NIAID Researchers Uncover How SARS-CoV-2 Variants May Emerge in People with Weakened Immune Systems

A NIAID study revealed how some variants of SARS-CoV-2—the virus that causes COVID-19—could evolve. The researchers used cutting-edge technology to examine genes from SARS-CoV-2 in people with and without HIV who also had COVID-19, looking at the different copies of the virus in individuals over time. They found that people with advanced HIV—as defined by reduced numbers of immune cells called CD4⁺ T cells—had dozens of SARS-CoV-2 variants in their bodies, compared to just one major variant in most people without HIV and people with HIV who had higher numbers of CD4⁺ T cells.

Like other viruses, SARS-CoV-2 evolves quickly. When the virus enters the body, it makes more copies of itself. During this process, called replication, the virus’s genetic material can change, or mutate, to arrive at new viral variants. Variants of concern (VOCs) are viral variants with traits that make them more dangerous—by causing worse disease, finding new ways to evade the immune system, or spreading more easily. It has been difficult to determine how new VOCs of SARS-CoV-2 arise. Some studies suggest that when people who are immune compromised get SARS-CoV-2, their bodies provide conditions that can promote variants by allowing the virus to linger during a weakened immune response. These prolonged infections could provide a sort of sandbox for different gene mutations to arise and test the body’s defenses, allowing for more new variants to evolve and spread. HIV can cause immune deficiency if its replication is not controlled by antiretroviral therapy (ART). ART taken as prescribed suppresses HIV viral replication and prevents or reduces immune system damage. 

To examine how VOCs may emerge, Eli Boritz, M.D., Ph.D., chief of the Virus Persistence and Dynamics Section at NIAID’s Vaccine Research Center, partnered with researchers at the South African National Institute of Communicable Diseases to conduct the study in a unique cohort of individuals with COVID-19 in South Africa. The study group included 47 people with and without HIV, 12 of whom had advanced HIV, characterized as having CD4⁺ T cell counts lower than 200 cells/mm³.

The research team investigated SARS-CoV-2 evolution in the study group using advanced technology developed in Dr. Boritz’s lab called high-throughput, single-genome amplification and sequencing (HT-SGS). This approach enabled them to obtain genetic information from thousands of individual SARS-CoV-2 viruses per sample, providing a snapshot of the different mutations present at a given time and allowing for analysis of viral evolution at a level of detail previously unavailable. They looked at the gene for the SARS-CoV-2 spike protein—which the virus uses to enter cells—to see which variants were present throughout the course of COVID-19 and found significant differences in the SARS-CoV-2 variants between the study participants.

People with advanced HIV who had COVID-19 were found to have multiple variants of SARS-CoV-2, and the population of viruses in each person became more diverse and evolved over the course of the infection. The median number of SARS-CoV-2 variants in people with advanced HIV was 47, and some individuals had over 100 detectable variants throughout the infection. In people without advanced HIV (those either without HIV or with HIV and CD4⁺ T cell numbers above 200 cells/mm³), the population of viruses in each individual was generally uniform. Most of these participants had only one major variant of SARS-CoV-2 in their bodies, with little evidence that the virus evolved during infection.

The findings reveal extensive variation of SARS-CoV-2 in people with advanced HIV and provide further understanding towards how new variants arise and adapt in people with compromised immune systems. More research is needed to understand how SARS-CoV-2 infection in people with advanced HIV and other immune deficits may contribute to the emergence of new VOCs. This work additionally highlights the importance of research to understand, treat, and prevent HIV, COVID-19 and immune conditions, as well as ensuring access to treatment for people with HIV and working towards a cure.

Reference:

Ko, SH, Radecki, P, et al. Rapid intra-host diversification and evolution of SARS-CoV-2 in advanced HIV infection. Nature Communications. DOI: 10.1038/s41467-024-51539-8 (2024).

NIAID-supported Clinical Studies Assess Therapeutics for Clearance of HIV from the Reservoir

Antiretroviral therapy (ART) has been a game-changer for people with HIV. But HIV is skilled at “hiding” and can reappear in the blood stream shortly after ART is stopped. That’s why NIAID and partners are investigating strategies to completely clear HIV from a person’s body, effectively curing them, or to reduce it to levels that can be suppressed by their own immune systems. 

Many promising HIV cure strategies use broadly neutralizing antibodies, or bNAbs, which can neutralize a wide range of HIV variants, homing in on and binding to specific viral components, and then acting to destroy the virus by triggering an immune response. Several HIV bNAbs have been developed and tested to determine whether they can prevent or treat HIV. NIAID and partners are evaluating bNAb-based strategies alone and in combination with other immunity-enhancing strategies for HIV clearance in clinical trials in in Africa, North and South America, and Southeast Asia.

Finding a cure for HIV is complex, largely due to the tenacity of the virus—it can persist in some tissues or cells without being attacked by the immune system. This is even the case for people whose viral load—the amount of virus in the blood—is suppressed below a level that can be detected by routine diagnostic tools. As a result, most people who experience an interruption in treatment will experience a viral rebound, in which the previously dormant virus begins to replicate and can attack the immune system. This problem is especially urgent for people with HIV who have limited access to treatment, including those in areas with limited resources. A treatment that can be given for a limited time to stop the virus from replicating long term, or one that removes it from the body entirely, could eliminate the need for lifelong treatment, improve quality of life for people with HIV, and reduce further HIV transmission.  

Two studies beginning this summer are assessing the use of bNAbs to enable HIV remission in people with HIV in African countries. Both studies will include closely monitored ART interruption to examine whether bNAbs can lead to long-term ART-free control of HIV. One trial, called Pausing Antiretroviral Treatment Under Structured Evaluation (PAUSE), enrolled its first participant in June 2024 and continues to enroll people with HIV in Botswana, Malawi, and South Africa. Participants on ART with no detectable virus in their blood stream will receive two long-acting bNAbs (3BNC117-LS-J and 10-1074-LS-J) and then pause ART to determine whether the bNAbs are sufficient to control HIV in the body when ART is stopped. 

A second study, called Antiretrovirals Combined With Antibodies for HIV-1 Cure In Africa (ACACIA), is starting soon and will examine the bNAbs 3BNC117-LS (also known as teropavimab) and 10-1074-LS (also known as zinlirvimab) in adults living with HIV in Botswana, Malawi, South Africa and Zimbabwe who are beginning ART. The bNAbs will be given while there is still virus in the blood stream to see if they can enhance the body’s immune response to HIV, which could reduce the amount of virus that hides in viral reservoirs in the body. Once the bNAbs are no longer present in the body, ART will be interrupted for each participant, and they will be evaluated to determine how long viral suppression is maintained without ART and whether the bNAbs affect the immune response to HIV.

Researchers are also evaluating bNAb-based HIV cure strategies in children through the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network. The IMPAACT P1115 study has examined very early HIV treatment strategies in infants who were exposed to or acquired HIV before birth. The study is assessing VRC01 and VRC07-523LS to see whether these bNAbs, when given with ART early in life, may enable ART-free remission in children. Another study, IMPAACT 2042, will evaluate the use of three bNAbs, VRC07-523LS, PGDM1400LS, and PGT121.414.LS, in children and young adults with HIV between the ages of 2 and 25 to determine whether the bNAbs can be part of a strategy to suppress HIV and clear the virus from the body.

Other clinical studies are combining bNAbs with therapeutic vaccines for HIV clearance. These vaccines are designed to improve the immune response to the virus in a person with HIV. ACTG A5374, which enrolled its first participant in early 2024, is evaluating the bNAbs teropavimab and zinlirvimab in combination with the therapeutic vaccines ChAdOx1.HIV cons1/62 and MVA.HIV cons3/4 and an immune booster called vesatolimod. The trial will assess the safety of the regimen in people with HIV in the U.S. and Brazil, and whether the combination can eliminate cells harboring HIV and prevent viral reservoirs from reactivating when ART is interrupted. 

The findings from these and related trials will provide researchers with new insights into how to effectively treat HIV or clear the virus from people’s bodies. This work is implemented by leveraging the strengths of all of the NIH-funded HIV clinical trials networks and collaborating institutions. The Bill & Melinda Gates Foundation is co-funding PAUSE and ACACIA. IMPAACT P1115 and 2042 are co-funded by the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

The bNAbs VRC01 and VRC07-523LS were developed by NIAID’s Vaccine Research Center and Division of Intramural Research. The bNAbs 3BNC117 and 10-1074 were discovered by researchers at the Rockefeller University, funded in part by NIAID. PGT121.414.LS and PGDM1400LS are being developed by NIAID and collaborators.

Additional information about the trials: 

• ACTG A5374: ClinicalTrials.gov ID NCT067071767.
• ACTG A5416 (also called PAUSE): ClinicalTrials.gov ID NCT06031272.
• ACTG A5417 (also called ACACIA): ClinicalTrials.gov ID NCT06205602.
• IMPAACT P1115: ClinicalTrials.gov ID NCT02140255. (Recent P1115 findings were presented at the 2024 Conference on Retroviruses and Opportunistic Infections.)
• IMPAACT 2042 (also called Tatelo Plus): ClinicalTrials.gov ID coming soon.

by Jeanne Marrazzo, M.D., M.P.H., NIAID Director

The power of word choice is obvious every day in my life as a researcher, clinician, colleague, patient, spouse, and friend. Language can inform, delight and inspire, but it can mislead and wound if words are not chosen carefully. At worst, language can invoke stigma, shame, and even violence, all of which undermine NIAID’s mission as part of a health agency. Our institute is responsible not only for advancing scientific knowledge, but for doing so in a way that honors the dignity, individuality, and autonomy of the people affected by the health issues we address. For this reason, I am very proud to share the updated NIAID HIV Language Guide, a thoroughly vetted resource to inform our written and verbal communications.

NIAID has long been engaged in rich and multifaceted collaborations with HIV advocates and community stakeholders—partnerships that I prize and am honored to carry forward. Among their many contributions to HIV science, our community partners ensure that our language evolves as fluidly as our knowledge of the virus itself. Through their insights, the words we choose to describe the pathogen, its effects on the body, and the people who are affected by and living with HIV, have become increasingly person-centered. This progress reflects and upholds a commitment to avoid defining people by the disease with which they live. 

Despite this progress, the scientific community often lags in adopting evolving language, and many of the terms and phrases we use today are still insensitive and disrespectful to the people we aim to serve. Harmful language undermines people’s trust in biomedical research, and language-driven stigma prevents people from seeking health services which provide benefit. Non-inclusive language perpetuates knowledge gaps, limiting our ability to fully understand the people participating in research. As scientists and public health practitioners, we cannot be cavalier about language. Our words matter.

This guide originated as a resource for the HIV field, but respectful, inclusive, and person-first language is essential in all scientific communication. To that end, I am committed to following the NIAID HIV Language Guide in my communications, and strongly encourage all NIAID staff, funded research networks, sites, centers, investigators, and partners to do the same. We will not always get it right, but we will continue to try. We must support each other in learning, hold each other accountable, and continue to adapt as terms and norms change. 

For more information about the language guide and supporting resources, please visit https://www.niaid.nih.gov/research/hiv-language-guide. Spanish and Portuguese translations are coming soon.

Vaccines consistently transform public health, and HIV vaccine research has been a pillar of NIAID’s scientific mission since the beginning of the HIV pandemic. An HIV vaccine has proven to be among the most daunting scientific challenges, but has inspired exceptional innovation and collaboration in all aspects of our research approach. On the 27th observance of HIV Vaccine Awareness Day (Saturday, May 18), we express our gratitude to the dedicated global community of scientists, advocates, study participants, study staff, and funders working toward a safe, effective, durable, and accessible HIV vaccine. 

As the lead of the National Institutes of Health HIV vaccine research effort, NIAID conducts basic, preclinical, and clinical research to characterize the safety, immunogenicity, and efficacy of promising HIV vaccine concepts. Through the HIV Vaccine Trials Network, NIAID supports clinical trials where HIV is most prevalent, including in the Global South. Over decades of research, with disappointing results from large efficacy studies, the HIV vaccine field has learned and iteratively evolved with every step. We have more knowledge now than ever before about how an HIV vaccine could work. Research teams are using discovery medicine trials and new vaccine technologies to identify and stimulate the types of immune responses that hold the most promise for preventing HIV.   

People with HIV have made priceless contributions to HIV vaccine science by participating in research that teaches us how the human immune system responds to HIV. Some people naturally keep the virus under control even without antiretroviral therapy. Through their participation in clinical research, we have identified aspects of both cellular immunity—which is driven by T cells—and humoral immunity—driven by antibody-producing B cells—that likely will need to be stimulated and substantially amplified by a safe and effective preventive vaccine. 

HIV’s genetic diversity makes it difficult to target with a vaccine, but broadly neutralizing antibodies (bNAbs) may be key to overcoming that hurdle because they bind to parts of the virus that are relatively consistent among variants. The NIAID Vaccine Research Center (VRC)—founded to accelerate HIV vaccine research on this day in 1997—isolated and then manufactured a bNAb called VRC01 that has prompted a cascade of other research, including HIV vaccine and passive antibody administration studies. 

Since the VRC’s discovery of VRC01, scientists have identified additional bNAbs that target other stable sites on HIV’s highly variable surface. This year, VRC scientists showed that a human bNAb called VRC34.01, which targets the fusion peptide on HIV’s surface, protected monkeys from acquiring simian-HIV in a proof-of-concept study that is informing human vaccine design. Researchers at the VRC and other NIAID-supported institutions are using a technique called germline targeting to closely guide naïve (new) B cells to develop into mature B cells that can produce bNAbs. Using this approach, researchers are making progress toward eliciting VRC01-like antibodies, as well as several other classes of bNAbs in human and animal studies.

Researchers also are advancing cellular immune approaches to HIV vaccines. A study conducted by NIAID’s Laboratory of Immunoregulation found that a safe and effective HIV vaccine will likely need to stimulate strong responses from CD8+ T cells. NIAID and its partners announced the launch of a clinical trial to examine the safety and immune response generated by VIR-1388, a T-cell based vaccine candidate that uses a cytomegalovirus (CMV) vector.  In this approach, a weakened version of CMV delivers HIV vaccine material to the immune system without causing disease in the study participants. The CMV vector technology has been in development with NIAID funding since 2004. 

We also are reminded how HIV vaccine research and discovery benefits the broader fields of immunology and vaccinology. In October 2023, the Nobel Prize for Physiology or Medicine was awarded to Drew Weissman, M.D., Ph.D., and Katalin Karikó, Ph.D., for their work that enabled the unprecedented rapid development of the mRNA vaccines that stemmed the COVID-19 pandemic and saved millions of lives. Both Nobel laureates have connections to NIAID and NIH. This research was made possible in part by NIAID HIV vaccine research grants that enabled a major evolution in understanding how immune cells recognize and react to different forms of mRNA. mRNA-based HIV vaccine candidates are now being tested in humans in early-stage trials.

Looking ahead, NIAID has clear priorities for HIV vaccine research and development. Ongoing research is guiding the next steps in vaccine strategies to elicit bNAbs and T-cell responses, to eventually trigger both with a single vaccine regimen. To enhance the precision of this research, more information is needed to define the correlates of protection for an HIV vaccine, that is, the specific immunologic markers that translate to a protective effect. Meanwhile, as promising concepts are identified and advanced through clinical trials, the field must continue to optimize vaccine formulations and dosing, and find novel adjuvants that can prolong and amplify immune responses. HIV vaccine research findings will continue to offer valuable insight in other areas, including HIV prevention and cure research, and broader medical countermeasure development for pandemic preparedness.

The pursuit of an HIV vaccine depends on supporting next the generation of HIV clinical investigators and community leaders. NIAID is committed to fostering the professional growth of early-stage HIV investigators and to nurturing the decades-long community partnerships that make this essential research possible.  

On this HIV Vaccine Awareness Day, we remain optimistic that exciting scientific advances and the efforts of diverse partners around the world will put a safe and effective HIV vaccine within our grasp.