBP1 acts as a sentry for innate immune response to HIV. The development of a highly effective HIV vaccine will likely depend on both combining the correct immunogens, which are viral proteins, and unlocking the innate response, to establish long-lived protection,' said Chanda. 'Now that we know the gatekeeper, it will be much easier to find a key.'

This story is taken from Science Daily

Online hookup sites increase HIV rates in sometimes surprising ways

The introduction of Craigslist led to an increase in HIV infection cases of 13.5 percent in Florida over a four-year period, according to a new study. The estimated medical costs for those patients will amount to $710 million over the course of their lives, research shows.

Online hookup sites have made it easier for people to have casual sex -- and also easier to transmit sexually transmitted diseases. The new study measured the magnitude of the effect of one platform on HIV infection rates in one state, and offered a detailed look at the varying effects on subpopulations by race, gender and socio-economic status. Looking at the period 2002 to 2006, it found that Craigslist led to an additional 1,149 Floridians contracting HIV.
The work, 'Matching platforms and HIV Incidence: an empirical investigation of race, gender, and socio-economic status,' is forthcoming in Management Science.
The study 'underscores the need for broader communication and dissemination of the risks posed by the type of online matching platforms studied here,' notes Ritu Agarwal, a professor at the University of Maryland's Robert H. Smith School of Business and founding director of the Center for Health Information and Decision Systems (CHIDS), and Brad N. Greenwood, a 2013 Smith School Ph.D. and assistant professor at Temple University's Fox School of Business.
The study also found that the new HIV cases came disproportionately from one racial-ethnic group, African Americans, who accounted for some 63 percent of the new cases. 'That is a bit of paradox,' says Agarwal, 'because research suggests that the African American community is one which uses the Internet the least, even though the gap is narrowing.'
Greenwood described African Americans as suffering the effects of a 'double digital divide.' He said, 'Not only have studies shown there is lower utilization of the Internet for welfare-enhancing activities, but now there's evidence of utilization for negative activities as well.'
Craigslist phased rollout a 'natural experiment'
Craigslist's arrival in different cities and different counties at different times made it possible to isolate the effects of the matching platforms; the phased rollout amounted to a 'natural experiment.' (Other matching sites, like Grindr or Tinder, have tended to become available across broad areas all at once, although neither of those platforms existed when this study was done, and Craigslist remains the largest). Agarwal and Greenwood focused on whether there was a change in HIV cases in the first full calendar quarter after Craigslist's arrival in a county or city. For patient data, the researchers drew on a census that included data on some 12 million patients; omitting institutions that had no HIV cases or which were open for only part of the period studied, there were 223 hospitals in the sample.
There was also an increase in new HIV cases among Latinos and Caucasians -- although only intermittently statistically significant and not statistically different from each other. The lack of difference between Latinos and Caucasians was notable, as Latinos have a higher baseline rate of HIV infection. One explanation could be that fewer Latinos may have sought treatment. Or Florida's Latino community, which is especially large and well-off, may not be reflective of national trends.
Women, wealthier individuals susceptible
Another counterintuitive result was that more cases came from non-Medicaid patients, the wealthier patients, than from the population covered by the government program. That was the case even though the base rate of HIV infection is higher among lower-income citizens. 'It could be the case that higher-income people face a higher social penalty for engaging in casual, quasi-anonymous sex, and that the freedom of Internet anonymity changes their behavior more than it does for the less wealthy,' Agarwal suggested. 'Or it could be a byproduct of substantially better Internet access.' (Together with the finding for African Americans, that would suggest that degree of Internet access affects different sub-populations in different ways).
HIV prevention efforts tend to focus on the highest-risk populations, such as the economically disadvantaged, but public-health officials should be aware that online platforms may be 'changing the game,' says Agarwal.
Perhaps most surprising of all, given the relatively high rates of infection among bisexual and homosexual men, there was not a statistically significant difference in HIV infection rate increases across men and women.
It could be the case that homosexual men with HIV who used Craigslist were more likely to practice safe sex than infected heterosexuals, the authors speculated. Or matching platforms may lead to more homosexual activity by men who do not identify publically as homosexuals, who then spread the virus to their female partners. The question demands more research, the authors said.
Agarwal and Greenwood were careful to note that they weren't making a statement about the overall value of Craigslist. Nevertheless, the study offers a reminder of the downside of connectivity. 'While there is a general belief that connectivity is good on average, unfortunately 'on average' means that some people are going to benefit more and others are going to lose more,' Agarwal says. 'We need to better understand both the beneficial as well as the punitive effects of the Internet on individual and public health.'

This story is taken from Science Daily

Bacterial communities of female genital tract have impact on inflammation, HIV risk

The most common bacterial community in the genital tract among healthy South African women not only is significantly different from that of women in developed countries but also leads to elevated levels of inflammatory proteins, which could increase the risk of HIV infection, new research concludes. 

"Ours is the first study to identify a specific bacterial community in the genital tract of healthy women that is highly pro-inflammatory, and we show this community is common in the women we studied in South Africa," says Douglas Kwon, MD, PhD, of the Ragon Institute and the MGH division of Infectious Diseases, senior author of the report. "We also identified specific mechanisms by which the immune system senses these bacterial species and potential mechanisms linking that response to increased HIV susceptibility."
The authors note that, although inflammatory reactions in the female genital tract can prevent or eliminate many sexually transmitted infections, activation of the immune system paradoxically increases the risk that exposure to HIV will lead to infection. In the past, the bacterial population of the female tract was believed to be very simple and -- based on what was seen in white, premenopausal women -- dominated by a single Lactobacillus species. Since mild vaginal infections that alter the dominant microbial community can increase the risk of acquiring HIV and other sexually transmitted diseases, the researchers designed the current study to investigate whether differences in the genital microbial communities of healthy women might affect overall susceptibility to infection.
Analysis of genital samples from a group of 94 young black South African women -- who were HIV negative and had no disease symptoms -- revealed that only a minority had the sort of Lactobacillus-dominant bacterial communities commonly seen in U.S. women. The researchers grouped the samples they studied into four community types -- what they called cervicotypes -- based on the dominant bacterial species. The most common cervicotype among the study participants was very diverse, with low levels of Lactobacillus and no single dominant bacterial group.
To assess levels of immune activation in the study participants, the researchers measured levels of the immune system signaling molecules called cytokines in vaginal fluid samples and found significant individual differences -- as much as 1,000-fold in some cases. Elevated cytokines were not associated with active sexually transmitted infections or with factors such as sexual frequency or the use of condoms or hormonal contraceptives. Comparing cytokine levels among the cervicotypes revealed that the low-Lactobacillus, high-diversity communities were more than four times as likely to have elevated genital inflammatory cytokines. In fact, the presence of community was a better predictor of inflammation than was the presence of sexually transmitted diseases or other vaginal infections.
The researchers found that women with the highest levels of genital inflammation also had elevated levels of CCR5+ CD4+ T cells, the cells that are infected by HIV, in their genital tracts. "It has been shown that having a higher frequency of these HIV target cells at the site of exposure increases the risk of infection," says study lead author Melis Anahtar, an MD/PhD candidate in the Harvard/MIT Division of Health Sciences and Technology. "It's possible that treatments targeting specific genital bacteria could improve the effectiveness of measures -- such as antiretroviral vaginal gels -- designed to prevent HIV infection. In addition, finding that women with elevated genital inflammation may be three times more likely to become HIV-infected suggests that generally targeting the genital microbial population may further reduce risk."
An assistant professor of Medicine at Harvard Medical School, Kwon adds, "Understanding the impact of differences in the genital microbial population could also have implications for pregnant women and their infants. Some of the pro-inflammatory species that we found in our study were originally found in infected amniotic fluid and may contribute to the risk for premature birth and other complications of pregnancy." The research team is now investigating the specific mechanisms by which the immune system senses the presence of specific bacterial species in the female genital tract as well as examining the potential role of the broader microbial population, including viruses and fungi.

This story is taken from Science Daily

Health, social inequities drives HIV in young men who have sex with other men

Researchers sought to identify the factors associated with incident HIV infection among a cohort of racially/ethnically and socioeconomically diverse young, gay, bisexual and other men who have sex with men. Socioeconomic status is key driver of HIV seroconversion, they concluded. 

Their paper, "Incidence of HIV infection in Young Gay, Bisexual, and other YMSM: The P18 Cohort Study," published in the Journal of Acquired Immune Deficiency Syndromes (JAIDS), reports on data collected from 600 YMSM between the ages of 18 and 19 enrolled in the P18 Cohort. These participants were followed over a three-year period and received HIV testing and counseling as part of the study.
Over the study period, the cumulative incidence of HIV was 7.2% and HIV seroconversion was associated with perceived SES and race/ethnicity. HIV seroconversions were lower among White YMSM, compared with their Black and Hispanic/Latino counterparts. Also, HIV seroconversions were more likely among those who self-reported a perceived lower and middle/average SES (49% and 40%, respectively), compared to those who reported a higher perceived SES (12%).
"The data from our P18 Cohort Study demonstrate the social and structural inequities that continue to drive racial/ethnic disparities in HIV infections," said Perry N. Halkitis and Farzana Kapadia, the study investigators. "Assumptions about differences in sexual behavior along racial lines are fueling stereotypes and these stereotypes are detrimental to prevention efforts. We find that young Black men are not engaging in more sexual activity but experience more structural and social inequities than their White peers."
"In fact, our study findings show that socioeconomic status (SES) is key driver of HIV seroconversion; individuals who reported a lower perceived SES were more likely to seroconvert over the course of the study period. Moreover, in our cohort study, Black YMSM were more likely to be of lower SES and were also more likely to seroconvert," said Halkitis and Kapadia.
The confluence of these factors is particularly problematic as low SES individuals are more likely to reside in neighborhoods with higher levels of poverty, environments associated with lower access to effective health services, and higher level of untreated sexually transmitted infections (STIs) including HIV, conditions which have been shown to be inextricably connected to each other and also linked to increased risk for HIV acquisition and transmission. In the study residing in a high HIV prevalence neighborhood was associated with seroconversion.
In addition, younger average age at sexual debut with another man was also associated with a greater likelihood of HIV seroconversion. Specifically, YMSM who initiated sex with another man at or after the age of 14 were substantially less likely to seroconvert. This suggests that access to comprehensive sexual education programs that include components on sexuality education are warranted to bolster HIV prevention programming among adolescent and emerging adult YMSM.
"Taken together, these findings provide further evidence for the existence of significant racial/ethnic and SES related disparities in HIV incidence among YMSM. In addition, these findings suggest that for sexual minority men, effective HIV prevention programs will need to attend to not only behavioral factors, such as age of sexual debut, but also structural and social conditions that continue to place this new generation of YMSM at heightened risk for acquiring HIV," said Halkitis and Kapadia.
Future studies are needed to understand the relative contributions of economic, psychosocial, and structural factors that perpetuate racial/ethnic disparities in HIV incidence. Such information will aid in the strategic scale-up of existing interventions and the development of new ones aimed at addressing these inequities at multiple levels.

This story  is taken from Science Daily

Why HIV's cloak has a long tail

A small section of the envelope protein, located on the 'tail' of the HIV virus is necessary for the protein to be sorted into viral particles. Figuring out how to manipulate the envelope protein could help researchers design more effective vaccines, experts say. 

For HIV to spread from cell to cell, the viral envelope protein needs to become incorporated into viral particles as they emerge from an infected cell. Researchers led by Paul Spearman, MD, have found that a small section of the envelope protein, located on its "tail," is necessary for the protein to be sorted into viral particles.
The results are scheduled for publication in PNAS.
The finding could explain why the HIV envelope protein has an unusually long tail, an element that distinguishes it from similar viruses. The tail is required for HIV to infect and replicate in the cells it prefers: macrophages and T cells. The long tail is also thought to help HIV avoid the immune system, and figuring out how to manipulate it could help researchers design more effective vaccines.
Spearman is Chief Research Officer for Children's Healthcare of Atlanta and Nahmias-Schinazi Professor and Vice Chair of Research in Emory University School of Medicine's Department of Pediatrics. Co-author Eric Hunter, PhD is co-director of Emory's Center for AIDS Research and a Georgia Research Alliance Eminent Scholar.
Working with Spearman, postdoctoral fellow Mingli Qi, PhD, and colleagues previously found that a protein from host cells called Rab11-FIP1C is important for the envelope protein to become part of viral particles in the cells HIV prefers.
"The new paper shows that the protein we found is the key factor in determining envelope incorporation in T cells and macrophages," Spearman says. "Now we know the part of the envelope protein required, which is probably the part that binds to Rab11-FIP1C, and have more evidence that this pathway is really important for the virus."
HIV particles are marked by a relatively sparse level of Env protein, which is thought to help HIV avoid provoking the immune system. It may be possible to either interfere with or enhance HIV envelope incorporation in cells, Spearman says. Enhancing the process could make the vaccines his lab is designing, based on non-infectious virus-like particles, more potent. Conversely, interfering with envelope incorporation could be an antiviral drug target.

This story is taken from Science Daily