MHC Class I Alleles Influence Set-Point Viral Load and Survival Time in Simian Immunodeficiency Virus-Infected Rhesus Monkeys

An effective vaccine against the human immunodeficiency virus should be capable of eliciting both an antibody and a cytotoxic T lymphocyte (CTL) response. However, when viral proteins and peptides are formulated with traditional immunological adjuvants and inoculated via a route acceptable for use in humans, they have not been successful at eliciting virus-specific, major histocompatibility complex (MHC) class I-restricted CTL. We have designed a novel viral subunit vaccine by encapsulating a previously defined synthetic peptide CTL epitope of the simian immunodeficiency virus (SIV) gag protein within a proteoliposome capable of attaching to and fusing with plasma membranes. Upon fusing, the encapsulated contents of this proteoliposome can enter the MHC class I processing pathway through the cytoplasm. In this report, we show that after a single intramuscular vaccination, rhesus monkeys develop a CD8+ cell-mediated, MHC class I-restricted CTL response that recognizes the synthetic peptide immunogen. The induced CTL also demonstrate antiviral immunity by recognizing SIV gag protein endogenously processed by target cells infected with SIV/vaccinia recombinant virus. These results demonstrate that virus-specific, MHC class I-restricted, CD8+ CTL can be elicited by a safe, nonreplicating viral subunit vaccine in a primate model for acquired immune deficiency syndrome. Moreover, the proteoliposome vaccine formation described can include multiple synthetic peptide epitopes, and, thus, offers a simple means of generating antiviral cell-mediated immunity in a genetically heterogeneous population.

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Variability of Viral Load in Plasma of Rhesus Monkeys Inoculated with Simian Immunodeficiency Virus or Simian-Human Immunodeficiency Virus: Implications for Using Nonhuman Primate AIDS Models To Test Vaccines and Therapeutics

Journal of Virology ◽

10.1128/jvi.75.22.11234-11238.2001 ◽

2001 ◽

Vol 75 (22) ◽

pp. 11234-11238 ◽

Cited By ~ 37

Author(s):

Robert A. Parker ◽

Meredith M. Regan ◽

Keith A. Reimann

Keyword(s):

Human Immunodeficiency Virus ◽

Viral Load ◽

Simian Immunodeficiency Virus ◽

Nonhuman Primate ◽

Rhesus Monkeys ◽

Nonhuman Primates ◽

Viral Rna ◽

Set Point ◽

Immunodeficiency Virus ◽

Aids Vaccines

ABSTRACT Viral RNA level in plasma is a sensitive experimental endpoint for evaluating the efficacy of AIDS vaccines or therapies in nonhuman primates. By quantifying viral RNA in the plasma of 77 rhesus monkeys for 10 weeks after inoculation with simian-human immunodeficiency virus 89.6P (SHIV-89.6P) or simian immunodeficiency virus mac 251 (SIVmac 251), we estimated variability in three viral load (VL) measures: peak VL, the postacute set point VL, and VL decline from peak. Such estimates of biological variability are essential for determining the number of animals needed per group and may be helpful for selecting the most appropriate measure to use as the experimental endpoint. Peak VL was positively correlated with set point VL for both viruses. Variability (standard deviation) was substantially higher in monkeys infected with SIVmac 251 than in those infected with SHIV-89.6P for set point VL and VL decline. The variability of peak VL was less than one-half that of set point VL variability and only about two-thirds of that of VL decline, implying that the same treatment-related difference in peak VL could be detected with fewer animals than set point VL or VL decline. Thus, differences in VL variability over the course of infection and between viruses need to be considered when designing studies using the nonhuman primate AIDS models.

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A Commonly Recognized Simian Immunodeficiency Virus Nef Epitope Presented to Cytotoxic T Lymphocytes of Indian-Origin Rhesus Monkeys by the Prevalent Major Histocompatibility Complex Class I Allele Mamu-A*02

Journal of Virology ◽

10.1128/jvi.75.21.10179-10186.2001 ◽

2001 ◽

Vol 75 (21) ◽

pp. 10179-10186 ◽

Cited By ~ 24

Author(s):

Suzanne Robinson ◽

William A. Charini ◽

Michael H. Newberg ◽

Marcelo J. Kuroda ◽

Carol I. Lord ◽

...

Keyword(s):

T Lymphocytes ◽

Rhesus Monkey ◽

Simian Immunodeficiency Virus ◽

Mhc Class I ◽

T Lymphocyte ◽

Rhesus Monkeys ◽

Cytotoxic T Lymphocyte ◽

Class I ◽

Mhc Class I Molecule ◽

Immunodeficiency Virus

ABSTRACT The ability to monitor vaccine-elicited CD8+ cytotoxic T-lymphocyte (CTL) responses in simian immunodeficiency virus (SIV)- and simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys has been limited by our knowledge of viral epitopes predictably presented to those lymphocytes by common rhesus monkey MHC class I alleles. We now define an SIV and SHIV Nef CTL epitope (YTSGPGIRY) that is presented to CD8+ T lymphocytes by the common rhesus monkey MHC class I molecule Mamu-A*02. All seven infectedMamu-A*02 + monkeys evaluated demonstrated this response, and peptide-stimulated interferon gamma Elispot assays indicated that the response represents a large proportion of the entire CD8+ T-lymphocyte SIV- or SHIV-specific immune response of these animals. Knowledge of this epitope and MHC class I allele substantially increases the number of available rhesus monkeys that can be used for testing prototype HIV vaccines in this important animal model.

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Impact of Nef-Mediated Downregulation of Major Histocompatibility Complex Class I on Immune Response to Simian Immunodeficiency Virus

Journal of Virology ◽

10.1128/jvi.78.23.13335-13344.2004 ◽

2004 ◽

Vol 78 (23) ◽

pp. 13335-13344 ◽

Cited By ~ 76

Author(s):

Tomek Swigut ◽

Louis Alexander ◽

Jennifer Morgan ◽

Jeff Lifson ◽

Keith G. Mansfield ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Simian Immunodeficiency Virus ◽

Mhc Class I ◽

Cellular Response ◽

Lymphocyte Activation ◽

Class I ◽

Wild Type Virus ◽

Major Histocompatibility ◽

Histocompatibility Complex ◽

Immunodeficiency Virus

ABSTRACT Functional activities that have been ascribed to the nef gene product of simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) include CD4 downregulation, major histocompatibility complex (MHC) class I downregulation, downregulation of other plasma membrane proteins, and lymphocyte activation. Monkeys were infected experimentally with SIV containing difficult-to-revert mutations in nef that selectively eliminated MHC downregulation but not these other activities. Monkeys infected with these mutant forms of SIV exhibited higher levels of CD8+ T-cell responses 4 to 16 weeks postinfection than seen in monkeys infected with the parental wild-type virus. Furthermore, unusual compensatory mutations appeared by 16 to 32 weeks postinfection which restored some or all of the MHC-downregulating activity. These results indicate that nef does serve to limit the virus-specific CD8 cellular response of the host and that the ability to downregulate MHC class I contributes importantly to the totality of nef function.

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Host factors determine differential disease progression after infection with nef-deleted simian immunodeficiency virus

Journal of General Virology ◽

10.1099/vir.0.066563-0 ◽

2014 ◽

Vol 95 (10) ◽

pp. 2273-2284 ◽

Cited By ~ 2

Author(s):

Sieghart Sopper ◽

Kerstin Mätz-Rensing ◽

Thorsten Mühl ◽

Jonathan Heeney ◽

Christiane Stahl-Hennig ◽

...

Keyword(s):

Viral Load ◽

Viral Replication ◽

Disease Progression ◽

Simian Immunodeficiency Virus ◽

Mhc Class Ii ◽

Cell Activation ◽

Host Factors ◽

Immunological Parameters ◽

Set Point ◽

Immunodeficiency Virus

Infection of macaques with live attenuated simian immunodeficiency virus (SIV) usually results in long-lasting efficient protection against infection with pathogenic immunodeficiency viruses. However, attenuation by deletion of regulatory genes such as nef is not complete, leading to a high viral load and fatal disease in some animals. To characterize immunological parameters and polymorphic host factors, we studied 17 rhesus macaques infected with attenuated SIVmac239ΔNU. Eight animals were able to control viral replication, whereas the remaining animals (non-controllers) displayed variable set-point viral loads. Peak viral load at 2 weeks post-infection (p.i.) correlated significantly with set-point viral load (P<0.0001). CD4+ T-cell frequencies differed significantly soon after infection between controllers and non-controllers. Abnormal B-cell activation previously ascribed to Nef function could already be observed in non-controllers 8 weeks after infection despite the absence of Nef. Two non-controllers developed an AIDS-like disease within 102 weeks p.i. Virus from these animals transmitted to naïve animals replicated at low levels and the recipients did not develop immunodeficiency. This suggested that host factors determined differential viral load and subsequent disease course. Known Mhc class I alleles associated with disease progression in SIV WT infection only marginally influenced the viral load in Δnef-infected animals. Protection from SIVmac251 was associated with homozygosity for MHC class II in conjunction with a TLR7 polymorphism and showed a trend with initial viral replication. We speculated that host factors whose effects were usually masked by Nef were responsible for the different disease courses in individual animals upon infection with nef-deleted viruses.

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Highly Pathogenic Simian Immunodeficiency Virus mne Variants That Emerge during the Course of Infection Evolve Enhanced Infectivity and the Ability To Downregulate CD4 but Not Class I Major Histocompatibility Complex Antigens

Journal of Virology ◽

10.1128/jvi.76.13.6425-6434.2002 ◽

2002 ◽

Vol 76 (13) ◽

pp. 6425-6434 ◽

Cited By ~ 23

Author(s):

Parul G. Patel ◽

Monica T. Yu Kimata ◽

Julia E. Biggins ◽

Joelle M. Wilson ◽

Jason T. Kimata

Keyword(s):

Major Histocompatibility Complex ◽

Simian Immunodeficiency Virus ◽

Mhc Class I ◽

Class I ◽

Major Histocompatibility ◽

Highly Pathogenic ◽

Pathogenic Variants ◽

Histocompatibility Complex ◽

Immunodeficiency Virus

ABSTRACT The replicative, cytopathic, and antigenic properties of simian immunodeficiency virus (SIV) variants influence its replication efficiency in vivo. To further define the viral properties and determinants that may be important for high-level replication in vivo and progression to AIDS, we compared a minimally pathogenic SIVmne molecular clone with two highly pathogenic variants cloned from late stages of infection. Both variants had evolved greater infectivity than the parental clone due to mutations in nef. Interestingly, a pol determinant in one of the highly pathogenic variants also contributed to its increased infectivity. Furthermore, because replication in vivo may also be influenced by the ability of a virus to evade the cellular immune response of the host, we examined whether the variants were more capable of downregulating surface expression of class I major histocompatibility complex (MHC). Decreased MHC class I expression was not observed in cells infected with any of the viruses. Furthermore, the Nef proteins of the highly pathogenic variants only slightly reduced surface MHC class I expression in transfected cells, although they efficiently downregulated CD4. Together, these data demonstrate that mutations which can enhance viral infectivity, as well as CD4 downregulation, may be important for efficient replication of SIV in the host. However, Nef-mediated reduction of MHC class I expression does not appear to be critical for the increased in vivo replicative ability of highly pathogenic late variants.

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