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HIV spreads through direct cell-to-cell contact

Despite over 30 years of research, many key aspects of how HIV, the causative agent of the acquired immune deficiency syndrome (AIDS) spreads are still not understood. One of these unresolved questions concerns the interactions between the virus with the environment in the human body.

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Microscopic recording and computer model of the interaction between infected cells (green) and non-infected cells (red) in collagen structures (grey). Credit: Oliver Fackler/Frederik Graw

The spread of pathogens like the human immunodeficiency virus (HIV) is often studied in a test tube, i.e. in two-dimensional cell cultures, even though it hardly reflects the much more complex conditions in the human body. Using cell culture systems, quantitative image analysis, and computer simulations, an interdisciplinary team of scientists from Heidelberg University has now explored how HIV spreads in three-dimensional tissue-like environments. The researchers’ results show that the tissue structure forces the virus to spread through direct cell-to-cell contact.

Despite over 30 years of research, many key aspects of how HIV, the causative agent of the acquired immune deficiency syndrome (AIDS) spreads are still not understood. One of these unresolved questions concerns the interactions between the virus with the environment in the human body.

Traditionally it has been assumed that infected cells release viral particles which then diffuse and eventually infect other cells. But it is also possible that viral particles are directly transferred from one infected cell to the next through close contact. Until now it was unknown which of these modes of transmission prevailed in tissue.

“Studies on HIV replication in the lab are mostly conducted in simple cell culture experiments in plastic dishes that do not reflect the complex architecture and heterogeneity of tissue”, explains study director Prof./Dr. Oliver Fackler of the Center for Integrative Infectious Disease Research (CIID) at Heidelberg University Hospital.

In their approach, the Heidelberg researchers took into account that the so-called CD4 T helper cells, the preferred cell type infected by HIV, are highly motile in their physiological environment. They used a novel cell culture system, in which a three-dimensional scaffold was generated with the help of collagen. This allowed for maintaining the cells’ mobility and monitoring primary CD4 T cells infected with HIV-1 in a tissue-like environment over the course of several weeks. Using this approach, the researchers measured a number of factors that characterize cell motility, virus replication, and the gradual loss of CD4 T helper cells.

“This yielded a very complex set of data that was impossible to interpret without the help from scientists of other disciplines,” explains Dr. Andrea Imle, who worked on the project during her PhD at the CIID.

In analyzing the data, the scientists who conducted the experiments collaborated with colleagues from the fields of image processing, theoretical biophysics and mathematical modeling. Together they were able to characterize the complex behavior of cells and viruses and simulate it on the computer. This made it possible to make important predictions on the key processes that determine HIV-1 spread in these 3D cultures, which were confirmed by subsequent experimentation. “Our interdisciplinary study is a good example of how iterative cycles of experimentation and simulation can help to quantitatively analyze a complex biological process,” states Prof./Dr. Ulrich Schwarz of the Institute for Theoretical Physics at Heidelberg University.

The data analysis revealed that the 3D environment of the cell culture system suppresses infection with a cell-free virus while simultaneously promoting direct virus transmission from cell to cell. “Our models allowed us to integrate short single-cell microscopy films with long-term cell population measurements and thereby to estimate the minimal time span required for cell-to-cell contacts to transmit infection,” explains Dr. Frederik Graw of the BioQuant Centre of Heidelberg University. The researchers hope that these findings will eventually lead to new therapeutic approaches in the treatment of HIV.

The research was conducted within the Collaborative Research Centre, “Integrative Analysis of Pathogen Replication and Spread”, (CRC 1129) funded by the German Research Foundation and supported by the Center for Modelling and Simulation in the Biosciences (BIOMS) of Heidelberg University. The results were published in Nature Communications.

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Researchers find diverse supportive partnerships among older gay men with and without HIV

Along with successful HIV treatments, it is known that the presence of social support impacts long-term survival among men living with HIV. However, little has been known about the types of supportive relationship among gay men in general, and none for those men living with HIV.

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Recent data reveals that gay men living with HIV report having supportive relationships with family, friends, or in informal relationships rather than with primary romantic partners, while gay men who are HIV negative report having relationships mainly with primary partners. Additionally, gay men living with HIV were more likely to report no primary or secondary supportive partnerships compared to men who are HIV negative.

The analysis was led by researchers at Georgetown University Medical Center. The finding appears in PLOS ONE.

Along with successful HIV treatments, it is known that the presence of social support impacts long-term survival among men living with HIV. However, little has been known about the types of supportive relationship among gay men in general, and none for those men living with HIV. Identifying the types of relationships could inform how they impact healthy aging among this community of men.

To fill this knowledge gap, Georgetown researchers conducted a study to identify the types of supportive relationships among middle-aged and older gay men living with and without HIV.

The average age of the men was 62, with similar numbers of HIV positive and negative men. The study participants were asked about any primary or secondary supportive relationships in their life. A primary relationship was defined as a long-term relationship that included marriage, other forms of legal commitment, or a strong romantic commitment between partners. Secondary relationships included close friends, biological family members, chosen family sexual partners, or former romantic partners.

“We recognized that little was known about the types of supportive relationships these men had — whether they were in committed romantic relationships, or if they relied on other non-romantic partnerships, such as family and friends,” said lead author Matthew Statz.

The large number of older gay men, regardless of their HIV status, who reported having neither a primary nor secondary supportive relationship was unexpected and concerning, according to Statz, adding that the importance of social support has been clearly established in the management of chronic illness, including HIV.

Statz says the study paves the way for further research into how these men’s partnerships impact all aspects of their mental and physical health, including implications for HIV viral suppression, frailty and loneliness.

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Self-testing trebles HIV testing rate among trans people

Despite increased vulnerability for trans people, they are seldom included in HIV testing or prevention research, and when they are their data is rarely presented separately from other priority groups such as gay and bisexual men.

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HIV self-testing could reduce the time between HIV infection and HIV diagnosis amongst trans people when compared to standard testing services, suggests new research in EClinicalMedicine.

The project was a collaboration between the London School of Hygiene & Tropical Medicine (LSHTM), University College London (UCL), and the Medical Research Council Clinical Trials Unit. It involved more than 100 trans men and trans women in England and Wales, and is the largest HIV self-testing trial in this community to be reported.

Participants were first randomised into two groups, one was given one self-test for HIV, the other group was offered a link to find standard testing services, and no self-tests. Some of the self-testing arm were randomised a second time and offered either repeat self-testing (an additional self-test every three months) or standard testing services. They were then followed up for two years.

More than 93% of participants in the self-testing group tested for HIV compared to 26% in the standard care group. HIV testing frequency was also increased by three times in the repeat testing group. Importantly there were no negative impacts on STI testing, but uptake of these services was very low across all arms in the trial.

Accompanying qualitative research led by the London School of Hygiene & Tropical Medicine revealed that the main reason HIV self-testing was so popular was because most sexual health services do not meet the needs of trans people. Services were reported to be often set-up and run in a way that did not recognise their unique needs.

Trans people are at increased risk of HIV and poor sexual health compared to other groups. They tend to test less often and have worse clinical outcomes when they are diagnosed with HIV.

The researchers say rolling out self-testing more widely and making sure it is accessible to trans people will increase HIV testing rates, and that staff require training aimed at improving the experiences of trans people when they access sexual health services.

Charles Witzel from LSHTM who led the qualitative study, said: “HIV has changed enormously. Thanks to effective treatment people with HIV can now live long and full lives. However, stigma and inappropriately designed services still act as a major barrier for individuals to access testing, the critical first step towards treatment for those with undiagnosed HIV and an important prevention opportunity for those who are HIV negative.

“Despite increased vulnerability for trans people, they are seldom included in HIV testing or prevention research, and when they are their data is rarely presented separately from other priority groups such as gay and bisexual men. Our research aimed to shed new light on how best to meet the HIV testing needs of trans men and trans women.”

HIV self-testing was legalised in the UK in 2014 but has not been made widely available on the NHS. Instead, self-testing has mostly been provided in fits and starts through pilot projects run by the voluntary sector and through a large clinical trial in England and Wales.

An HIV Self-testing Public Health Intervention (SELPHI) study was a large randomised trial of HIV self-testing in England and Wales which recruited men (cis and trans) and trans women, all who have sex with men.

The trial assessed whether providing free self-testing would increase HIV testing uptake and frequency, and if it had any impacts on STI testing.

Acceptability of the HIV self-test kit was very high: 97% found the instructions easy to understand, 97% found the test easy to use and 100% reported a good overall experience.

The qualitative peer-interview study sourced additional insights of the experiences of trans people when accessing HIV testing services, including HIV self-testing. It found staff working in sexual health clinics frequently misgendered them or provided stigmatising care which wasn’t respectful of their gender identity and/or their sexual orientation.

However, participants who had accessed sexual health services specifically designed for and by trans people said that these services were excellent.

Alison Rodger from UCL who co-led the trial said: “Put together, the results of our study clearly show the potential HIV self-testing has to meet some of the immediate HIV testing needs for trans men and trans women. This could mean more people with HIV receive treatment earlier which will have benefits for their health and will also reduce onward transmissions.”

Talen Wright, a peer researcher who worked on the study said. “It is critical that sexual health clinics adapt to be more inclusive, welcoming and to make sure they meet the diverse needs of these groups. Trans people must be actively included in these initiatives to make them successful.”

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Phl ends 2020 with 22 new HIV cases per day

The government figures may not show the real situation because HIV-related services – including testing – have been affected by Covid-19.

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The other pandemic.

HIV is still a major issue in the Philippines, with 22 Filipinos getting infected with the virus every day, at least as of December 2020 as reported to the HIV/AIDS & ART Registry of the Philippines (HARP) of the Department of Health (DOH).

The number is actually lower than 2019’s 35 new HIV cases per day. However, the new number may not represent the real HIV situation of the country since HIV-related services have been affected by Covid-19.

According to HARP, in December 2020, there were 1,076 confirmed HIV-positive individuals. Eighteen percent (198) had clinical manifestations of advanced HIV infection at the time of testing.

Ninety-five percent (1,017) of the reported cases were male, with a median age of 28 years old (age range: 2-74 years old). More than half of the cases (54%, 579) were 25-34 years old, and 25% (273) were 15-24 years old at the time of diagnosis.

More than a quarter (28%, 300) were from the National Capital Region (NCR). Region 7 (26%, 281), Region 4A (13%, 136), Region 3 (8%, 90), and Region 1 (6%, 68) comprised the top five regions with the most number of newly reported cases for this reporting period, together accounting for 81% of the total cases.

Sexual contact remained as the predominant mode of transmission (92%, 985). Among the newly reported cases acquired HIV through sexual contact, 62% (613) were through male to male sex, 24% (236) through males who have sex with both males and females, and 14% (136) through male to female sex. Further, 47 (4%) were infected through sharing of needles and three cases (<1%) were infected through mother-to-child transmission. Forty-one cases (4%) had no data on mode of transmission.

YOUTH IN FOCUS

273 (25%) cases were among youth 15-24 years old, and 94% were male. Ninety-seven percent (264) were infected through sexual contact (29 male-female sex, 182 male-male sex, 53 sex with both males and females), and four (1%) were infected through sharing of needles. Five (2%) cases had no data on the MOT.

There were 37 newly-reported adolescents with HIV. Of these, 3% (1) were 10-14 years old, 21% (8) were 15-17 years old, and 76% (28) were 18-19 years old. All adolescents were infected through sexual contact (7 male-female sex, 23 male-male sex, 7 sex with both males and females).

Further, five children were diagnosed with HIV in this reporting period. Three were infected through vertical (nee mother-to-child) transmission, while two had no data on MOT.

PREGNANT WOMEN WITH HIV

In December 2020, 13 cases were reported pregnant at the time of diagnosis. Eight cases were from Region 7, four cases from NCR, and one case from Region 3.

Reporting of pregnancy status at the time of diagnosis was included in the HARP only starting 2011.

From January to December 2020, there were 105 HIV positive women reported pregnant at the time of diagnosis. Of these, 35% (37) were from NCR, 19% (20) were from Region 4A, 16% (17) were from Region 3 and 30% (31) were from the rest of the country. The age of diagnosis ranged from 15 to 45 years old (median age: 25).

TRANSACTIONAL SEX

In December 2020, 11% (118) of the newly-diagnosed engaged in transactional sex. All were male and aged from 15 to 56 years old (median: 30 years old). Fifty- eight percent (68) of the males reported paying for sex only, 27% (32) reported accepting payment for sex only, and 15% (18) engaged in both.

People who engage in transactional sex are those who reported that they either pay for sex, regularly accept payment for sex, or do both. Reporting of transactional sex was included in the HARP only starting December 2012.

ACCESS TO TREATMENT

In December 2020, there were 639 people with HIV who were initiated on ART. The median CD4 count of these patients upon enrollment was 195 cells/mm .

By end-2020, a total of 47,977 PLHIV were on ART. Most (96%) were males. The age of reported cases ranged from 1 to 82 years (median: 32 years old). Ninety-five percent were on first line regimen, 4% were on second line, and 1% were on other line of regimen.

DEATHS AMONG PEOPLE WITH HIV

Highlighting that HIV still kills in the Philippines, in December 2020, there were 51 reported deaths due to any cause among people with HIV. Ninety-eight percent (50) were males. Five (10%) cases were 15-24 years old, 25 (49%) were 25-34 years old, 19 (37%) were 35-49 years old and 2 (4%) were 50 years and older.

Most (92%, 47) of those who died were reported to have acquired HIV through sexual contact (7 through sex with male and female, 24 through male-male sex, and 16 through sex with both males and females), and 8% (4) through sharing of infected needles.

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USC study measures brain volume differences in people with HIV

Brain scans of more than 1,200 HIV-infected adults across 5 continents show smaller volumes associated with lower white blood cell counts.

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Nearly 38 million people around the world are living with HIV, which, with access to treatment, has become a lifelong chronic condition. Understanding how infection changes the brain, especially in the context of aging, is increasingly important for improving both treatment and quality of life.

Researchers at the Mark and Mary Stevens Neuroimaging and Informatics Institute (USC Stevens INI), part of the Keck School of Medicine of USC, and other international NeuroHIV researchers, published one of the largest-ever neuroimaging studies of HIV. The researchers pooled magnetic resonance imaging (MRI) data from 1,203 HIV-positive individuals across Africa, Asia, Australia, Europe and North America. Their findings were published in JAMA Network Open, an open-access journal from the American Medical Association.

“Brain injury caused by HIV can lead to cognitive challenges, even in those receiving treatment,” says Talia Nir, PhD, a postdoctoral scholar at the USC Stevens INI’s Laboratory of Brain eScience (LoBeS) and first author of the study. “Establishing a common pattern of effects on the brain across different populations is a key step toward addressing those issues. The strength of this large dataset is that it is more representative of an era where treatment for HIV infection is widely available.”

The researchers looked at the link between blood plasma, which is routinely collected to monitor immune function and treatment response, and the volume of various structures in the brain. Lower white blood cell counts generally indicate that the immune system is being suppressed. Here, they found, for example, that participants with lower white blood cell counts also had less brain volume in the hippocampus and thalamus, parts of the brain’s limbic system involved in regulating memory, emotion and behavior.

These findings are important because they were largely derived from brain scans of individuals undergoing antiretroviral therapy–and they indicate that people receiving such treatment may exhibit a different brain injury signature compared to untreated individuals, which earlier studies tended to focus on. They highlight deficits in brain areas that are also vulnerable to age-related neurodegenerative diseases.

Accelerated atrophy of the hippocampus, the region that showed the most consistent effects in the study, is a hallmark of neurodegenerative diseases such as Alzheimer’s disease. Common age and HIV-related pathological processes, such as inflammation and blood brain barrier impairment, may accelerate age-related neurodegenerative processes.

“There are many factors that contribute to brain tissue loss and subsequent cognitive impairments as we age, and a person’s immune function is no exception,” says Neda Jahanshad, PhD, associate professor of neurology at the INI and one of the senior authors of the study. “Through these large-scale efforts, we’re beginning to understand the link between immune function and brain alterations in individuals living, and aging, with HIV.”

The analysis was a product of the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium’s HIV Working Group, established by Jahanshad and colleagues in 2013 to pool harmonized data across neuroimaging studies. The ENIGMA network at large, led by the institute’s associate director, Paul M. Thompson, PhD, unites neuroimaging researchers in 45 countries to study psychiatric disorders, neurodegenerative diseases and other aspects of brain function. In addition to housing ENIGMA, the USC Stevens INI is a powerhouse of neuroimaging and related science, known for large cohort analyses of imaging, genetics, behavioral, clinical and other data. Investigators from 13 existing HIV studies in the United States, France, Serbia, Australia, Thailand and South Africa collaborated on the JAMA Network Open paper.

Next, the team will analyze imaging data over time, including diffusion imaging data, another type of MRI data that maps the brain’s white matter pathways, to further understand how clinical markers of HIV infection affect the brain and the rate of neurodegeneration. As part of that ongoing work, they are inviting researchers around the world to join the ENIGMA-HIV Working Group.

“With a greater collaborative effort, we hope to be able to assess how genetic, environmental, lifestyle and treatment-related factors may further impact neurological outcomes,” Nir says.

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Reforming harmful laws, policies essential to end AIDS by 2030 in APAC

New report provides update on trends in the region and outlines the problematic laws and policies that continue to impact people living with HIV and key populations.

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Reforming laws and policies to ensure they are grounded in evidence and human rights is essential for an effective HIV response in Asia and the Pacific, says a new joint report by UNAIDS and the United Nations Development Programme (UNDP).

In 2015, 193 United Nations Member States agreed on the 2030 Agenda for Sustainable Development. This included a goal of ending the AIDS epidemic by 2030 and leaving no one behind through a multisectoral, rights-based, people-centred approach that addresses the determinants of health. Yet, legal and policy obstacles continue to undermine an effective HIV response in the region – particularly among vulnerable populations – limiting access to prevention, testing, treatment and care services.

The new report, Legal and policy trends impacting people living with HIV and key populations in Asia and the Pacific 2014–2019, provides a summary of recent key developments and outlines laws and policies that are hindering the response in the region. 

There is a large body of international evidence demonstrating that decriminalization and introduction of protective and enabling laws and policies result in significant health benefits to key populations by reducing stigma and supporting improved access to health and HIV services. In contrast, punitive laws and policies increase vulnerability to HIV and act as major barriers to health services for the people who need them most.

“Overall, we’re seeing uneven progress in efforts to achieve enabling laws and policies for HIV responses among key populations at higher risk of HIV. In some countries in the region the trend is towards a harsher and more punitive environment,” said Eamonn Murphy, UNAIDS Regional Director for Asia and the Pacific. “We hope that the evidence laid out in this report will lead to the necessary reforms of harmful laws and policies – the structural barriers that are essential to ending AIDS by 2030.”

The report highlighted comprehensive HIV legislation introduced in India and the Philippines as models for other countries to follow. These laws address multiple aspects of the national HIV response in a single law, including legal frameworks for prevention, testing, treatment, discrimination, legal redress mechanisms, national leadership and coordination mechanisms.

There has also been positive progress with the legal recognition of transgender people in Pakistan, which is vital to combat stigma and ensure people can enjoy equal access to health services. Pakistan’s Transgender Persons Act, enacted in 2018, has enabled transgender persons to freely express their gender according to their gender identity, and have that choice reflected in their legal identity.

While progress has been made, there have also been major setbacks. For instance, there has been a resurgence of harsh laws and policies for drug control in some Asian countries, whereby governments continue to apply criminal punishments rather than public health approaches. The report found that approaches which include the use of punitive laws against people who use drugs, impede the implementation of effective HIV prevention measures.

Criminalization of consensual same-sex sexual conduct between men also continues to impede HIV responses by deterring access to HIV testing and treatment services. In Asia and the Pacific, many countries currently have laws that criminalize same-sex sexual relations. The report points to the decision by India’s Supreme Court to decriminalize same-sex relations in 2018 as a landmark ruling for the region and globally. In many other countries, however, the legal environment for gay men and other men who have sex with men remains hostile.

Sex work in most countries in the region remains prohibited. In some countries, however, sex work is quasi-legal and subject to official oversight, or other types of regulation. Some countries in the region have seen regression to punitive laws and law enforcement practices, forcing sex workers to go underground and increasing vulnerability to HIV, loss of access to health services, violence, stigma and discrimination. 

Moving forward, the report acknowledges, legislators and policy-makers in the region seeking to advance a human rights-based approach to HIV are facing a highly challenging context. Nonetheless, the report reaffirms the critical importance of enabling laws and policies if countries are to reach the goal of ending AIDS by 2030.

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FDA approves first long-acting HIV treatment

The FDA in the US approved CABENUVA as the first once-monthly, long-acting injectable (LAI) for the treatment of HIV-1 infection in adults. CABENUVA consists of rilpivirine (Janssen) and cabotegravir (ViiV Healthcare Ltd.), for treating HIV-1 infection in adults.

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The FDA in the US approved CABENUVA as the first once-monthly, long-acting injectable (LAI) for the treatment of HIV-1 infection in adults. CABENUVA consists of rilpivirine (Janssen) and cabotegravir (ViiV Healthcare Ltd.), for treating HIV-1 infection in adults.

Before proceeding with the news (and dampening the good news), here’s an FYI: As quoted by NBC News, ViiV Healthcare Ltd. stated that the shot combo would cost $5,940 for an initial, higher dose and $3,960 per month afterward.

According to the FDA, the safety and efficacy of CABENUVA were established through two randomized, open-label, controlled clinical trials in 1,182 HIV-infected adults who were virologically suppressed (HIV-1 RNA less than 50 copies/milliliter) before initiation of treatment with CABENUVA. The patients in both trials continued to show virologic suppression at the conclusion of each study, and no clinically relevant change from baseline in CD4+ cell counts was observed (https://www.fda.gov/news-events/press-announcements/fda-approves-first-extended-release-injectable-drug-regimen-adults-living-hiv).

In first trial, the ATLAS study, CABENUVA was said to have met the primary endpoint for noninferiority (or the proportion of participants with plasma HIV-1 RNA ≥50 copies per milliliter [c/mL] at Week 48), with a comparable number of patients receiving either CABENUVA or their daily current antiretroviral regimen (CAR) having an HIV-1 RNA level ≥50 c/mL. Two percent of patients receiving the long-acting injectable and 1% of patients receiving CAR had an HIV-1 RNA level ≥50 c/mL at Week 48 (Treatment difference 0.7%; 95% CI: -1.2%, 2.5%).

In second trial, the FLAIR study, a comparable number of patients receiving either CABENUVA or daily oral dolutegravir/abacavir/lamivudine therapy had an HIV-1 RNA count ≥50 c/mL, meeting noninferiority criteria. Two percent of patients in both treatment arms had an HIV-1 RNA count ≥50 c/mL at Week 48 (Treatment difference -0.4%; 95% CI: -2.8%, 2.1%).

Rilpivirine and cabotegravir are able to act as a complete regimen for people with HIV, allowing it to replace the antiretroviral regimen for those who are virologically suppressed with HIV-1 RNA at less than 50 copies per milliliter [c/mL], have no history of treatment failure, and are not known or suspected to have any resistance to either cabotegravir or rilpivirine.

To administer the therapy, a provider would conduct a once-monthly administration that would consist of two individual intramuscular injections in the buttocks.

Added the FDA: The most common adverse reactions with CABENUVA were injection site reactions, fever (pyrexia), fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness and rash. Cabenuva should not be used if there is a known previous hypersensitivity reaction to cabotegravir or rilpivirine, or in patients who are not virally suppressed (HIV-1 RNA greater than 50 copies/milliliter).

In a press release, Paul Stoffels, MD, vice chairman of the executive committee and chief scientific officer at Johnson & Johnson said: “With the approval of CABENUVA, we’re proud to bring a new treatment option to people living with HIV that removes the burden of taking a daily pill… While much more remains to be done to make HIV history, today’s milestone reminds us how far medical innovation has come since the first reported cases of the virus almost 40 years ago.”

Now, and realistically, with newer HIV medicines like rilpivirine and cabotegravir not even widely offered in countries like the Philippines yet, the even newer injectables may sound promising but remain stuff of dreams…

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