BASIC BIOMEDICAL AND TRANSLATIONAL SCIENCE DISCOVERY INITIATIVE (2024)

Basic Biomedical Discovery Initiative 2022

Single-Cell HIV Reservoir Dynamics Following Gene Modified Autologous Stem Cell Transplantation
Timothy Henrich, MD MMDc
UC San Francisco

The use of gene-modified cells to reduce HIV reservoir size and delay HIV recrudescence is on the forefront of HIV curative science. However, current approaches may have limited impact in people with HIV (PWH) and may only provide a single layer of protection against infection.  As a result, the AMC #097 study, “A Phase I Study of Stem Cell Gene Therapy for HIV Mediated by Lentivector Transduced, Pre-Selected CD34+ Cells: A Trial of the AIDS Malignancy Consortium,” was implemented to use multiple anti-HIV gene-modified cells to block HIV infection at different states of the viral life cycle. We hypothesize that the combined gene-modification approach in the AMC097 study will lead to reductions in the overall burden of HIV infection and lead to post-treatment control during analytical treatment interruption (ATI). Furthermore, we have developed a novel assay to determine if HIV infects gene-modified cells. Our aims are to determine the long-term impact of autologous SCT with gene-modified stem cells simultaneously targeting different stages of the HIV replication cycle on the burden of HIV infection, and to determine if gene-modified cells become infected prior to and following cessation of ART in the AMC097 trial. 

Neuroimaging and Inflammation among People Living with HIV with History of Methamphetamine Use
Judith Lobo, PhD
UC San Diego

Methamphetamine (METH) is the most commonly used illicit substance in San Diego and there is limited treatment available for METH dependence. Understanding the how METH use changes the way the brain works is an essential step in developing the best patient care possible. Based on previous studies using brain imaging, we hypothesize that the same brain regions are negatively affected by HIV status, history of METH-use, and inflammation. However, little is known about how the brain behaves when an individual is both living with HIV and has a history of METH use. Our goal is to help better understand how brain activity is changed in this setting, and whether those changes are due to HIV status, METH use or both. Inflammation is thought to be related to these brain function alterations, so we will use inflammatory levels measured by blood sample to determine if these changes are related to increased levels of inflammation. The data used in this study has already been collected, by the University of California San Diego: Translational Methamphetamine AIDS Research Center. We will add to this dataset by running more inflammatory marker-panels on frozen blood samples. In order to be able to compare the effects of HIV and METH, we will compare the data of individuals in four groups: 1) HIV+ METH+, 2)HIV- METH+, 3) HIV+ METH-, 4) HIV- METH-. Our neuroimaging analysis will focus on two brain regions, the dorsolateral prefrontal cortex and the anterior cingulate cortex. To our knowledge, this would be the first neuroimaging and inflammation study in this population. The goal of this work is to help better understand the complex relationships between substance use, inflammation, and the brain in people with HIV who also have a history of METH use, a growing population in California.

Cannabinoid Receptor 2-Signaling in Endothelial Integrity and Functions in the Context of HIV
Maria Cecilia Marcondes, PhD
Ballad Research Institute, San Diego Biomedical Research Institute

Cannabis is broadly used by persons living with HIV. The mechanisms by which cannabinoids harm or benefit the brain in the context of HIV have yet to be defined, particularly on endothelial function and the blood brain barrier (BBB). Our goal is to examine the influence of cannabis, via CB2R-signaling, on vascular integrity and function, in the context of HIV, with implications on cell migration and penetration of antiretroviral drugs (ART). The project is novel for multiple reasons: (i) it will address a knowledge gap on the effects of cannabinoids on BBB molecular and functional properties in the context of HIV, (ii), it will build on evidence of a beneficial role for CB2R stimulation in the context of HIV infection, to recover damaged endothelium, (iii)it will utilize gene editing strategies to produce cell line tools to study outcomes influenced by CBR2, (iv) it will provide mechanistic and translational information on the impact of cannabis on eradication strategies such as ART penetration through the BBB to target latent CNS reservoirs, (v) it will employ clinically-relevant systems, with a multidisciplinary team, and state of the art technical expertise, and (v)it will test biomarkers of intact BBB in the context of HIV and cannabis.

Modulating Therapeutic HIV Vaccine Responses Using Rapamycin to Achieve Post-Treatment Control
Gema Mendez Lagares, PhD
UC Davis

Most HIV-infected patients who stop taking antiretroviral drugs experience rapid viral rebound and suffer in the longer term from presence of more virus in blood and lower CD4+ T-cell counts. HIV-1 infection generally increases T-cell metabolism, which means that cells are more active, which promotes successful viral integration and replication. Our preliminary data show that although therapeutic T-cell vaccination can effectively generate cytotoxic “killer” T-cells that kill HIV-infected cells, in most cases this antiviral activity is insufficient to limit viral replication. It is critical to improve upon these promising vaccine strategies and to design novel approaches for enhancing vaccine-induced immunity. Given intriguing data indicating that rapamycin, a drug that targets T-cell metabolism and is used at high doses as an immunosuppressive agent, can enhance the magnitude and the quality of vaccine-induced virus specific memory T-cells, we hypothesized that stringent post-treatment control requires both effective anti-SIV responses to a therapeutic vaccine and unfavorable metabolic conditions for viral replication. Here we propose to modulate the mTOR pathway during antiretroviral therapy interruption, to reduce T-cell activation and the availability of new target cells, and during vaccination, to enhance SIV-specific cellular immunity. To achieve our goal, we will investigate two important effects of rapamycin in rhesus macaques; 1) its effect in controlling inflammation and immune activation and 2) its ability to create effective T-cell responses in recipients of therapeutic vaccination.

A Novel Primary Cell HIV-CRISPR Screen to Elucidate Mechanisms of a Noncytotoxic Antiviral Response
Ujjwal Rathore, PhD
David Gladstone Institutes

HIV attacks the body’s immune system by infecting a specific type of immune cells called CD4 T-cells. If left untreated, the destruction of CD4 T-cells makes it difficult for the body to fight infections, a condition known as Acquired Immunodeficiency Syndrome (AIDS). Despite 40 years of research, we still do not have a cure for HIV. Current anti-HIV drugs (also known as antiretrovirals) keep the HIV virus under control but cannot eliminate it from the body, necessitating a life-long dependence on these drugs. However, some rare HIV-positive individuals can stay symptom-free and disease-free for years without any antiretroviral therapy and are called elite controllers or HIV long-term non-progressors. If we can crack the mystery of how these individuals keep HIV under control without drugs, then we can use that knowledge to find a cure for HIV. In some of these HIV controllers, it was found that their CD8 T-cells, another type of immune cells important for killing virus-infected cells in the body, can stop the HIV virus from multiplying in the HIV-infected CD4 cells, without killing the latter. This phenomenon is called CD8 T-cell non-cytotoxic antiviral response (CNAR). CD4 T-cell numbers are usually maintained well in such persons, without developing symptoms of immune deficiency. We aim to understand how CD8 T-cells stop HIV replication in CD4 T-cells. In the proposed project, we will use a type of molecular scissors called CRISPR-Cas9 to cut and mutate the genes of HIV-infected CD4 T-cells. This pool of mutated CD4 T-cells will be grown with CD8 T-cells from i) elite HIV controllers, ii) non-elite-controlling persons with HIV, and/or iii) healthy individuals without HIV. If deletion of certain gene(s) in CD4 T-cells inhibits the antiviral activity of CD8 T-cells, we can infer involvement of these genes in the antiviral response. In this study, we propose to delete all 20,000 human genes in CD4 T-cells at once and examine their effect on the anti-viral activity of CD8 T-cells. The knowledge gained from these experiments is hoped to contribute towards a cure for HIV.

Genetic modification of HIV-specific T cell differentiation state to promote control of HIV
Rachel Rutishauser, MD PhD
UC San Francisco

HIV is an infection for which there is currently no cure. Many approaches to curing HIV seek to harness the power of anti-HIV T cells to specifically recognize and kill cells in the body that are infected with HIV. Because T-cells can become dysfunctional - or “exhausted” - during chronic HIV infection, we need to find approaches that prevent anti-HIV T-cells from losing their function. In this proposal, we will test cutting-edge approaches to overcome anti-HIV T-cell exhaustion that are concurrently being evaluated to improve T-cell-based therapies for cancer, another setting where T-cell exhaustion can hinder the efficacy of these treatments. Specifically, we will make anti-HIV T-cells (called CAR-T-cells, or chimeric antigen receptor T-cells) that we genetically engineer to not become exhausted by targeting the expression of genes that control T-cell exhaustion. We will target one gene that we have found gives anti-HIV T-cells the ability to proliferate robustly when they encounter HIV. Using CRISPR technology for gene editing, we will then target several other genes that we hypothesize may have a similar effect based on our preliminary studies in T-cells isolated from people with HIV who naturally control the infection and have highly functional anti-HIV T-cells. Finally, we are proposing to develop a novel system in the laboratory that will allow us to evaluate the function of anti-HIV CAR-T-cells in lymph nodes, the natural environment where HIV-infected cells persist in the body. Our studies will help us to identify and test new targets to improve the function of anti-HIV T-cells for HIV cure.

A molecular link between neuronal activity and CNS inflammation.
Sunnie Yoh, PhD
The Scripps Research Institute

Due to the advent of combination antiretroviral therapies (cART), systemic viral loads and morbidity rates in people leaving with HIV have been drastically reduced. Nonetheless, a significant portion of persons living with HIV exhibit neurocognitive disorders, which manifest in a broad spectrum from mild to severe conditions that include dementia or encephalitis. Several lines of evidence suggest that HIV continues to replicate at low levels in the central nervous system (CNS) even when cART suppresses systemic viremia. Other evidence suggests that persistent CNS inflammation, potentially induced by this low-level viral replication, may be a significant cause of HIV-1 associated neurocognitive disorders (HANDs). Phenotypic approaches to understanding the impact of HIV-associated neuroinflammation on CNS homeostasis is challenged by the fact that neuroinflammation is a concerted action of immune cells, vascular cells and neurons, whose responses can be inflammatory to anti-inflammatory simultaneously and whose outcome can be both neuroprotective and neuropathic.  Thus, we propose to identify molecular links among neuronal activity, CNS inflammation and neuropathological outcome in people living with HIV. We hypothesize that a master regulator of neuronal synaptic plasticity Arc (activity regulated cytoskeleton associated protein) modulates the inflammatory response to HIV infection in the CNS, and that this action potentially contributes to neuropathological outcomes in people living in HIV.

Basic Biomedical Discovery Initiative 2020

Microbiome Mechanisms in Substance Use and HIV Inflammation
Jennifer Fulcher, MD PhD
UCLA

Despite the success of antiretroviral therapy in controlling HIV replication, chronic HIV infection causes persistent inflammation and increases risks of other health problems such as cardiovascular disease, bone disease, and cancer. These risks are even greater among substance using persons living with HIV, especially with stimulant use such as methamphetamine. It is important to understand what causes this chronic inflammation in order to develop better tools to treat substance use and HIV disease.

Many studies have shown a connection between the body’s commensal microbiota (also called the microbiome), mucosal immune system, and HIV-related inflammation. Substance use can also affect the body’s microbiota, and this may be one reason why HIV disease is worse among substance users. While the intestinal microbiome has been the focus of intense research, less is known about the role of the oral microbiome in health and disease. Studies examining the oral microbiome in the setting of HIV are limited and inconclusive. In non-HIV settings, the oral microbiome has been associated with increased risk of inflammation-related diseases such as cardiovascular disease. No published studies have examined the oral microbiome in methamphetamine users, despite known detrimental effects of methamphetamine on oral health. We intend to fill this gap in knowledge by examining the effects of methamphetamine use and HIV on the oral microbiome and resultant immune changes.

Our study will utilize a well-defined longitudinal cohort with archived saliva specimens and detailed substance use data for comprehensive microbiome analyses using metagenomics and novel analytic approaches. We will correlate the oral microbiome with systemic inflammation using immune biomarker analysis of paired blood specimens. Additional studies will use human oral mucosal tissue explants and mass cytometry to test relevant immune functions.

The data from this study will identify oral microbiome changes associated with HIV and/or methamphetamine use, and importantly will correlate these changes with immune and inflammatory outcomes. The goal of this work is to help better understand the complex relationships between substance use, the microbiome, and inflammation in HIV. The impact of the oral microbiome is an overlooked, yet potentially important, area for intervention. This is a critical step for developing better therapeutics.

The human immunodeficiency virus (HIV) infects human immune cells, avoids detection by the immune system, and causes acquired immune deficiency syndrome (AIDS). HIV encodes only 15 proteins, compared to more than 20,000 encoded by the human genome. HIV exerts profound effects on the cells it infects by virtue of its so-called accessory factors, whose job is to hijack our own cellular machinery. Over 400 human proteins are known to interact with HIV accessory factors.  One of these factors is the Nef protein. Patients infected with strains of HIV that have a defective version of Nef remain disease-free for years to decades, and are known as "long-term non-progressors". It would be highly desirable to have HIV Nef inhibitors that would have a similar effect in patients infected with normal HIV, however, the Nef protein does not have any one obvious point of vulnerability for us to attack.

Our laboratory uses structural biology and biochemistry to study how Nef interacts with human protein complexes, in search of sites that could be targeted to make Nef inhibitors. We have spent a number of years productively working out how Nef targets the cell process of endocytosis. Our lab also studies cellular self-eating, known as "autophagy". Autophagy is used to survive in starvation but can also be used by cells as a host defense against invading intracellular pathogens, which include HIV. Until now, little has been known about whether HIV is targeted by autophagy in the cell, and whether HIV has ways to fight back against autophagy, or even manipulate autophagy to its own ends. Our lab recently obtained some evidence that HIV Nef directly binds to and inhibits one of the main human protein complexes involved in autophagy. In this project, we will work out how this happens in enough detail to determine whether and how important this effect really is for HIV infection. If we are able to verify the effect is important for infection, the data we obtain will be the starting point for designing Nef inhibitors that reverse the effect and so help enable our own cell's defense to fight back against infection.

After entering human CD4 T lymphocytes, HIV integrates within human DNA and immediately engages a variety of host genes. In most cells, viral replication occurs allowing dissemination of the virus. However, in some rare cells, the virus is repressed giving rise to a reservoir of latently infected cells. These latent proviruses are not affected by antiretroviral therapy (ART). However, if ART is withdrawn, virus present in the latent reservoir can reseed systemic viral infection. Currently, people living with HIV must take antiretroviral pills daily for their entire life to prevent viral rebound from the latent reservoir. Efforts to achieve a cure for HIV infection require a better understanding of the host genes involved in establishing and maintaining HIV latency.

This two-year Basic Biomedical Pilot Award from California HIV/AIDS Research Program seeks to identify host genes that repress HIV replication resulting in latently infected cells. In Aim 1, using a new technique termed CRISPR interference (CRISPRi), we will examine the potential repressive function of each of the 20,000 human protein-coding genes. Groups of these genes will be shut down and the cells assessed for a return of HIV expression. Isolation of the virus-producing cells will permit the generation of enriched CRISPRi libraries. Serial rounds of enrichment will allow us to home in on a set of latency-promoting genes.

Identification of these HIV repressors could lead to strategies for either purging or silencing the latent reservoir. In Aim 2, we will validate the function of these latency promoting genes in primary CD4 T cell models of HIV latency and in latently infected cells obtained from HIV-infected individuals on long term ART. We have already isolated four candidate latency promoting genes and are currently testing their function in the primary CD4 T cell models. Ultimately, small molecule inhibitors of these latency genes could form a new and exciting class of latency reversing agents. Conversely, activators of these cellular genes might be useful in block and lock strategies designed to permanently silence latent HIV proviruses.

Rates of newly diagnosed HIV infection are 3 times the national average in the transgender/non-binary (TGNB) population and nearly 14% of TGNB individuals are living with HIV infection. Currently, there are two commercially available drug products approved for preventing HIV: emtricitabine (F) in combination with either tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). The use of these F/TDF or F/TAF to prevent HIV is commonly referred to as pre-exposure prophylaxis (PrEP). While both F/TDF and F/TAF are effective at preventing HIV, these medications are cleared by the kidneys and their dosing relies on accurate estimation of kidney function to initiate PrEP and monitor for side effects. The most prevalent method of estimating kidney function involves calculating creatinine clearance (CRCL) using the Cockcroft-Gault (CG) equation. The CG equation was developed over 40 years ago and only considers age, weight, sex and serum creatinine. It does not differentiate sex assigned at birth versus current gender identity, nor does it account for the use of hormones, such as testosterone or estrogen. This is important because hormones are very commonly used in the TGNB population.

We are interested in assessing the relatedness of using of hormones (tablets, injections, creams, etc), actual amount of hormones measured in blood (i.e. estradiol, free/total testosterone), different blood/urine biomarkers that predict kidney injury or function, drug levels of F/TDF and F/TAF in the blood and measured kidney function. Our hypothesis is that use of masculinizing hormones like testosterone and having higher levels of testosterone in the blood will be associated with decreased kidney function and higher PrEP drug levels.

We plan to assess a population of 40 TGNB adults who are taking F/TDF for PrEP and plan on switching to F/TAF. The study population will be comprised of  four groups: i) TGNB individuals assigned male at birth (MtF) taking estrogen, ii) MtF not taking estrogens, TGNB individuals assigned female at birth (FtM) taking testosterone  and iv) FtM not taking testosterone. Study participants will come in for two study visits: once while on F/TDF and again after starting F/TAF. At each visit, they will be given a small dose of iohexol (medication that will help determine how well the kidneys are functioning) and four blood and one urine sample will be collected.

This study will be among the first to refine the estimation of kidney function in TGNB individuals. We will determine if the accuracy of CRCL estimating equations can be improved by including the use of hormones, the presence of various kidney biomarkers, and gender identity. The study’s potential findings have broad implications for clinical practice beyond HIV prevention and include management of other medications for other health conditions that require an accurate understanding of kidney function in the TGNB population.

When immune cells targeted by HIV, such as CD4+ T cells, become latently-infected, they do not produce virus and are largely invisible to the immune system. However, this hidden infection is reversibly-silent, meaning that latently-infected cells cannot be cleared by the immune system and can reactivate once an individual ceases drug treatment. These latently-infected CD4+ T cells are thought to be the main barrier to HIV cure and likely also contribute to the reduced life expectancy and higher incidence of diseases that are observed even in individuals who are optimally treated with currently available drugs.

In order to develop better therapies for HIV, including those aimed at cure, it is essential to understand the mechanisms that determine whether an infected cell will produce virus (productively infected) or establish this silent, latent infection. A major goal of HIV cure research is understanding which human cellular proteins govern latent vs. productive infection, and whether there is a cellular gene signature that can identify and target latently-infected cells.

Most CD4+ T cells and most HIV-infected cells reside in lymphoid tissues, particularly the gut. Several challenges exist for studying HIV latency in vivo: (1) latently-infected CD4+ T cells are indistinguishable from uninfected cells and are rare; (2) exceedingly low RNA expression is emblematic of latently-infected cells; and (3) bulk cell analyses fail to provide the necessary resolution to study these cells. Also, most methods rely on T cell activation to detect latently-infected cells, which can cause dramatic changes to the cell and preclude study of the original cell state. Single cell analyses of the blood and gut are necessary to examine the precise mechanisms that underlie lifelong maintenance of HIV latency.

We propose novel single-cell approaches that are sensitive enough to detect the viral genome in single infected cells from HIV-infected individuals (with and without activation) and simultaneously characterize multiple key aspects of the infection (such as the proviral genome, viral transcriptome, and human transcriptome) to identify differences between latently-infected, productively-infected, and uninfected cells from the blood and gut. These studies will provide insight into the mechanisms that underlie the maintenance of HIV latency, which could help us to devise better strategies to target and eliminate HIV.

An infant’s immune system is functionally immature making it difficult to combat infections.  The immune system of infants infected with or exposed to HIV, is even more compromised as reflected by a higher incidence of morbidity and mortality due to infectious causes, including other virus infections.  This is in part related to the immaturity of immune cells that make antiviral proteins including Type I interferons (IFN). The main producers of IFN are the plasmacytoid dendritic cells (pDC).  It has been reported that neonatal peripheral blood and cord blood pDC produce lower levels of Interferon-α (IFN-α) after exposure to viruses such as human Cytomegalovirus (CMV) or Herpes Simplex virus 1 (HSV1) as compared to adult pDC. 

Type I IFN include several subtypes of IFN-α as well as IFN-β. The IFN-α subtypes have different functions.  For example IFN-α2, has been studied extensively for its antiviral effects in acute HIV infection in adults and was found to have only a minor effect on HIV replication.  In contrast, IFN-α14 and IFN-α8 do show anti-HIV activity.  However there is limited information on the impact of HIV infection, or exposure to HIV, on the production of different subtypes of IFN-α and IFN-β by cord blood pDC.  Furthermore, little is known about how HIV infection/exposure alters the expression of the Type I IFN receptors on cord blood mononuclear cells.

In the proposed research we will test our hypothesis that “Neonatal/cord blood pDC exposed to, or infected with, HIV produce IFN-α subtypes with low antiviral activity with negative consequences for antiviral responses”.  A decrease in IFN-α subtypes with antiviral activity has consequences for effective control of HIV in neonates born to HIV infected mothers and should therefore be examined.  In addition to differences in anti-HIV activity of the IFN-α subtypes, we need to investigate the differential impact of HIV infection on IFN-β as we found that IFN-α and IFN-β play distinct roles in HIV infection.

The proposed research is significant as it addresses a neglected facet of the immune response in HIV infection and could reveal new targets for therapeutic approaches to improve the control of HIV and secondary infections.  This proposal leverages the expertise of the lead PI and co-PIs in pDC biology and innate immunity, and the synergy among the laboratories will facilitate the investigation of this highly innovative and underexplored question.  

Chimeric antigen receptors (CARs) can be delivered to immune cells via gene therapy to retarget the immune system. This targeting is generally achieved by a portion of the CAR that is an antibody against the desired target. When that antibody portion binds its target, such as a particular protein on a cancer cell, the CAR activates the immune cell to attack the cell with the target. In recent years, CAR gene therapy has made remarkable inroads into treating some cancers.

Ironically, the very first CAR therapy was targeted against HIV, but abandoned after clinical trials about 20 years ago showed no obvious efficacy. Gene therapy was in its infancy at that time, and technical challenges probably contributed to this failure. Meanwhile, there have been significant technological advances making CAR gene delivery successful in cancer treatment. Scientists are now revisiting the possibility of trying CARs for HIV treatment again.

One significant issue is the remarkable ability of HIV to mutate. It generally easily adapts to avoid immunity including antibodies. This is an area that has yet received little attention in the CAR field, but will certainly be a barrier for CAR therapy for HIV, which are based on the ability of antibodies to bind the virus. Analogous to current drug therapies, it is likely that combinations of antibody targeting will be required for successful CAR.

This project will tackle this issue. It will utilize a novel antibody engineering technology to combine two different antibodies into HIV-targeted CARs, which will make them more resistant to viral escape because HIV would need to avoid two different antibodies simultaneously. Two antibodies may still not pose enough of a barrier to prevent viral escape, so the project will also test combinations of these dual-CARs. The overall goal is to identify combinations of CARs that will be able to contain HIV without allowing it to mutate and escape from immune control. This would be a key advance in applying CARs to the functional cure of HIV infection.

Microglia cells are residential macrophages of the CNS and the key innate immune cells whose response dictates inflammatory states in the brain.  Aberrant microglial activation, including pathogenic infection, is considered as a key contributor to neurodegenerative diseases such as HIV-associated neurocognitive disorders (HANDs). In accordance with the current unmet need to understand the molecular details of HIV-1 induced neuroinflammation, we are interested in understanding the innate immune sensing of HIV-1 infection in microglia.

Previously, we and others have discovered that cyclic GMP-AMP synthetase (cGAS) is a key player of the innate immune response to HIV-1 infection in myeloid cells such as macrophages and dendritic cells.  Importantly, through siRNA screening, we identified polyglutamine track binding protein 1 (PQBP1) as an essential cofactor of the cGAS mediated innate immune sensing of HIV-1 infection. This application leverages a large body of preliminary data generated in HIV-1 infection sensing by PQBP1/cGAS complex in myeloid cells. Based on the functional similarity between blood macrophages and microglia, we hypothesize that an analogous mode of innate immune sensing of HIV-1 infection occurs in microglial cells.

The goal of this study is to establish the presence of the cGAS sensing of HIV-1 infection in microglia which will test a feasibility of future full-scale interrogation on this innate sensing circuits in the microglia.  Abundant clinical evidences on chronically infected patients including the ones with HIV-1 encephalitis indicate that microglial activation exist in a spectrum of activation status. Nonetheless, how the mechanisms regulating the differential microglial activation are largely veiled. If our hypothesis is proven such that the PQBP1/cGAS functions as a rate limiting step of the innate immune responses against HIV-1 infection and this step is regulated differently depending on the cellular context, our model can provide a molecular basis of the apparent diversity in microglial activation states during the course of HIV-1 infection.

Unraveling the interface between the cellular state and permissiveness to innate response will certainly provide insight into the aging-associated dysfunction of microglia whose phenotypes resembles immune senescence.  

Basic Biomedical Discovery Initiative 2016

CHRP selected nine investigators from various institutions across California as recipients of the 2016 Innovative, Developmental Exploratory Awards (IDEAs) in basic biomedical science. Learn more about these projects by clicking on the following link (Basic Biomedical Science Awards 2016).