The majority of preclinical and clinical human immunodeficiency virus type 1 (HIV-1) vaccine deve... more The majority of preclinical and clinical human immunodeficiency virus type 1 (HIV-1) vaccine development efforts have focused on HIV-1 subtype B strains from the western world. However, the overwhelming majority of HIV/AIDS-related deaths occur in the developing world and are from other HIV-1 subtype strains. Therefore, we sought to develop and generate the first mucosally transmissible simian-human immunodeficiency virus (SHIV) challenge stocks from HIV-1 subtype AE env sequences. The sequences were identified from acutely infected HIV-1 individuals from Southeast Asia. The challenge stocks efficiently infected rhesus monkeys, replicated to high levels during acute infection, and established chronic setpoint viremia. The SHIV challenge stocks should facilitate the evaluation of vaccines and other interventions aimed at controlling the spread of HIV-1 subtype AE infection.
s: Nieuwe inzichten in pathogenese en cure ..................... 3 Abstracts: PreP ................. more s: Nieuwe inzichten in pathogenese en cure ..................... 3 Abstracts: PreP ................................................................................. 4s: PreP ................................................................................. 4 Abstracts: HIV farmacologie is dit nog belangrijk? ...................... 5s: HIV farmacologie is dit nog belangrijk? ...................... 5 Abstracts: Hepatitis C, TBC en andere co-morbiditeiten ................ 6s: Hepatitis C, TBC en andere co-morbiditeiten ................ 6 Abstracts: Bredere indicatie antiretrovirale therapie .................... 7s: Bredere indicatie antiretrovirale therapie .................... 7
Background Zika virus (ZIKV) was first isolated from a sentinel rhesus monkey in 1947. ZIKV infec... more Background Zika virus (ZIKV) was first isolated from a sentinel rhesus monkey in 1947. ZIKV infection in humans is associated with serious neurological and reproductive complications. No antiviral or protective vaccine is yet available. Galidesivir an adenosine analog is a potent viral RNA-dependent RNA polymerase inhibitor with demonstrated broad-spectrum antiviral activity. Methods We have conducted four pre-clinical studies in rhesus macaques to assess the safety, antiviral efficacy and dosing strategies of galidesivir against ZIKV infection. Collectively, we have challenged 70 rhesus macaques by various routes using 1x105 TCID50of a Puerto Rican ZIKV isolate. We have evaluated galidesivir therapy administered via IM injection as early as 90 minutes and up to 72 hours after subcutaneous (SC) ZIKV challenge, and as late as 5 days after intravaginal (IVAG) challenge. In these studies, we evaluated the efficacy of a range of loading and maintence doses of galidesivir. The highest do...
Retroviruses are known to exhibit remarkable genomic pliancy, a capacity that has been attributed... more Retroviruses are known to exhibit remarkable genomic pliancy, a capacity that has been attributed to one or more error prone steps in the viral replication cycle. However, increasing evidence suggests that such error represents a key element in viral survival, as exemplified by studies on virus immune evasion, shifts of cellular tropism, and anatomic compartmentalization, which facilitate persistent virus reservoirs. Understanding the dynamic mechanisms that contribute to the establishment and maintenance of retroviral persistence is critical toward the goal of attaining HIV-1 eradication.
The cytoplasmic TRIM5a proteins of certain mammalian lineages efficiently recognize the incoming ... more The cytoplasmic TRIM5a proteins of certain mammalian lineages efficiently recognize the incoming capsids of particular retroviruses and potently restrict infection in a species-specific manner. Successful retroviruses have evolved capsids that are less efficiently recognized by the TRIM5a proteins of the natural hosts. To address whether TRIM5a contributes to the outcome of retroviral infection in a susceptible host species, we investigated the impact of TRIM5 polymorphisms in rhesus monkeys on the course of a simian immunodeficiency virus (SIV) infection. Full-length TRIM5a cDNAs were derived from each of 79 outbred monkeys and sequenced. Associations were explored between the expression of particular TRIM5 alleles and both the permissiveness of cells to SIV infection in vitro and clinical sequelae of SIV infection in vivo. Natural variation in the TRIM5a B30.2(SPRY) domain influenced the efficiency of SIVmac capsid binding and the in vitro susceptibility of cells from the monkeys ...
A novel method to identify and characterise peptide mimotopes of heat shock protein 70-associated... more A novel method to identify and characterise peptide mimotopes of heat shock protein 70-associated antigens
CCL3 is a ligand for the HIV-1 co-receptor CCR5. There have recently been conflicting reports in ... more CCL3 is a ligand for the HIV-1 co-receptor CCR5. There have recently been conflicting reports in the literature concerning whether CCL3-like gene (CCL3L) copy number variation (CNV) is associated with resistance to HIV-1 acquisition and with both viral load and disease progression following infection with HIV-1. An association has also been reported between CCL3L CNV and clinical sequelae of the simian immunodeficiency virus (SIV) infection in vivo in rhesus monkeys. The present study was initiated to explore the possibility of an association of CCL3L CNV with the control of virus replication and AIDS progression in a carefully defined cohort of SIVmac251-infected, Indian-origin rhesus monkeys. Although we demonstrated extensive variation in copy number of CCL3L in this cohort of monkeys, CCL3L CNV was not significantly associated with either peak or set-point plasma SIV RNA levels in these monkeys when MHC class I allele Mamu-A*01 was included in the models or progression to AIDS i...
Prior exposure to an attenuated Listeria vaccine does not reduce immunogenicity: pre-clinical ass... more Prior exposure to an attenuated Listeria vaccine does not reduce immunogenicity: pre-clinical assessment of the efficacy of a Listeria vaccine in the induction of immune responses against HIV
Zika virus infection in humans has been associated with serious reproductive and neurological com... more Zika virus infection in humans has been associated with serious reproductive and neurological complications. At present, no protective antiviral drug treatment is available. Here, we describe the testing and evaluation of the antiviral drug, galidesivir, against Zika virus infection in rhesus macaques. We conducted four preclinical studies in rhesus macaques to assess the safety, antiviral efficacy, and dosing strategies for galidesivir (BCX4430) against Zika virus infection. We treated 70 rhesus macaques infected by various routes with the Puerto Rico or Thai Zika virus isolates. We evaluated galidesivir administered as early as 90 min and as late as 72 hours after subcutaneous Zika virus infection and as late as 5 days after intravaginal infection. We evaluated the efficacy of a range of galidesivir doses with endpoints including Zika virus RNA in plasma, saliva, urine, and cerebrospinal fluid. Galidesivir dosing in rhesus macaques was safe and offered postexposure protection agai...
Intrinsic resistance is a crucial line of defense against virus infections, and members of the Tr... more Intrinsic resistance is a crucial line of defense against virus infections, and members of the Tripartite Ring Interaction Motif (TRIM) family of proteins are major players in this system, such as cytoplasmic TRIM5α or nuclear promyelocytic leukemia (PML/TRIM19) protein. Previous reports on the antiviral function of another TRIM protein, TRIM22, emphasized its innate immune role as a Type I and Type II interferon-stimulated gene against RNA viruses. This study shows that TRIM22 has an additional intrinsic role against DNA viruses. Here, we report that TRIM22 is a novel restriction factor of HSV-1 and limits ICP0-null virus replication by increasing histone occupancy and heterochromatin, thereby reducing immediate-early viral gene expression. The corresponding wild-type equivalent of the virus evades the TRIM22-specific restriction by a mechanism independent of ICP0-mediated degradation. We also demonstrate that TRIM22 inhibits other DNA viruses, including representative members of t...
After over three decades of research, an effective anti-HIV vaccine remains elusive. Unconvention... more After over three decades of research, an effective anti-HIV vaccine remains elusive. Unconventional and novel vaccine strategies are needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provides greater than 80% protection of Mauritian cynomolgus macaques (MCMs) against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses are correlated with vaccine efficacy. The PCS vaccine does not induce immune activation and inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune environment generated by the PCS vaccine predicts vaccine efficacy. Our study demonstrates for the first time that a novel vaccine which targets viral maturation, but lacks full Env and Gag proteins as immunogens, can prevent intravaginal infection in a highly stringent NHP/SIV challenge model. Targeting HIV maturation thus offers ...
The majority of preclinical and clinical human immunodeficiency virus type 1 (HIV-1) vaccine deve... more The majority of preclinical and clinical human immunodeficiency virus type 1 (HIV-1) vaccine development efforts have focused on HIV-1 subtype B strains from the western world. However, the overwhelming majority of HIV/AIDS-related deaths occur in the developing world and are from other HIV-1 subtype strains. Therefore, we sought to develop and generate the first mucosally transmissible simian-human immunodeficiency virus (SHIV) challenge stocks from HIV-1 subtype AE env sequences. The sequences were identified from acutely infected HIV-1 individuals from Southeast Asia. The challenge stocks efficiently infected rhesus monkeys, replicated to high levels during acute infection, and established chronic setpoint viremia. The SHIV challenge stocks should facilitate the evaluation of vaccines and other interventions aimed at controlling the spread of HIV-1 subtype AE infection.
s: Nieuwe inzichten in pathogenese en cure ..................... 3 Abstracts: PreP ................. more s: Nieuwe inzichten in pathogenese en cure ..................... 3 Abstracts: PreP ................................................................................. 4s: PreP ................................................................................. 4 Abstracts: HIV farmacologie is dit nog belangrijk? ...................... 5s: HIV farmacologie is dit nog belangrijk? ...................... 5 Abstracts: Hepatitis C, TBC en andere co-morbiditeiten ................ 6s: Hepatitis C, TBC en andere co-morbiditeiten ................ 6 Abstracts: Bredere indicatie antiretrovirale therapie .................... 7s: Bredere indicatie antiretrovirale therapie .................... 7
Background Zika virus (ZIKV) was first isolated from a sentinel rhesus monkey in 1947. ZIKV infec... more Background Zika virus (ZIKV) was first isolated from a sentinel rhesus monkey in 1947. ZIKV infection in humans is associated with serious neurological and reproductive complications. No antiviral or protective vaccine is yet available. Galidesivir an adenosine analog is a potent viral RNA-dependent RNA polymerase inhibitor with demonstrated broad-spectrum antiviral activity. Methods We have conducted four pre-clinical studies in rhesus macaques to assess the safety, antiviral efficacy and dosing strategies of galidesivir against ZIKV infection. Collectively, we have challenged 70 rhesus macaques by various routes using 1x105 TCID50of a Puerto Rican ZIKV isolate. We have evaluated galidesivir therapy administered via IM injection as early as 90 minutes and up to 72 hours after subcutaneous (SC) ZIKV challenge, and as late as 5 days after intravaginal (IVAG) challenge. In these studies, we evaluated the efficacy of a range of loading and maintence doses of galidesivir. The highest do...
Retroviruses are known to exhibit remarkable genomic pliancy, a capacity that has been attributed... more Retroviruses are known to exhibit remarkable genomic pliancy, a capacity that has been attributed to one or more error prone steps in the viral replication cycle. However, increasing evidence suggests that such error represents a key element in viral survival, as exemplified by studies on virus immune evasion, shifts of cellular tropism, and anatomic compartmentalization, which facilitate persistent virus reservoirs. Understanding the dynamic mechanisms that contribute to the establishment and maintenance of retroviral persistence is critical toward the goal of attaining HIV-1 eradication.
The cytoplasmic TRIM5a proteins of certain mammalian lineages efficiently recognize the incoming ... more The cytoplasmic TRIM5a proteins of certain mammalian lineages efficiently recognize the incoming capsids of particular retroviruses and potently restrict infection in a species-specific manner. Successful retroviruses have evolved capsids that are less efficiently recognized by the TRIM5a proteins of the natural hosts. To address whether TRIM5a contributes to the outcome of retroviral infection in a susceptible host species, we investigated the impact of TRIM5 polymorphisms in rhesus monkeys on the course of a simian immunodeficiency virus (SIV) infection. Full-length TRIM5a cDNAs were derived from each of 79 outbred monkeys and sequenced. Associations were explored between the expression of particular TRIM5 alleles and both the permissiveness of cells to SIV infection in vitro and clinical sequelae of SIV infection in vivo. Natural variation in the TRIM5a B30.2(SPRY) domain influenced the efficiency of SIVmac capsid binding and the in vitro susceptibility of cells from the monkeys ...
A novel method to identify and characterise peptide mimotopes of heat shock protein 70-associated... more A novel method to identify and characterise peptide mimotopes of heat shock protein 70-associated antigens
CCL3 is a ligand for the HIV-1 co-receptor CCR5. There have recently been conflicting reports in ... more CCL3 is a ligand for the HIV-1 co-receptor CCR5. There have recently been conflicting reports in the literature concerning whether CCL3-like gene (CCL3L) copy number variation (CNV) is associated with resistance to HIV-1 acquisition and with both viral load and disease progression following infection with HIV-1. An association has also been reported between CCL3L CNV and clinical sequelae of the simian immunodeficiency virus (SIV) infection in vivo in rhesus monkeys. The present study was initiated to explore the possibility of an association of CCL3L CNV with the control of virus replication and AIDS progression in a carefully defined cohort of SIVmac251-infected, Indian-origin rhesus monkeys. Although we demonstrated extensive variation in copy number of CCL3L in this cohort of monkeys, CCL3L CNV was not significantly associated with either peak or set-point plasma SIV RNA levels in these monkeys when MHC class I allele Mamu-A*01 was included in the models or progression to AIDS i...
Prior exposure to an attenuated Listeria vaccine does not reduce immunogenicity: pre-clinical ass... more Prior exposure to an attenuated Listeria vaccine does not reduce immunogenicity: pre-clinical assessment of the efficacy of a Listeria vaccine in the induction of immune responses against HIV
Zika virus infection in humans has been associated with serious reproductive and neurological com... more Zika virus infection in humans has been associated with serious reproductive and neurological complications. At present, no protective antiviral drug treatment is available. Here, we describe the testing and evaluation of the antiviral drug, galidesivir, against Zika virus infection in rhesus macaques. We conducted four preclinical studies in rhesus macaques to assess the safety, antiviral efficacy, and dosing strategies for galidesivir (BCX4430) against Zika virus infection. We treated 70 rhesus macaques infected by various routes with the Puerto Rico or Thai Zika virus isolates. We evaluated galidesivir administered as early as 90 min and as late as 72 hours after subcutaneous Zika virus infection and as late as 5 days after intravaginal infection. We evaluated the efficacy of a range of galidesivir doses with endpoints including Zika virus RNA in plasma, saliva, urine, and cerebrospinal fluid. Galidesivir dosing in rhesus macaques was safe and offered postexposure protection agai...
Intrinsic resistance is a crucial line of defense against virus infections, and members of the Tr... more Intrinsic resistance is a crucial line of defense against virus infections, and members of the Tripartite Ring Interaction Motif (TRIM) family of proteins are major players in this system, such as cytoplasmic TRIM5α or nuclear promyelocytic leukemia (PML/TRIM19) protein. Previous reports on the antiviral function of another TRIM protein, TRIM22, emphasized its innate immune role as a Type I and Type II interferon-stimulated gene against RNA viruses. This study shows that TRIM22 has an additional intrinsic role against DNA viruses. Here, we report that TRIM22 is a novel restriction factor of HSV-1 and limits ICP0-null virus replication by increasing histone occupancy and heterochromatin, thereby reducing immediate-early viral gene expression. The corresponding wild-type equivalent of the virus evades the TRIM22-specific restriction by a mechanism independent of ICP0-mediated degradation. We also demonstrate that TRIM22 inhibits other DNA viruses, including representative members of t...
After over three decades of research, an effective anti-HIV vaccine remains elusive. Unconvention... more After over three decades of research, an effective anti-HIV vaccine remains elusive. Unconventional and novel vaccine strategies are needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provides greater than 80% protection of Mauritian cynomolgus macaques (MCMs) against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses are correlated with vaccine efficacy. The PCS vaccine does not induce immune activation and inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune environment generated by the PCS vaccine predicts vaccine efficacy. Our study demonstrates for the first time that a novel vaccine which targets viral maturation, but lacks full Env and Gag proteins as immunogens, can prevent intravaginal infection in a highly stringent NHP/SIV challenge model. Targeting HIV maturation thus offers ...
Uploads
Papers by So-Yon Lim