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The Evolutionary Flexibility of Herpes Simplex Virus 1 in Different Cellular Contexts

Award Number: R01AI203226
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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The Evolutionary Flexibility of Herpes Simplex Virus 1 in Different Cellular Contexts - Project Summary Herpes simplex virus infects millions of individuals in the USA and has an even higher prevalence globally. HSV-1 infects at epithelial surfaces and then establishes lifelong latency in the nervous system, from which it reactivates and returns to the skin to cause recurrent lesions and shedding. Human skin is the main site of HSV-1 lesion formation in humans – causing overt pain and disease in infected individuals – as well as being the main site of transmission between individuals. Viral populations shed from the skin of HSV-1-infected individuals contain alternative alleles, known as minor variants, which can be transmitted to new hosts. These variants include drug resistance loci and viral missense mutations that can influence the success of future infections. There are critical gaps in our knowledge of HSV-1 population variation, in that we do not know the rate or frequency at which viral genetic differences arise, or how this variation influences the development of antiviral drug resistance. This proposal will measure where and how viral genetic variations arise in skin cells, by combining viral experimental evolution with current circulating populations of HSV-1, and different skin models and sources. In Aim 1 we will quantify HSV-1 genetic differences that arise during experimental evolution in primary cells such as keratinocytes, as well as renewable cell line and skin organoid models. Over sequential passages in each cell population, we will measure viral phenotypes and viral evolution, by deeply sequencing the entire viral population. These comparisons will reveal how different viral populations are shaped by replication in these different skin models. In Aim 2 we will use whole-genome sequencing and experimental evolution to quantify changes in minor variant frequency during acyclovir exposure of viral populations in skin cells. We will analyze variations in the viral populations before, during, and after the evolution of acyclovir resistance. We will also test the fitness of drug-susceptible vs. drug-resistant variants derived from the same starting population. These data will reveal how antiviral drug selection influences viral fitness, and how viral population variation is shaped by competition and selection. In Aim 3 we will determine the effects of cellular stress on HSV-1 evolution in skin cells. This aim will evaluate how naturally occurring stressors impact viral evolution, using conditions that are associated with HSV-outbreaks in infected individuals. We will use stimuli such as UV and cortisol to induce a stress response in keratinocytes, and measure the impacts on viral population variation, along with phenotypic metrics of infection. These data will reveal how physiologically relevant skin cell stressors impact viral population variation during shedding. These aims address the research priorities of the 2023-2028 NIH Strategic Plan for Herpes Simplex Virus Research, by providing new insights on how HSV-1 evolves in different individuals, and the evolution and transmission of drug resistance.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $549,764 )
2026	2026	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Allergy and Infectious Diseases Research	000	1	8/20/2026	NEW	$549,764
														Subtotal = $549,764

Grand Total All Awards = $549,764

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The Evolutionary Flexibility of Herpes Simplex Virus 1 in Different Cellular Contexts

Award Number: R01AI203226

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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