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Viruses sense cellular states and environmental signals by recruiting host transcription factors to cis -regulatory elements (CREs) in viral genomes. Viral CREs act as signal integration hubs that impart specificity to viral gene regulation. Viral CREs are highly evolvable due to their high mutation rate and ability to rapidly change sensing mechanisms, affecting infection spread and patient outcomes. Latent viral infections can be treated by targeting viral CREs for reactivation or permanent silencing. To withstand a hostile cellular environment and replicate, viruses must sense, interpret, and respond to many internal and external cues. Retroviruses and DNA viruses can intercept these cues impinging on host transcription factors via cis -regulatory elements (CREs) in viral genomes, allowing them to sense and coordinate context-specific responses to varied signals. Here, we explore the characteristics of viral CREs, the classes of signals and host transcription factors that regulate them, and how this informs outcomes of viral replication, immune evasion, and latency. We propose that viral CREs constitute central hubs for signal integration from multiple pathways and that sequence variation between viral isolates can rapidly rewire sensing mechanisms, contributing to the variability observed in patient outcomes. [ABSTRACT FROM AUTHOR]

While most NOD‐like receptors (NLRs) are predominately expressed by innate immune cells, NLRC3, an inhibitory NLR of immune signaling, exhibits the highest expression in lymphocytes. The role of NLRC3 or any NLRs in B lymphocytes is completely unknown. Gammaherpesviruses, including human Epstein–Barr virus (EBV) and murine gammaherpesvirus 68 (MHV‐68), establish latent infection in B lymphocytes, which requires elevated NF‐κB. This study shows that during latent EBV infection of human B cells, viral‐encoded latent membrane protein 1 (LMP1) decreases NLRC3 transcript. LMP1‐induced‐NF‐κB activation suppresses the promoter activity of NLRC3 via p65 binding to the promoter. Conversely, NLRC3 inhibits NF‐κB activation by promoting the degradation of LMP1 in a proteasome‐dependent manner. In vivo, MHV‐68 infection reduces Nlrc3 transcripts in splenocytes, and Nlrc3‐deficient mice show greater viral latency than controls. These results reveal a bidirectional regulatory circuit in B lymphocytes, where viral latent protein LMP1 reduces NLRC3 expression, while NLRC3 disrupts gammaherpesvirus latency, which is an important step for tumorigenesis. [ABSTRACT FROM AUTHOR]

Worldwide, almost 40 million people are currently living with HIV-1. The implementation of cART inhibits HIV-1 replication and reduces viremia but fails to eliminate HIV-1 from latently infected cells. These cells are considered viral reservoirs from which HIV-1 rebounds if cART is interrupted. Several efforts have been made to identify these cells and their niches. There has been little success in diminishing the pool of latently infected cells, underscoring the urgency to continue efforts to fully understand how HIV-1 establishes and maintains a latent state. Reactivating HIV-1 expression in these cells using latency-reversing agents (LRAs) has been successful, but only in vitro. This review aims to provide a broad view of HIV-1 latency, highlighting Canadian contributions toward these aims. We will summarize the research efforts conducted in Canadian labs to understand the establishment of latently infected cells and how this informs curative strategies, by reviewing how HIV latency is established, which cells are latently infected, what methodologies have been developed to characterize them, how new compounds are discovered and evaluated as potential LRAs, and what clinical trials aim to reverse latency in people living with HIV (PLWH). [ABSTRACT FROM AUTHOR]

Antiretroviral therapy (ART) has brought the HIV/AIDS epidemic under control, but a curative strategy for viral eradication is still needed. The cessation of ART results in rapid viral rebound from latently infected CD4+ T cells, showing that control of viral replication alone does not fully restore immune function, nor does it eradicate viral reservoirs. With a better understanding of factors and mechanisms that promote viral latency, current approaches are primarily focused on the permanent silencing of latently infected cells ("block and lock") or reactivating HIV-1 gene expression in latently infected cells, in combination with immune restoration strategies to eliminate HIV infected cells from the host ("shock and kill"). In this review, we provide a summary of the current, most promising approaches for HIV-1 cure strategies, including an analysis of both latency-promoting agents (LPA) and latency-reversing agents (LRA) that have shown promise in vitro, ex vivo, and in human clinical trials to reduce the HIV-1 reservoir. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Human cytomegalovirus (HCMV) is a global health threat due to its ubiquity and lifelong persistence in infected people. During latency, host CD8+ T cell responses to HCMV continue to increase in a phenomenon known as memory inflation. We used murine CMV (MCMV) as a model for HCMV to characterize the memory inflation response to wild-type MCMV (KP) and a latency-defective mutant (ΔM33stop), which lacks M33, an MCMV chemokine receptor homolog. M33 is essential for normal reactivation from latency and this was leveraged to determine whether reactivation in vivo contributes to T cell memory inflation. METHODS: Mice were infected with wild-type or mutant MCMV and T cell responses were analyzed by flow cytometry at acute and latent time points. Ex vivo reactivation and cytotoxicity assays were carried out to further investigate immunity and virus replication. Quantitative reverse-transcriptase polymerase chain reaction (q-RTPCR) was used to examine gene expression during reactivation. MHC expression on infected cells was analyzed by flow cytometry. Finally, T cells were depleted from latently-infected B cell-deficient mice to examine the in vivo difference in reactivation between wild-type and ΔM33stop. RESULTS: We found that ΔM33stop triggers memory inflation specific for peptides derived from the immediate-early protein IE1 but not the early protein m164, in contrast to wild-type MCMV. During ex vivo reactivation, gene expression in DM33stop-infected lung tissues was delayed compared to wild-type virus. Normal gene expression was partially rescued by substitution of the HCMV US28 open reading frame in place of the M33 gene. In vivo depletion of T cells in immunoglobulin heavy chain-knockout mice resulted in reactivation of wild-type MCMV, but not ΔM33stop, confirming the role of M33 during reactivation from latency. Further, we found that M33 induces isotype-specific downregulation of MHC class I on the cell surface suggesting previously unappreciated roles in immune evasion. DISCUSSION: Our results indicate that M33 is more polyfunctional than previously appreciated. In addition to its role in reactivation, which had been previously described, we found that M33 alters viral gene expression, host T cell memory inflation, and MHC class I expression. US28 was able to partially complement most functions of M33, suggesting that its role in HCMV infection may be similarly pleotropic.

Background: HIV DNA mirrors the number of infected cells and the size of the HIV viral reservoir. The aim of this study was to evaluate the effect of pre-cART HIV DNA levels as a predictive marker of immune reconstitution and on the post-cART CD4 counts trends. Methods: HIV DNA was isolated from PBMCs and quantified by real-time PCR. Immune reconstitution was assessed up to four years. Piecewise-linear mixed models were used to describe CD4 count changes. Results: 148 people living with HIV (PLWH) were included. The highest rate of immune reconstitution was observed during the first trimester. There was a trend showing that high HIV RNA level resulted in greater increase in CD4 count, especially during the first trimester of cART (difference above vs. below median 15.1 cells/μL/month; 95% CI −1.4–31.5; p = 0.073). Likewise, higher HIV DNA level would predict greater CD4 increases, especially after the first trimester (difference above vs. below median 1.2 cells/μL/month; 95% CI −0.1–2.6; p = 0.071). Higher DNA and RNA levels combined were significantly associated with greater CD4 increase past the first trimester (difference high/high vs. low/low 2.1 cells/μL/month; 95% CI 0.3–4.0; p = 0.024). In multivariable analysis, lower baseline CD4 counts predicted a greater CD4 rise. Conclusions: In successfully treated PLWH, pre-cART HIV DNA and HIV RNA levels are predictors of immune reconstitution. [ABSTRACT FROM AUTHOR]

HIV-1 latency posts a major obstacle for HIV-1 eradication. Currently, no desirable latency reversing agents (LRAs) have been implicated in the “Shock and Kill” strategy to mobilize the latently infected cells to be susceptible for clearance by immune responses. Identification of key cellular pathways that modulate HIV-1 latency helps to develop efficient LRAs. In this study, we demonstrate that the Wnt downstream β-catenin/TCF1 pathway is a crucial modulator for HIV-1 latency. The pharmacological activation of the β-catenin/TCF1 pathway with glycogen synthase kinase-3 (GSK3) inhibitors promoted transcription of HIV-1 proviral DNA and reactivated latency in CD4+ T cells; the GSK3 kinase inhibitor 6-bromoindirubin-3′-oxime (6-BIO)-induced HIV-1 reactivation was subsequently confirmed in resting CD4+ T cells from cART-suppressed patients and SIV-infected rhesus macaques. These findings advance our understanding of the mechanisms responsible for viral latency, and provide the potent LRA that can be further used in conjunction of immunotherapies to eradicate viral reservoirs.

Antiretroviral therapy (ART) has brought the HIV/AIDS epidemic under control, but a curative strategy for viral eradication is still needed. The cessation of ART results in rapid viral rebound from latently infected CD4+ T cells, showing that control of viral replication alone does not fully restore immune function, nor does it eradicate viral reservoirs. With a better understanding of factors and mechanisms that promote viral latency, current approaches are primarily focused on the permanent silencing of latently infected cells (“block and lock”) or reactivating HIV-1 gene expression in latently infected cells, in combination with immune restoration strategies to eliminate HIV infected cells from the host (“shock and kill”). In this review, we provide a summary of the current, most promising approaches for HIV-1 cure strategies, including an analysis of both latency-promoting agents (LPA) and latency-reversing agents (LRA) that have shown promise in vitro, ex vivo, and in human clinical trials to reduce the HIV-1 reservoir.

Objective(s)The short-term safety of treatment interruptions, a necessary part of cure studies, is not well established, particularly in women. We explored viral rebound kinetics and safety in a group of postpartum women discontinuing ART and compared results to men in historical interruption trials.DesignProspective evaluation of time to virologic rebound.MethodsOne thousand and seventy-six asymptomatic, virally suppressed, postpartum women living with HIV enrolled in the PROMISE trial with baseline CD4 cell counts at least 350 cells/μl underwent antiretroviral treatment (ART) discontinuation. Proportion with virologic suppression at weeks 4 and 12 were compared with participants in ACTG treatment interruption trials (91% male population).ResultsIn PROMISE, using interval censored methods, the estimated median time to HIV viral rebound was 2 weeks. An estimated 6% of women would remain virally suppressed at 30 weeks. Of those who had viral rebound by 30 weeks (N = 993), less than 4% experienced grade 3 or higher laboratory events, and 1% experienced WHO stage 2 or higher clinical events. Overall, less than 1% of participants progressed from WHO Stage 1 to Stage 2 or higher after discontinuation of ART, and 3.9% experienced a decline in CD4 cell count to less than 350 cells/μl or local treatment guidelines. A significantly higher proportion of women in PROMISE (25.4%) were virologically suppressed (

Background and Aim: Ribonucleic acid viruses remain latent in different cell types, including mesenchymal stem cells; however, the distemper virus remains undetected in these cells. This study aimed to determine whether adipose stem cells (ASCs) from dogs with distemper disease are infected with the canine morbillivirus (CM). Materials and Methods: Twelve dogs with the neurological phase of the disease and who were positive for CM by reverse transcription polymerase chain reaction (RT-PCR), were studied. ASCs from adipose tissue of the lesser omentum of these infected dogs were isolated and characterized. Direct fluorescence was used to detect the viral antigen in cell cultures. Flow cytometry and RT-PCR identified detectable quantities of the virus in two cultures, while electron microscopy confirmed the CM particles within ASCs. Results: This study revealed that ASCs of the omentum of dogs with distemper disease can be infected with CM, indicating their possible involvement in this virus latency and persistence. This suggests that its detection should be considered within the quality control process of stem cells intended for regenerative medicine. Conclusion: To the best of our knowledge, this is the first study that demonstrates that omentum ASCs from dogs with distemper disease can be infected with CM and may be involved in viral latency or persistence. Our study also suggests that the detection of CM should be considered within the quality control process of stem cells intended for regenerative medicine.

microRNAs are a class of small, single-stranded, noncoding RNAs that regulate gene expression. They can be significantly dysregulated upon exposure to any infection, serving as important biomarkers and therapeutic targets. Numerous human DNA viruses, along with several herpesviruses, have been found to encode and express functional viral microRNAs known as vmiRNAs, which can play a vital role in host–pathogen interactions by controlling the viral life cycle and altering host biological pathways. Viruses have also adopted a variety of strategies to prevent being targeted by cellular miRNAs. Cellular miRNAs can act as anti- or proviral components, and their dysregulation occurs during a wide range of infections, including herpesvirus infection. This demonstrates the significance of miRNAs in host herpesvirus infection. The current state of knowledge regarding microRNAs and their role in the different stages of herpes virus infection are discussed in this review. It also delineates the therapeutic and biomarker potential of these microRNAs in future research directions. [ABSTRACT FROM AUTHOR]

Transactive response DNA binding protein 43 kDa (TDP-43) was discovered in 2001 as a cellular factor capable to inhibit HIV-1 gene expression. Successively, it was brought to new life as the most prevalent RNA-binding protein involved in several neurological disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the fact that these two research areas could be considered very distant from each other, in recent years an increasing number of publications pointed out the existence of a potentially important connection. Indeed, the ability of TDP-43 to act as an important regulator of all aspects of RNA metabolism makes this protein also a critical factor during expression of viral RNAs. Here, we summarize all recent observations regarding the involvement of TDP-43 in viral entry, replication and latency in several viruses that include enteroviruses (EVs), Theiler's murine encephalomyelitis virus (TMEV), human immunodeficiency virus (HIV), human endogenous retroviruses (HERVs), hepatitis B virus (HBV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), West Nile virus (WNV), and herpes simplex virus-2 (HSV). In particular, in this work, we aimed to highlight the presence of similarities with the most commonly studied TDP-43 related neuronal dysfunctions. [ABSTRACT FROM AUTHOR]

IntroductionHuman cytomegalovirus (HCMV) is a global health threat due to its ubiquity and lifelong persistence in infected people. During latency, host CD8+ T cell responses to HCMV continue to increase in a phenomenon known as memory inflation. We used murine CMV (MCMV) as a model for HCMV to characterize the memory inflation response to wild-type MCMV (KP) and a latency-defective mutant (ΔM33stop), which lacks M33, an MCMV chemokine receptor homolog. M33 is essential for normal reactivation from latency and this was leveraged to determine whether reactivation in vivo contributes to T cell memory inflation.MethodsMice were infected with wild-type or mutant MCMV and T cell responses were analyzed by flow cytometry at acute and latent time points. Ex vivo reactivation and cytotoxicity assays were carried out to further investigate immunity and virus replication. Quantitative reverse-transcriptase polymerase chain reaction (q-RTPCR) was used to examine gene expression during reactivation. MHC expression on infected cells was analyzed by flow cytometry. Finally, T cells were depleted from latently-infected B cell-deficient mice to examine the in vivo difference in reactivation between wild-type and ΔM33stop.ResultsWe found that ΔM33stop triggers memory inflation specific for peptides derived from the immediate-early protein IE1 but not the early protein m164, in contrast to wild-type MCMV. During ex vivo reactivation, gene expression in DM33stop-infected lung tissues was delayed compared to wild-type virus. Normal gene expression was partially rescued by substitution of the HCMV US28 open reading frame in place of the M33 gene. In vivo depletion of T cells in immunoglobulin heavy chain-knockout mice resulted in reactivation of wild-type MCMV, but not ΔM33stop, confirming the role of M33 during reactivation from latency. Further, we found that M33 induces isotype-specific downregulation of MHC class I on the cell surface suggesting previously unappreciated roles in immune evasion.DiscussionOur results indicate that M33 is more polyfunctional than previously appreciated. In addition to its role in reactivation, which had been previously described, we found that M33 alters viral gene expression, host T cell memory inflation, and MHC class I expression. US28 was able to partially complement most functions of M33, suggesting that its role in HCMV infection may be similarly pleotropic.

The persistent challenge posed by viruses that infect the central nervous system lies in their sophisticated ability to evade the host immune system. This review explores into the complex mechanisms of immune evasion employed by these neurotropic viruses, focussing on their modulation of host immune responses, evasion of adaptive immunity, and the cellular and molecular strategies that enable their persistence. Key areas explored include viral latency and reactivation, the inhibition of apoptosis, and antigenic variation, with a detailed examination of viral proteins and their interactions with host cellular processes., (© 2024 John Wiley & Sons Ltd.)

Of the 38 million people currently living with Human Immunodeficiency Virus type-1 (HIV-1), women, especially adolescents and young women, are disproportionally affected by the HIV-1 pandemic. Acquired immunodeficiency syndrome (AIDS) - related illnesses are the leading cause of death in women of reproductive age worldwide. Although combination antiretroviral therapy (cART) can suppress viral replication, cART is not curative due to the presence of a long-lived viral reservoir that persists despite treatment. Biological sex influences the characteristics of the viral reservoir as well as the immune responses to infection, factors that can have a significant impact on the design and quantification of HIV-1 curative interventions in which women are grossly underrepresented. This mini-review will provide an update on the current understanding of the impact of biological sex on the viral reservoir and will discuss the implications of these differences in the context of the development of potential HIV-1 curative strategies, with a focus on the shock and kill approach to an HIV-1 cure. This mini-review will also highlight the current gaps in the knowledge of sex-based differences in HIV-1 persistence and will speculate on approaches to address them to promote the development of more scalable, effective curative approaches for people living with HIV-1.

Background: HIV DNA mirrors the number of infected cells and the size of the HIV viral reservoir. The aim of this study was to evaluate the effect of pre-cART HIV DNA levels as a predictive marker of immune reconstitution and on the post-cART CD4 counts trends. Methods: HIV DNA was isolated from PBMCs and quantified by real-time PCR. Immune reconstitution was assessed up to four years. Piecewise-linear mixed models were used to describe CD4 count changes. Results: 148 people living with HIV (PLWH) were included. The highest rate of immune reconstitution was observed during the first trimester. There was a trend showing that high HIV RNA level resulted in greater increase in CD4 count, especially during the first trimester of cART (difference above vs. below median 15.1 cells/μL/month; 95% CI −1.4–31.5; p = 0.073). Likewise, higher HIV DNA level would predict greater CD4 increases, especially after the first trimester (difference above vs. below median 1.2 cells/μL/month; 95% CI −0.1–2.6; p = 0.071). Higher DNA and RNA levels combined were significantly associated with greater CD4 increase past the first trimester (difference high/high vs. low/low 2.1 cells/μL/month; 95% CI 0.3–4.0; p = 0.024). In multivariable analysis, lower baseline CD4 counts predicted a greater CD4 rise. Conclusions: In successfully treated PLWH, pre-cART HIV DNA and HIV RNA levels are predictors of immune reconstitution.

Background and Aim: Ribonucleic acid viruses remain latent in different cell types, including mesenchymal stem cells; however, the distemper virus remains undetected in these cells. This study aimed to determine whether adipose stem cells (ASCs) from dogs with distemper disease are infected with the canine morbillivirus (CM). Materials and Methods: Twelve dogs with the neurological phase of the disease and who were positive for CM by reverse transcription polymerase chain reaction (RT-PCR), were studied. ASCs from adipose tissue of the lesser omentum of these infected dogs were isolated and characterized. Direct fluorescence was used to detect the viral antigen in cell cultures. Flow cytometry and RT-PCR identified detectable quantities of the virus in two cultures, while electron microscopy confirmed the CM particles within ASCs. Results: This study revealed that ASCs of the omentum of dogs with distemper disease can be infected with CM, indicating their possible involvement in this virus latency and persistence. This suggests that its detection should be considered within the quality control process of stem cells intended for regenerative medicine. Conclusion: To the best of our knowledge, this is the first study that demonstrates that omentum ASCs from dogs with distemper disease can be infected with CM and may be involved in viral latency or persistence. Our study also suggests that the detection of CM should be considered within the quality control process of stem cells intended for regenerative medicine. [ABSTRACT FROM AUTHOR]

HIV-1 infection remains non-curative due to the latent reservoir, primarily a small pool of resting memory CD4+ T cells bearing replication-competent provirus. Pharmacological reversal of HIV-1 latency followed by intrinsic or extrinsic cell killing has been proposed as a promising strategy to target and eliminate HIV-1 viral reservoirs. Latency reversing agents have been extensively studied for their role in reactivating HIV-1 transcription in vivo , although no permanent reduction of the viral reservoir has been observed thus far. This is partly due to the complex nature of latency, which involves strict intrinsic regulation at multiple levels at transcription and RNA processing. Still, the molecular mechanisms that control HIV-1 latency establishment and maintenance have been almost exclusively studied in the context of chromatin remodeling, transcription initiation and elongation and most known LRAs target LTR-driven transcription by manipulating these. RNA metabolism is a largely understudies but critical mechanistic step in HIV-1 gene expression and latency. In this review we provide an update on current knowledge on the role of RNA processing mechanisms in viral gene expression and latency and speculate on the possible manipulation of these pathways as a therapeutic target for future cure studies. [ABSTRACT FROM AUTHOR]

Introduction: Understanding whether human papillomavirus (HPV) may establish latency in the uterine cervix is important. A better understanding of HPV natural history is useful for clinical counseling of women attending screening and to accurately inform health prevention strategies such as screening and HPV vaccination. We evaluated the extent of latent HPV infections in older women with a history of abnormal cytology. Material and Methods: We conducted a cross‐sectional study in Aarhus, Denmark, from March 2013 through April 2015. Women were enrolled if they underwent cervical amputation or total hysterectomy because of benign disease. Prior to surgery, women completed a questionnaire and a cervical smear was collected for HPV testing and morphological assessment. For evaluation of latency (i.e., no evidence of active HPV infection, but HPV detected in the tissue), we selected women with a history of abnormal cervical cytology or histology, as these women were considered at increased risk of harboring a latent infection. Cervical tissue underwent extensive HPV testing using the SPF10‐DEIA‐LipA25 assay. Results: Of 103 women enrolled, 26 were included in this analysis. Median age was 55 years (interquartile range [IQR] 52–65), and most women were postmenopausal and parous. The median number of sexual partners over the lifetime was six (IQR 3–10), and 85% reported no recent new sexual partner. Five women (19.2%) had evidence of active infection at the time of surgery, and 19 underwent latency evaluation. Of these, a latent infection was detected in 11 (57.9%), with HPV16 being the most prevalent type (50%). Nearly 80% (n = 14) of the 18 women with a history of previous low‐grade or high‐grade cytology with no treatment had an active or latent HPV infection, with latent infections predominating. HPV was detected in two of the six women with a history of high‐grade cytology and subsequent excisional treatment, both as latent infections. Conclusions: HPV can be detected in cervical tissue specimens without any evidence of an active HPV infection, indicative of a latent, immunologically controlled infection. Modeling studies should consider including a latent state in their model when estimating the appropriate age to stop screening and when evaluating the impact of HPV vaccination. [ABSTRACT FROM AUTHOR]

HIV-1 infection remains non-curative due to the latent reservoir, primarily a small pool of resting memory CD4+ T cells bearing replication-competent provirus. Pharmacological reversal of HIV-1 latency followed by intrinsic or extrinsic cell killing has been proposed as a promising strategy to target and eliminate HIV-1 viral reservoirs. Latency reversing agents have been extensively studied for their role in reactivating HIV-1 transcription in vivo, although no permanent reduction of the viral reservoir has been observed thus far. This is partly due to the complex nature of latency, which involves strict intrinsic regulation at multiple levels at transcription and RNA processing. Still, the molecular mechanisms that control HIV-1 latency establishment and maintenance have been almost exclusively studied in the context of chromatin remodeling, transcription initiation and elongation and most known LRAs target LTR-driven transcription by manipulating these. RNA metabolism is a largely understudies but critical mechanistic step in HIV-1 gene expression and latency. In this review we provide an update on current knowledge on the role of RNA processing mechanisms in viral gene expression and latency and speculate on the possible manipulation of these pathways as a therapeutic target for future cure studies.

Single‐cell RNA sequencing (scRNA‐seq) is a powerful technique for dissecting the complexity of normal and diseased tissues, enabling characterization of cell diversity and heterogeneous phenotypic states in unprecedented detail. However, this technology has been underutilized for exploring the interactions between the host cell and viral pathogens in latently infected cells. Herein, we use scRNA‐seq and single‐molecule sensitivity fluorescent in situ hybridization (smFISH) technologies to investigate host single‐cell transcriptome changes upon the reactivation of a human neurotropic virus, herpes simplex virus‐1 (HSV‐1). We identify the stress sensor growth arrest and DNA damage–inducible 45 beta (Gadd45b) as a critical antiviral host factor that regulates HSV‐1 reactivation events in a subpopulation of latently infected primary neurons. We show that distinct subcellular localization of Gadd45b correlates with the viral late gene expression program, as well as the expression of the viral transcription factor, ICP4. We propose that a hallmark of a "successful" or "aborted" HSV‐1 reactivation state in primary neurons is determined by a unique subcellular localization signature of the stress sensor Gadd45b. Synopsis: This study employs single‐cell analyses to identify and characterize cellular host factors that regulate latent viral genome reactivation in primary neurons. Stress sensor Gadd54b is identified as an important viral reactivation determinant. Neuronal‐infection model cultures contain multiple cell types; however latency and reactivation are exclusive to neurons.Single‐cell analyses identify stress sensor Gadd45b and heat shock response factors as determinants of viral reactivation.Accumulation of Gadd45b in subnuclear puncta correlates with reduced expression of viral productive cycle genes.Subcellular localization of Gadd45b signifies the capacity of individual neurons to support reactivation. [ABSTRACT FROM AUTHOR]

The pathogenesis of plasmablastic lymphoma (PBL) involves the Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and MYC gene aberrations. We aimed to determine the EBV latent infection pattern and frequency of MYC gene aberrations in PBLs. Immunohistochemistry was performed using antibodies for EBNA1, EBNA2, and LMP1 while fluorescence in situ hybridization was performed using a MYC probe. The patient cohort comprised 49 adult cases (44 were HIV-positive and three were HIV-negative). Forty-one cases were EBV-positive with 11 EBNA1-positive cases, all cases EBNA2-negative, and four LMP1-positive cases. Latency 0 was determined in 29 cases, latency I in eight cases, and latency II in four cases. The MYC gene was rearranged in eight cases, showed copy number alterations in 11 cases and, no rearrangement in 11 cases. This is the largest cohort of PBLs from South Africa to show a predominantly restricted EBV latency pattern with MYC gene aberrations as a common finding. [ABSTRACT FROM AUTHOR]

microRNAs are a class of small, single-stranded, noncoding RNAs that regulate gene expression. They can be significantly dysregulated upon exposure to any infection, serving as important biomarkers and therapeutic targets. Numerous human DNA viruses, along with several herpesviruses, have been found to encode and express functional viral microRNAs known as vmiRNAs, which can play a vital role in host–pathogen interactions by controlling the viral life cycle and altering host biological pathways. Viruses have also adopted a variety of strategies to prevent being targeted by cellular miRNAs. Cellular miRNAs can act as anti- or proviral components, and their dysregulation occurs during a wide range of infections, including herpesvirus infection. This demonstrates the significance of miRNAs in host herpesvirus infection. The current state of knowledge regarding microRNAs and their role in the different stages of herpes virus infection are discussed in this review. It also delineates the therapeutic and biomarker potential of these microRNAs in future research directions.

Transactive response DNA binding protein 43 kDa (TDP-43) was discovered in 2001 as a cellular factor capable to inhibit HIV-1 gene expression. Successively, it was brought to new life as the most prevalent RNA-binding protein involved in several neurological disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the fact that these two research areas could be considered very distant from each other, in recent years an increasing number of publications pointed out the existence of a potentially important connection. Indeed, the ability of TDP-43 to act as an important regulator of all aspects of RNA metabolism makes this protein also a critical factor during expression of viral RNAs. Here, we summarize all recent observations regarding the involvement of TDP-43 in viral entry, replication and latency in several viruses that include enteroviruses (EVs), Theiler’s murine encephalomyelitis virus (TMEV), human immunodeficiency virus (HIV), human endogenous retroviruses (HERVs), hepatitis B virus (HBV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), West Nile virus (WNV), and herpes simplex virus-2 (HSV). In particular, in this work, we aimed to highlight the presence of similarities with the most commonly studied TDP-43 related neuronal dysfunctions.

A large body of work in the last four decades has revealed the key pillars of HIV-1 transcription control at the initiation and elongation steps. Here, I provide a recount of this collective knowledge starting with the genomic elements (DNA and nascent TAR RNA stem-loop) and transcription factors (cellular and the viral transactivator Tat), and later transitioning to the assembly and regulation of transcription initiation and elongation complexes, and the role of chromatin structure. Compelling evidence support a core HIV-1 transcriptional program regulated by the sequential and concerted action of cellular transcription factors and Tat to promote initiation and sustain elongation, highlighting the efficiency of a small virus to take over its host to produce the high levels of transcription required for viral replication. I summarize new advances including the use of CRISPR-Cas9, genetic tools for acute factor depletion, and imaging to study transcriptional dynamics, bursting and the progression through the multiple phases of the transcriptional cycle. Finally, I describe current challenges to future major advances and discuss areas that deserve more attention to both bolster our basic knowledge of the core HIV-1 transcriptional program and open up new therapeutic opportunities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8) is a γ-herpesvirus linked to Kaposi's sarcoma (KS) and two lymphoproliferative disorders, primary effusion lymphoma (PEL or body-cavity B-lymphoma [BCBL]) and a subset of Multicentric Castleman's Disease. During lytic growth, pervasive viral transcription generating a variety of transcripts with uncertain protein-coding potential has been described on a genome-wide scale in β- and γ-herpesviruses. One class of such RNAs is called long non-coding RNAs (lncRNAs). KSHV encodes a viral lncRNA known as polyadenylated nuclear RNA (PAN RNA), a copious early gene product. PAN RNA has been implicated in KSHV gene expression, replication, and immune modulation. PAN RNA expression is required for optimal expression of the entire KSHV lytic gene expression program. Latent KSHV episomes are coated with viral latency-associated nuclear antigen (LANA). LANA rapidly dissociates from episomes during reactivation. Here we review recent studies suggesting that PAN RNA may function as a viral lncRNA, including a role in the facilitation of LANA-episomal dissociation during lytic replication.

Hosts influence and are influenced by viral replication. Cell size, for example, is a fundamental trait for microbial hosts that can not only alter the probability of viral adsorption, but also constrain the host physiological processes that the virus relies on to replicate. This intrinsic connection can affect the fitness of both host and virus, and therefore their mutual evolution. Here, we study the coevolution of bacterial hosts and their viruses by considering the dependence of viral performance on the host physiological state (viral plasticity). To this end, we modified a standard host-lytic phage model to include viral plasticity, and compared the coevolutionary strategies emerging under different scenarios, including cases in which only the virus or the host evolve. For all cases, we also obtained the evolutionary prediction of the traditional version of the model, which assumes a non-plastic virus. Our results reveal that the presence of the virus leads to an increase in host size and growth rate in the long term, which benefits both interacting populations. Our results also show that viral plasticity and evolution influence the classic host quality-quantity trade-off. Poor nutrient environments lead to abundant low-quality hosts, which tends to increase viral infection time. Conversely, richer nutrient environments lead to fewer but high-quality hosts, which decrease viral infection time. Our results can contribute to advancing our understanding of the microbial response to changing environments. For instance, both cell size and viral-induced mortality are essential factors that determine the structure and dynamics of the marine microbial community, and therefore our study can improve predictions of how marine ecosystems respond to environmental change. Our study can also help devise more reliable strategies to use phage to, for example, fight bacterial infections.

With the discovery of antiretroviral therapy, HIV-1 infection has transitioned into a manageable but chronic illness, which requires lifelong treatment. Nevertheless, complete eradication of the virus has still eluded us. This is partly due to the virus’s ability to remain in a dormant state in tissue reservoirs, ‘hidden’ from the host’s immune system. Also, the high mutation rate of HIV-1 results in escape mutations in response to many therapeutics. Regardless, the development of novel cures for HIV-1 continues to move forward with a range of approaches from immunotherapy to gene editing. However, to evaluate in vivo pathogenesis and the efficacy and safety of therapeutic approaches, a suitable animal model is necessary. To this end, the humanized mouse was developed by McCune in 1988 and has continued to be improved on over the past 30 years. Here, we review the variety of humanized mouse models that have been utilized through the years and describe their specific contribution in translating HIV-1 cure strategies to the clinic.

Hosts influence and are influenced by viral replication. Cell size, for example, is a fundamental trait for microbial hosts that can not only alter the probability of viral adsorption, but also constrain the host physiological processes that the virus relies on to replicate. This intrinsic connection can affect the fitness of both host and virus, and therefore their mutual evolution. Here, we study the coevolution of bacterial hosts and their viruses by considering the dependence of viral performance on the host physiological state (viral plasticity). To this end, we modified a standard host-lytic phage model to include viral plasticity, and compared the coevolutionary strategies emerging under different scenarios, including cases in which only the virus or the host evolve. For all cases, we also obtained the evolutionary prediction of the traditional version of the model, which assumes a non-plastic virus. Our results reveal that the presence of the virus leads to an increase in host size and growth rate in the long term, which benefits both interacting populations. Our results also show that viral plasticity and evolution influence the classic host quality-quantity trade-off. Poor nutrient environments lead to abundant low-quality hosts, which tends to increase viral infection time. Conversely, richer nutrient environments lead to fewer but high-quality hosts, which decrease viral infection time. Our results can contribute to advancing our understanding of the microbial response to changing environments. For instance, both cell size and viral-induced mortality are essential factors that determine the structure and dynamics of the marine microbial community, and therefore our study can improve predictions of how marine ecosystems respond to environmental change. Our study can also help devise more reliable strategies to use phage to, for example, fight bacterial infections. [ABSTRACT FROM AUTHOR]

Background: HIV-1 infection remains incurable through combination antiretroviral therapy. Previous studies have shown statins have immunomodulatory effects, and interruption of statins may cause an immune rebound. Methods: In this proof-of-concept study, we longitudinally assessed the impact of immune rebound by cyclic treatment-interruption (CTI) of rosuvastatin on the reversal of HIV latency. The HIV-1-infected persons with stable viral control were considered to be enrolled for CTI of rosuvastatin with a fixed 12-week interval for 72 weeks (3 treatment-interruption cycles). HIV-1 Gag-specific T-cell responses, cell-associated RNA, and proviral DNA were determined. Results: From Feb 2017 to Dec 2019, 10 subjects were enrolled. During the 72-week follow-up, their CD4+ T-cell counts did not significantly change, and plasma HIV RNA remained undetectable. Transient but remarkable increases in levels of cell-associated RNA, Gag-specific interferon-γ production from CD4+ T cells and Gag-specific CD8+ cytotoxic capacity were detected shortly after stopping rosuvastatin in every cycle of CTI of rosuvastatin. Furthermore, there was a 2.63-fold reduction (range, 1.41-4.82) in proviral DNA levels (P = 0.005) during the 72-week follow-up. A significant linear association was demonstrated between their nadir CD4+ T-cell counts and the fold decrease in proviral DNA levels (R = 0.81, P = 0.004). Conclusion: It may be possible to reverse viral latency in CD4+ T cells, activate Gag-specific T cells, and reduce viral reservoir size through CTI of rosuvastatin in HIV-1-infected subjects with stable combination antiretroviral therapy, especially in those with nadir CD4+ T-cell counts > 350 cells/µL. [ABSTRACT FROM AUTHOR]

With the discovery of antiretroviral therapy, HIV-1 infection has transitioned into a manageable but chronic illness, which requires lifelong treatment. Nevertheless, complete eradication of the virus has still eluded us. This is partly due to the virus's ability to remain in a dormant state in tissue reservoirs, 'hidden' from the host's immune system. Also, the high mutation rate of HIV-1 results in escape mutations in response to many therapeutics. Regardless, the development of novel cures for HIV-1 continues to move forward with a range of approaches from immunotherapy to gene editing. However, to evaluate in vivo pathogenesis and the efficacy and safety of therapeutic approaches, a suitable animal model is necessary. To this end, the humanized mouse was developed by McCune in 1988 and has continued to be improved on over the past 30 years. Here, we review the variety of humanized mouse models that have been utilized through the years and describe their specific contribution in translating HIV-1 cure strategies to the clinic. [ABSTRACT FROM AUTHOR]

Detection of latent human immunodeficiency virus type 1 (HIV-1) in “putative” infectious reservoirs is required for determining treatment efficiency and for viral elimination strategies. Such tests require induction of replication competent provirus and quantitative testing of viral load for validation. Recently, humanized mice were employed in the development of such tests by employing a murine viral outgrowth assay (mVOA). Here blood cells were recovered from virus infected antiretroviral therapy suppressed patients. These cells were adoptively transferred to uninfected humanized mice where replication competent virus was recovered. Prior reports supported the notion that an mVOA assay provides greater sensitivity than cell culture-based quantitative VOA tests for detection of latent virus. In the current study, the mVOA assays was adapted using donor human hematopoietic stem cells-reconstituted mice to affirm research into HIV-1 elimination. We simulated an antiretroviral therapy (ART)-treated virus-infected human by maintaining the infected humanized mice under suppressive treatment. This was operative prior to human cell adoptive transfers. Replication-competent HIV-1 was easily detected in recipient animals from donors with undetectable virus in plasma. Moreover, when the assay was used to investigate viral presence in tissue reservoirs, quantitative endpoints were determined in “putative” viral reservoirs not possible in human sample analyses. We conclude that adoptive transfer of cells between humanized mice is a sensitive and specific assay system for detection of replication competent latent HIV-1.

ABSTRACT Human cytomegalovirus (HCMV) latency is an active process which remodels the latently infected cell to optimize latent carriage and reactivation. This is achieved, in part, through the expression of viral genes, including the G-protein-coupled receptor US28. Here, we use an unbiased proteomic screen to assess changes in host proteins induced by US28, revealing that interferon-inducible genes are downregulated by US28. We validate that major histocompatibility complex (MHC) class II and two pyrin and HIN domain (PYHIN) proteins, myeloid cell nuclear differentiation antigen (MNDA) and IFI16, are downregulated during experimental latency in primary human CD14+ monocytes. We find that IFI16 is targeted rapidly during the establishment of latency in a US28-dependent manner but only in undifferentiated myeloid cells, a natural site of latent carriage. Finally, by overexpressing IFI16, we show that IFI16 can activate the viral major immediate early promoter and immediate early gene expression during latency via NF-κB, a function which explains why downregulation of IFI16 during latency is advantageous for the virus. IMPORTANCE Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus which infects 50 to 100% of humans worldwide. HCMV causes a lifelong subclinical infection in immunocompetent individuals but is a serious cause of mortality and morbidity in the immunocompromised and neonates. In particular, reactivation of HCMV in the transplant setting is a major cause of transplant failure and related disease. Therefore, a molecular understanding of HCMV latency and reactivation could provide insights into potential ways to target the latent viral reservoir in at-risk patient populations.

A new study in monkeys suggests that treating HIV infection early with antiretroviral therapy reduces the number of latent viruses, but has little impact on viral reactivation when treatment stops.

Human herpesviruses (HVs) have developed ingenious mechanisms that enable them to traverse the defenses of the central nervous system (CNS). The ability of HVs to enter a state of latency, a defining characteristic of this viral family, allows them to persist in the human host indefinitely. As such, HVs represent the most frequently detected pathogens in the brain. Under constant immune pressure, these infections are largely asymptomatic in healthy hosts. However, many neurotropic HVs have been directly connected with CNS pathology in the context of other stressors and genetic risk factors. In this review, we discuss the potential mechanisms by which neurotropic HVs contribute to neurodegenerative disease (NDD) pathology by highlighting two prominent members of the HV family, herpes simplex virus 1 (HSV-1) and human herpesvirus 6 (HHV-6). We (i) introduce the infectious pathways and replicative cycles of HSV-1 and HHV-6 and then (ii) review the clinical evidence supporting associations between these viruses and the NDDs Alzheimer's disease (AD) and multiple sclerosis (MS), respectively. We then (iii) highlight and discuss potential mechanisms by which these viruses exert negative effects on neurons and glia. Finally, we (iv) discuss how these viruses could interact with other disease-modifying factors to contribute to the initiation and/or progression of NDDs.

The complexities of viral evolution can be difficult to elucidate. Software simulating viral evolution provides powerful tools for exploring hypotheses of viral systems, especially in situations where thorough empirical data are difficult to obtain or parameters of interest are difficult to measure. Human immunodeficiency virus 1 (HIV-1) infection has no durable cure; this is primarily due to the virus' ability to integrate into the genome of host cells, where it can remain in a transcriptionally latent state. An effective cure strategy must eliminate every copy of HIV-1 in this 'persistent reservoir' because proviruses can reactivate, even decades later, to resume an active infection. However, many features of the persistent reservoir remain unclear, including the temporal dynamics of HIV-1 integration frequency and the longevity of the resulting reservoir. Thus, sophisticated analyses are required to measure these features and determine their temporal dynamics. Here, we present software that is an extension of SANTA-SIM to include multiple compartments of viral populations. We used the resulting software to create a model of HIV-1 within host evolution that incorporates the persistent HIV-1 reservoir. This model is composed of two compartments, an active compartment and a latent compartment. With this model, we compared five different date estimation methods (Closest Sequence, Clade, Linear Regression, Least Squares, and Maximum Likelihood) to recover the integration dates of genomes in our model's HIV-1 reservoir. We found that the Least Squares method performed the best with the highest concordance (0.80) between real and estimated dates and the lowest absolute error (all pairwise t tests: P  < 0.01). Our software is a useful tool for validating bioinformatics software and understanding the dynamics of the persistent HIV-1 reservoir. [ABSTRACT FROM AUTHOR]

Detection of latent human immunodeficiency virus type 1 (HIV-1) in "putative" infectious reservoirs is required for determining treatment efficiency and for viral elimination strategies. Such tests require induction of replication competent provirus and quantitative testing of viral load for validation. Recently, humanized mice were employed in the development of such tests by employing a murine viral outgrowth assay (mVOA). Here blood cells were recovered from virus infected antiretroviral therapy suppressed patients. These cells were adoptively transferred to uninfected humanized mice where replication competent virus was recovered. Prior reports supported the notion that an mVOA assay provides greater sensitivity than cell culture-based quantitative VOA tests for detection of latent virus. In the current study, the mVOA assays was adapted using donor human hematopoietic stem cells-reconstituted mice to affirm research into HIV-1 elimination. We simulated an antiretroviral therapy (ART)-treated virus-infected human by maintaining the infected humanized mice under suppressive treatment. This was operative prior to human cell adoptive transfers. Replication-competent HIV-1 was easily detected in recipient animals from donors with undetectable virus in plasma. Moreover, when the assay was used to investigate viral presence in tissue reservoirs, quantitative endpoints were determined in "putative" viral reservoirs not possible in human sample analyses. We conclude that adoptive transfer of cells between humanized mice is a sensitive and specific assay system for detection of replication competent latent HIV-1. [ABSTRACT FROM AUTHOR]

Murine models of cytomegalovirus (CMV) infection have revealed an immunological phenomenon known as “memory inflation” (MI). After a peak of a primary CD8+ T-cell response, the pool of epitope-specific cells contracts in parallel to the resolution of productive infection and the establishment of a latent infection, referred to as “latency.” CMV latency is associated with an increase in the number of cells specific for certain viral epitopes over time. The inflationary subset was identified as effector-memory T cells (iTEM) characterized by the cell surface phenotype KLRG1+CD127−CD62L−. As we have shown recently, latent viral genomes are not transcriptionally silent. Rather, viral genes are sporadically desilenced in a stochastic fashion. The current hypothesis proposes MI to be driven by presented viral antigenic peptides encoded by the corresponding, stochastically expressed viral genes. Although this mechanism suggests itself, independent evidence for antigen presentation during viral latency is pending. Here we fill this gap by showing that T cell-receptor transgenic OT-I cells that are specific for peptide SIINFEKL proliferate upon adoptive cell transfer in C57BL/6 recipients latently infected with murine CMV encoding SIINFEKL (mCMV-SIINFEKL), but not in those latently infected with mCMV-SIINFEKA, in which antigenicity is lost by mutation L8A of the C-terminal amino acid residue.

To happen, autoimmunity in man requires triggering by environmental factors: the viruses and cellular stress, in genetically primed individuals. The viruses and stress are operatives in this scene as stimuli for the activation of the transcription factor (TF), NF-ΚB. NF-ΚB is unusually activated: the viral activation occurs via serine residues-phosphorylation by IKKβ and IKKε, while the activation by oxidative stress occurs via tyrosine phosphorylation of IΚBα. The phosphorylation of particular amino acid residues of a given protein molecule modulates that protein’s polymorphic conformations, appropriately. For a TF, a given conformation influences its choice of cognate DNA sequence recognition as well as its interactions with neighboring molecules. The TF NF-ΚB performs a battery of regulatory functions. Because it is variously phosphorylated as seen above this implies that NF-ΚB is capable of assuming a multitude of polymorphic conformations that we refer to as “derivative isoforms”. Thus the virus activation of NF-ΚB occurring by phosphorylation at serines S536 and S468 is observed to generate the isoforms with the potential to activate the transcription of viral latency genes, hereby installing a latent infection. But oxidative stress activation of NF-ΚB occurs via phosphorylation of Tyr42 of IΚBα and this yields isoforms that activate the transcription of replication and transcription activator (RTA), the master lytic switch, which thereby abrogates the latency. The steps involved are that the stress-activated NF-ΚB and the viral miRNAs conjoin in a regulatory circuitry identified as feedback and feed-forward network motifs that co-accomplish the switching on of RTA which in turn activates the transcription of the immediate early genes BZLF1 and BRLF1. These two latter genes together mobilize the expression of the set of lytic genes, resulting in a lytic cascade and consequentially set in trend the viral journey to the triggering of autoimmunity (Figure 1).

Gammaherpesviruses are important pathogens that establish latent infection in their natural host for lifelong persistence. During latency, the viral genome persists in the nucleus of infected cells as a circular episomal element while the viral gene expression program is restricted to non-coding RNAs and a few latency proteins. Among these, the genome maintenance protein (GMP) is part of the small subset of genes expressed in latently infected cells. Despite sharing little peptidic sequence similarity, gammaherpesvirus GMPs have conserved functions playing essential roles in latent infection. Among these functions, GMPs have acquired an intriguing capacity to evade the cytotoxic T cell response through self-limitation of MHC class I-restricted antigen presentation, further ensuring virus persistence in the infected host. In this review, we provide an updated overview of the main functions of gammaherpesvirus GMPs during latency with an emphasis on their immune evasion properties.

Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus and the causative agent of varicella (chickenpox) in humans. Following primary infection, VZV establishes latency in the sensory ganglia and can reactivate to cause herpes zoster, more commonly known as shingles, which causes significant morbidity, and on rare occasions mortality, in the elderly. Because VZV infection is highly restricted to humans, the development of a reliable animal model has been challenging, and our understanding of VZV pathogenesis remains incomplete. As an alternative, infection of rhesus macaques with the homologous simian varicella virus (SVV) recapitulates the hallmarks of VZV infection and thus constitutes a robust animal model to provide critical insights into VZV pathogenesis and the host antiviral response. In this model, SVV infection results in the development of varicella during primary infection, generation of an adaptive immune response, establishment of latency in the sensory ganglia, and viral reactivation upon immune suppression. In this review, we discuss our current knowledge about host and viral factors involved in the establishment of SVV latency and reactivation as well as the important role played by T cells in SVV pathogenesis and antiviral immunity.

Kaposi's sarcoma-associated herpesvirus (KSHV) has latent and lytic replication phases, both of which contribute to the development of KSHV-induced malignancies. Among numerous factors identified to regulate KSHV life cycle, oxidative stress, caused by imbalanced clearing and production of reactive oxygen species (ROS), has been shown to robustly disrupt KSHV latency and induce viral lytic replication. In this study, we identify an important role of antioxidant defense factor forkhead box protein O1 (FoxO1) in KSHV lifecycle. Either chemical inhibition of the FoxO1 function or knockdown of FoxO1 expression led to the increase of intracellular ROS level that was subsequently sufficient to disrupt KSHV latency and induce viral lytic reactivation. On the other hand, treatment with N-acetyl-L-cysteine (NAC), an oxygen free radical scavenger, led to the reduction of FoxO1 inhibition-induced ROS level and ultimately the attenuation of KSHV lytic reactivation. These findings reveal that FoxO1 plays a critical role in keeping KSHV latency in check by maintaining intracellular redox balance. [ABSTRACT FROM AUTHOR]

Etiology, transmission and protection: Herpes simplex virus-2 (HSV-2) is a leading cause of sexually transmitted infections with recurring manifestations throughout the lifetime of infected hosts. Currently no effective vaccines or prophylactics exist that provide complete protection or immunity from the virus, which is endemic throughout the world. Pathology/Symptomatology: Primary and recurrent infections result in lesions and inflammation around the genital area and the latter accounts for majority of genital herpes instances. Immunocompromised patients including neonates are susceptible to additional systemic infections including debilitating consequences of nervous system inflammation. Epidemiology, incidence and prevalence: More than 500 million people are infected worldwide and most reported cases involve the age groups between 16-40 years, which coincides with an increase in sexual activity among this age group. While these numbers are an estimate, the actual numbers may be underestimated as many people are asymptomatic or do not report the symptoms. Treatment and curability: Currently prescribed medications, mostly nucleoside analogs, only reduce the symptoms caused by an active infection, but do not eliminate the virus or reduce latency. Therefore, no cure exists against genital herpes and infected patients suffer from periodic recurrences of disease symptoms for their entire lives. Molecular mechanisms of infection: The last few decades have generated many new advances in our understanding of the mechanisms that drive HSV infection. The viral entry receptors such as nectin-1 and HVEM have been identified, cytoskeletal signaling and membrane structures such as filopodia have been directly implicated in viral entry, host motor proteins and their viral ligands have been shown to facilitate capsid transport and many host and HSV proteins have been identified that help with viral replication and pathogenesis. New understanding has emerged on the role of autophagy and other innate immune mechanisms that are subverted to enhance HSV pathogenesis. This review summarizes our current understanding of HSV-2 and associated diseases and available or upcoming new treatments.