Sexually transmitted infections (STIs) are caused by bacteria, viruses, or parasites. STIs have a devastating impact on adults and infants and annually affect millions of people in the United States. Certain STIs can increase a person’s risk of developing cancer and increase the likelihood of acquiring or transmitting HIV. In addition, STIs can cause long-term health complications, especially in the reproductive and central nervous systems. In rare cases, they can lead to serious illness or death. 

NIAID supports research across the spectrum from basic to clinical science to develop effective diagnostic, preventive and therapeutic approaches to STIs in alignment with the National STI Strategic Plan. In recognition of National STI Awareness Week, NIAID shares a snapshot of new projects and recent scientific advances in STI research. 

Improving treatment for syphilis and trichomoniasis

New reports of syphilis and congenital syphilis are increasing at an alarming rate in the United States. Syphilis is caused by the bacterium Treponema pallidum. Benzathine penicillin G (BPG) is one of only a few antibiotics known to effectively treat syphilis. There is currently a shortage of BPG, and some people are allergic to penicillin antibiotics. In February 2024, NIAID convened a workshop with a wide range of experts on alternative therapies to BPG for the treatment of adult syphilis, neurosyphilis, and syphilis in pregnant persons and infants. The workshop addressed preclinical evaluation of candidate drugs, the potential need for studies on how candidate drugs are processed in the body during pregnancy, and how to approach clinical trials of treatment for congenital syphilis. This work is part of NIAID’s comprehensive portfolio of syphilis diagnosis, prevention, and treatment research. 

Trichomoniasis is the most common parasitic STI, caused by Trichomonas vaginalis. Trichomoniasis can increase the risk of getting or spreading other STIs, including HIV. The parasite can also cause inflammation of the cervix and the urethra. T. vaginalis is treated with an antibiotic drug class called nitroimidazoles. The currently recommended nitroimidazole, called metronidazole, cures 84-98% of T. vaginalis cases but does have high rates of breakthrough infection. A new project led by Tulane University will examine a single dose of secnidazole, a medicine in the same drug class, as a more effective and cost-effective treatment option for women and men. 

Developing a vaccine for herpes simplex virus 2

Herpes simplex virus 2 (HSV-2) is a common subtype of herpes simplex virus that is transmitted through sexual contact. The Centers for Disease Control and Prevention estimates that 18.6 million people aged 15 years and older United States live with HSV-2. In severe cases, HSV-2 may lead to life-threatening or long-term complications. There is no licensed preventive HSV-2 vaccine, and there is no cure. A new project led by the University of Pennsylvania seeks to define correlates of protection for HSV-2, meaning they intend to identify immune processes involved in preventing HSV-2 disease. They will do this by analyzing laboratory samples from animal studies of a promising preventive vaccine candidate that they developed with prior funding. That vaccine candidate is also now in an industry-sponsored early-stage clinical trial. The same project will expand on the HSV-2 targets in the preventive vaccine to develop a therapeutic vaccine concept to reduce recurrent outbreaks. This research responds to the scientific priorities in the NIH Strategic Plan for Herpes Simplex Virus Research.

Increasing fundamental knowledge of bacterial vaginosis 

Bacterial vaginosis (BV) results from an imbalance in the vaginal microbiome. BV can be caused by sexual activity, douches and menstrual products. BV can increase women’s biological susceptibility to HIV and other STIs and can cause premature birth or low birthweight if untreated in pregnant people. In a recent publication, NIAID-supported researchers, led by researchers at the University of Washington and University of California San Diego, shared findings on how damage to the vaginal skin barrier occurs during bacterial vaginosis. Those skin barrier cells, called epithelial cells, are covered in carbohydrate molecules called glycans. The research team found that people with BV had damaged glycans on their vaginal epithelial cells. They suggested that future work should examine the relationship between treatment and restoration of normal glycans. If an association is detected, it could help healthcare providers monitor for successful treatment outcomes to reduce the likelihood that BV will return after a course of treatment. The findings were published in Science Translational Medicine. 

These activities are among the research investments in NIAID’s STI portfolio. For more information on STIs, please visit:

• NIAID Diseases & Conditions: Sexually Transmitted Infections
• U.S. Department of Health and Human Services STI National Strategic Plan

The National Institutes of Health recently issued $26M in awards to HIV research institutions in its fifth year supporting implementation science under the Ending the HIV Epidemic in the U.S. (EHE) initiative. These awards are the latest investments in a program that is rapidly and rigorously generating evidence to inform the unified domestic HIV response by agencies in the Department of Health and Human Services. 

The EHE initiative aims to achieve a 90% reduction in the number of new HIV infections in the United States by 2030. Since the initiative was announced in 2019, NIH has contributed by supporting implementation science projects through its network of Centers for AIDS Research (CFAR) and the National Institute of Mental Health (NIMH) AIDS Research Centers (ARC). CFARs are co-funded by 11 NIH institutes and centers (ICs), including the National Institute of Allergy and Infectious Diseases (NIAID). NIH ICs provide scientific stewardship to participating institutions in collaboration with the Fogarty International Center and the NIH Office of AIDS Research, which coordinates the NIH HIV research program across the agency. CFAR and ARC-affiliated investigators conduct research in jurisdictions that are disproportionately affected by HIV, and many of the CFAR and ARC member institutions are based in these communities. 

VIDEO: Jeanne Marrazzo, M.D., M.P.H., NIAID Director, discusses NIH’s role in the EHE (audio description version here):

NIH EHE projects enable academic institutions to partner with state and local leaders to jointly translate implementation research findings into improved delivery of HIV testing, prevention, treatment, and response services for priority populations and in priority geographic areas. Projects funded this year are designed to increase and share available knowledge on locally appropriate strategies to: 

• detect and respond to HIV “clusters,” i.e., groups of people and communities experiencing rapid HIV transmission;
• leverage pharmacies as HIV service locations; 
• ensure uninterrupted HIV care for people returning to their communities following incarceration; and
• develop approaches that address intersecting diseases and conditions that exacerbate health inequities and impact HIV outcomes, including such as viral hepatitis, sexually transmitted infections, and substance use and mental health disorders.

Since Fiscal Year 2019, NIH has funded 253 projects across 50 geographic areas prioritized by EHE. The latest EHE awards to CFARs and ARCs support 47 projects, 8 implementation science hubs, and 1 coordinating center. Hubs provide technical support, coaching, training, and consultative services to funded EHE research teams. The coordinating center provides infrastructure for collaboration and sharing best practices in HIV implementation science. In addition to the CFAR/ARC supplements, NIH supported multiple larger research projects in 2023, including 3 R01 awards, 2 R34 awards, and 1 coordinating center. In September 2023, NIH released a Notice of Special Interest to solicit project proposals from independent investigators for Fiscal Year 2024.

EHE Project Spotlights

The knowledge generated by NIH EHE projects is reviewed with HHS EHE partners to accelerate learning and program improvement. Two projects below illustrate how EHE implementation science projects have already enhanced locally tailored HIV service delivery:

Miami, Florida

Miami-Dade County, Florida has one of the highest rates of HIV incidence in the United States, and yet use of pre-exposure prophylaxis (PrEP) to prevent HIV acquisition remains relatively low. Researchers at the University of Miami, in collaboration with the Florida Department of Health (DOH) and a local community-based organization called Prevention305, developed a process to apply real-time DOH epidemiologic data to prioritize new geographic locations for placement of their mobile PrEP clinics. In collaboration with community partners, the project developed a new outreach approach: “Test-to-PrEP,” in which people using PrEP are engaged to distribute free HIV self-tests and PrEP referrals through their social networks. They have worked with 100 current PrEP clients to engage members of their social network with information about PrEP provide them with HIV self-tests. More than one third of the 117 HIV self-test kit recipients who confirmed they used the test reported they had not previously known about PrEP. Self-reported knowledge and likelihood to use PrEP increased significantly after kit receipt. PrEP clients also reported feeling comfortable with the distribution and enthusiastic about the strategy. Their work has provided a blueprint for mobile HIV prevention and related services as a strategy to interrupt further transmission.

Mobile clinic service team in the Liberty City neighborhood of Miami, Florida

Credit: University of Miami

Shelby County, Tennessee

Rural areas like Shelby County pose distinct challenges to HIV service delivery, including a lack of outpatient providers and fragmented health care and social services, as well as stigma and medical mistrust. To overcome these barriers, researchers from University of Massachusetts, Lowell, in collaboration with the University of Memphis and the Shelby County Health Department, used an implementation research approach to adapt and provide an evidence-based training and capacity-building program in HIV care for existing community health workers (CHWs), with input from HIV care providers, people with HIV, and CHWs. CHWs are frontline public health workers who are also members of the community they serve. The team has trained 67 CHW to support HIV care across eight agencies and has provided coaching sessions to supervisors around how to sustain this workforce. They are assessing the sustainability and effectiveness of this program in addressing service gaps and improving health outcomes through follow-up surveys with health care agency staff and county health leaders. 

Community health worker Michelle Anderson discussing culturally relevant care HIV care with colleagues in Memphis, Tennessee.

Credit: University of Massachusetts, Lowell

In addition to NIH, HHS agencies and offices participating in EHE include the Centers for Disease Control and Prevention; the Health Resources and Services Administration; the Indian Health Service; the Office of the Assistant Secretary for Health; and the Substance Abuse and Mental Health Services Administration. 

To view a complete list of NIH research projects supported with EHE initiative funding, please visit the awards page. 

To learn more about EHE, please visit HIV.gov.

Reference: 

Butts, SA et al. Addressing disparities in Pre-exposure Prophylaxis (PrEP) access: implementing a community-centered mobile PrEP program in South Florida. BMC Health Services Research. DOI 10.1186/s12913-023-10277-1 (2023).

Johnson, AL et al. “Test-To-PrEP”: Assessing Reach and Adoption of a New Approach to Increase HIV Testing and PrEP Knowledge Using HIV Self-Test Kit Distribution Through PrEP Clients' Social Networks. Journal of Acquired Immune Deficiency Syndromes. DOI 10.1097/QAI.0000000000003294 (2023). 

Rajabiun, S et al. Using Implementation Science to Promote Integration and Sustainability of Community Health Workers in the HIV Workforce. Journal of Acquired Immune Deficiency Syndromes. DOI 10.1097/QAI.0000000000002966 (2023).

Stem Cell Changes Rejuvenate Immune System in Aged Mice

NIAID, Stanford Exploring Potential for Revitalizing Human Immunity

Aging is associated with a reduced ability to generate immune responses against novel infections, as was recently illustrated by the high mortality among older people during the COVID-19 pandemic. Using a mouse model of human aging and disease, NIAID scientists and Stanford University colleagues have shown that immune systems of aged laboratory mice can be made more youthful and effective at fighting disease by depleting a subset of haematopoietic stem cells (HSCs). The researchers think the method they developed may have potential for rejuvenating immunity in elderly people and are pursuing further study. Their findings are published in Nature.

When the immune system is young, balanced HSCs (bal-HSCs) dominate, producing a healthy mix of lymphoid and myeloid cells. Lymphoid cells develop into B and T cells that can adapt to new infections. Myeloid cells develop into non-adaptive and inflammatory cells that drive the immediate response of the innate immune system.

As the immune system ages, myeloid-biased HSCs (my-HSCs) start to dominate, increasing inflammatory responses and decreasing the number of lymphoid cells that can adapt to novel infections. The scientists hypothesized that if they could increase the proportion of bal-HSCs in an aged immune system by reducing the number of my-HSCs, the adaptive immune response could be returned to a more youthful state.

To test their hypothesis they identified my-HSC-specific genes in laboratory mice and then developed three methods using antibodies to deplete the targeted my-HSC gene products. Within a week the team began observing a “rebalancing” of the immune system, with increases in lymphoid cells and decreases in myeloid cells. Markers of inflammation and “immune exhaustion” associated with age also were decreased. Even after 16 weeks, a single treatment remained effective in the aged mice.

To test for functionality of the immune response, they challenged aged animals with mouse retroviruses. They observed increased virus-specific T-cell development in treated mice compared to aged untreated controls, reduced pathology, and significantly increased virus control, with four of nine treated mice completely clearing the infection.

“Taken together, these results demonstrated that my-HSC depletion in aged mice significantly improved immune responses to live viral infections,” the researchers write.

The scientists found that the my-HSC-specific antigens targeted for depletion in mice are also present in human my-HSC, suggesting that similar protocols could be used in humans.

“These experiments represent the first steps towards identifying therapeutic targets to deplete human my-HSCs and to rejuvenate the aged immune system using this strategy,” according to the researchers.

Reference:

J Ross, L Myers, et al. Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature DOI: https://www.nature.com/articles/s41586-024-07238-x (2024).

Switching to an antiretroviral therapy (ART) regimen containing the drug dolutegravir was associated with a significant temporary increase in reservoirs of latent HIV, according to a new analysis from a study in Uganda. HIV reservoirs are cells where HIV lies dormant and cannot be reached by the immune system or ART. They are central to HIV’s persistence, preventing current treatments from clearing the virus from the body. The findings were published today in eBioMedicine.

When taken as prescribed, ART can stop HIV from replicating. The different classes of available antiretroviral drugs (ARVs) interrupt different stages of HIV replication. People are often prescribed drug regimens composed of multiple drug classes to increase the likelihood that ART will fully suppress HIV replication. In 2018, many countries began using dolutegravir-based ART regimens following studies that showed the drug had higher efficacy and fewer side effects than the drugs that had been in use previously. Uganda was among these countries and recommended dolutegravir together with the ARVs tenofovir and lamivudine for all people whose HIV was treatable with those drugs.

In 2015, NIH scientists and researchers from the Rakai Health Sciences Program in Uganda began a longitudinal study of reservoirs among people with HIV in the Rakai and Kyotera Districts in Uganda. Study participants were people whose HIV was suppressed by ART and had agreed to provide blood samples and receive a routine physical examination annually. People meeting study entry criteria continued to enroll each year. As part of this study, the team examined whether the introduction of dolutegravir-based regimens in 2018 had any effect on the makeup of HIV reservoirs in study participants. At the time of the published analysis, 63% of participants were female. The study observed that HIV reservoir size was generally decreasing as participants remained virally suppressed for longer periods. In the analysis of samples provided post-dolutegravir introduction, they observed a surprising 1.7-fold average increase in HIV reservoir size above pre-dolutegravir levels, which lasted for approximately a year, then returned to normal. This effect was consistent across the majority of study participants regardless of how long they had been living with HIV. 

According to the study authors, no other study has found significant differences in HIV reservoir characteristics due to ART regimen changes, but previous research has identified changes in immune characteristics and cardiovascular disease risk, as well as other effects in the period after dolutegravir initiation, suggesting the body goes through a period of adjustment when switching to use the new drug. The authors state that it is important to explore whether other populations experience the same temporary reservoir increase post-dolutegravir initiation, and that more research is needed to understand the mechanism causing the increase, especially if it is starting dolutegravir or stopping the previous ARV. They further suggest that these findings may inform HIV cure research, including approaches referred to as “Shock and Kill” that attempt to stimulate HIV reservoirs to resume activity, then promptly remove them. The authors did not observe any negative clinical ramifications, such as loss of viral control, associated with this finding.  

Most HIV reservoir research has been conducted among predominantly male study populations in Europe and North America, unlike the primarily female participants in this study. The authors highlight the importance of exploring sex-based differences in HIV reservoir characteristics and the inclusion of representative populations in HIV studies.

This research was conducted by NIAID, Western University, and the Rakai Health Sciences Program and with co-funding from other NIH institutes, the Gilead HIV Cure Grants Program, the Canadian Institutes of Health Research, and the Ontario Genomics-Canadian Statistical Sciences Institute.

Reference:

RC Ferreira, et al., Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen. eBioMedicine DOI: 10.1016/j.ebiom.2024.105040 (2024)

This blog is adapted and cross-posted from HIV.gov. 

On March 6 as the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) was winding down, HIV.gov spoke with Carl Dieffenbach, Ph.D., director of NIAID's Division of AIDS, about highlights of long-acting HIV treatment research discussed at the conference. He spoke with Brian Minalga, M.S.W., deputy director of the NIH-supported Office of HIV/AIDS Network Coordination. Watch their conversation below:

Research Suggests Possible Expanded Options for Long-Acting HIV Treatment

Dr. Dieffenbach highlighted findings from several clinical trials and a plenary session presented at CROI about current and future options for long-acting antiretroviral treatment (ART) for HIV.

First, he discussed a NIAID-supported randomized clinical trial that found that long-acting ART with cabotegravir and rilpivirine was superior in suppressing HIV replication compared to daily oral ART in adults who had been unable to maintain viral suppression through an oral daily regimen. The LATITUDE study enrolled participants in 31 sites in the United States. Last month, the trial’s Data and Safety Monitoring Board conducted a planned review of interim data and recommended halting randomization and offering all eligible study participants long-acting ART based on its observed superior viral suppression of HIV. At CROI, study leaders reported that the interim analysis of data from 294 participants showed that the chance of experiencing unsuppressed HIV was 7% among people taking long-acting ART compared to 25% among those taking daily oral ART. The likelihood of discontinuing the assigned regimen due to adverse events or experiencing unsuppressed HIV was 10% among people taking long-acting ART compared to 26% among those taking daily ART. These findings were statistically significant. Dr. Dieffenbach observed that these results may support expanding the use of long-acting ART among a broader population. Read the study abstract. Read more in this NIAID news release.

Another ongoing clinical trial reported initial findings on the safety of the same long-acting injectable treatment regimen for adolescents with HIV with a suppressed viral load. The NIH-supported MOCHA study enrolled participants aged 12 to 17 who were virally suppressed in Botswana, South Africa, Thailand, Uganda, and the United States. In what he characterized as very encouraging results, Aditya Gaur, M.D. of St. Jude Children's Research Hospital, one of the trial’s co-chairs, reported that after the first six months all participants remained virally suppressed, and the level of the ART in their systems was comparable to what has been shown as efficacious in adult studies of the same drug. He also reported that, while about one-third of the participants reported an injection-site reaction, there were no surprising or unanticipated adverse events. These data support the use of cabotegravir and rilpivirine in virally suppressed adolescents, according to Dr. Gaur and colleagues. Dr. Dieffenbach noted that NIH will continue to support safety and dosing studies to determine the proper doses for adolescents and that these studies could eventually expand access to this long-acting HIV treatment to more people.
Read the abstract. Read NIAID’s news release about the study.

In addition, Dr. Dieffenbach mentioned an industry-sponsored Phase 2 trial that presented 24-week results of an oral once-weekly investigational combination of two drugs (islatravir and lenacapavir). Researchers reported that the investigational combination maintained a high level of viral suppression among study participants and was well tolerated. The study will continue to gather data and suggests that a weekly oral HIV treatment regimen could someday be possible. Read the abstract.

Finally, Dr. Dieffenbach discussed Wednesday’s plenary session by Charles Flexner, M.D. of The Johns Hopkins University School of Medicine, which was titled “The End of Oral? How Long-Acting Formulations Are Changing the Management of Infectious Diseases.” In his big picture, future-focused presentation exploring long-acting drug delivery, Dr. Flexner observed that there is a need for HIV products with less frequent dosing, greater convenience, and greater likelihood of viral suppression, as well as for the prevention and treatment of other diseases, including tuberculosis, malaria, and viral hepatitis. He discussed recent advances in formulation science that are going to help make available better replacements for daily oral drugs for HIV and many other infectious diseases. Dr. Dieffenbach underscored Dr. Flexner’s point that these novel products must be developed with access and equity in mind so that people who need them, especially in resource-limited settings, can use them.

Key Takeaways

Reflecting on key takeaways from the entire conference, both Dr. Dieffenbach and Brian pointed to the importance of partnership between the HIV community and scientists in all aspects of HIV research, a theme also discussed in HIV.gov’s conversation with Dr. LaRon Nelson from the conference. In terms of research highlights, Dr. Dieffenbach pointed to the results reported from the IMPAACT P1115 study in which several children who started HIV treatment within hours of birth later surpassed a year of HIV remission after a treatment pause. (See HIV.gov’s interview with Dr. Deborah Persaud about this study.) He also noted that the additional data accumulating on the effectiveness of Doxy-PEP is encouraging and will hopefully soon be reflected in clinical guidelines that help to reduce the incidence of syphilis, chlamydia, and gonorrhea in men who have sex with men and transgender women.

Catch Up on More HIV Research Updates

HIV.gov has shared other interviews from CROI 2024 with federal HIV leaders, participating researchers, and community members. You can find all of them on HIV.gov’s blog and social media channels.

About CROI

More than 3,600 HIV and infectious disease researchers from 73 countries gathered in Denver and virtually from March 3-6 this year for CROI, an annual scientific meeting on the latest research that can help accelerate global progress in the response to HIV and other infectious diseases, including STIs and viral hepatitis. Over 1,000 summaries of original research were presented. Visit the conference Web site for more information. Session webcasts and more information will be published there for public access.