scholarly journals A Limited Number of Simian Immunodeficiency Virus (SIV) env Variants Are Transmitted to Rhesus Macaques Vaginally Inoculated with SIVmac251

2010 ◽  
Vol 84 (14) ◽  
pp. 7083-7095 ◽  
Author(s):  
Mars Stone ◽  
Brandon F. Keele ◽  
Zhong-Min Ma ◽  
Elizabeth Bailes ◽  
Joseph Dutra ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Systemic Infection ◽  
High Dose ◽  
Macaque Model ◽  
Single Genome ◽  
Immunodeficiency Virus ◽  
Positive Time ◽  
Modeling Strategy ◽  
Hiv 1

ABSTRACT Single-genome amplification (SGA) and sequencing of HIV-1 RNA in plasma of acutely infected humans allows the identification and enumeration of transmitted/founder viruses responsible for productive systemic infection. Use of this strategy as a means for identifying transmitted viruses suggested that intrarectal simian immunodeficiency virus (SIV) inoculation of macaques recapitulates key features of human rectal infection. However, no studies have used the SGA strategy to identify vaginally transmitted virus(es) in macaques or to determine how early SIV diversification in vaginally infected animals compares with HIV-1 in humans. We used SGA to amplify 227 partial env sequences from a SIVmac251 challenge stock and from seven rhesus macaques at the earliest plasma viral RNA-positive time point after low- and high-dose intravaginal inoculation. Sequences were analyzed phylogenetically to determine the relationship of transmitted/founder viruses within and between each animal and the challenge stock. In each animal, discrete low-diversity env sequence lineages were evident, and these coalesced phylogenetically to identical or near-identical env sequences in the challenge stock, thus confirming the validity of the SGA sequencing and modeling strategy for identifying vaginally transmitted SIV. Between 1 and 10 viruses were responsible for systemic infection, similar to humans infected by sexual contact, and the set of viruses transmitted to the seven animals studied represented the full genetic constellation of the challenge stock. These findings recapitulate many of the features of sexual HIV-1 transmission in women. Furthermore, the SIV rhesus macaque model can be used to understand the factors that influence the transmission of single versus multiple SIV variants.

scholarly journals A Period of Transient Viremia and Occult Infection Precedes Persistent Viremia and Antiviral Immune Responses during Multiple Low-Dose Intravaginal Simian Immunodeficiency Virus Inoculations

2004 ◽  
Vol 78 (24) ◽  
pp. 14048-14052 ◽  
Author(s):  
Zhong-Min Ma ◽  
Kristina Abel ◽  
Tracy Rourke ◽  
Yichuan Wang ◽  
Christopher J. Miller
Keyword(s):  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Low Dose ◽  
Rhesus Macaques ◽  
Systemic Infection ◽  
Variable Number ◽  
Transmission Model ◽  
High Dose ◽  
Persistent Viremia ◽  
Immunodeficiency Virus

ABSTRACT In rhesus macaques, classic systemic infection, characterized by persistent viremia and seroconversion, occurred after multiple low-dose (103 50% tissue culture infective doses) intravaginal (IVAG) inoculations with simian immunodeficiency virus (SIV) strain SIVmac251. Monkeys developed classic SIV infections after a variable number of low-dose IVAG exposures to SIVmac251. Once established, the systemic infection was identical to SIV infection following high-dose IVAG SIV inoculation. However, occult systemic infection characterized by transient cell-associated or cell-free viremia consistently occurred early in the series of multiple vaginal SIV exposures. Further, antiviral cellular immune responses were present prior to the establishment of a classic systemic infection in the low-dose vaginal SIV transmission model.

scholarly journals Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques.

1996 ◽  
Vol 183 (1) ◽  
pp. 215-225 ◽  
Author(s):  
A I Spira ◽  
P A Marx ◽  
B K Patterson ◽  
J Mahoney ◽  
R A Koup ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Sexual Transmission ◽  
Mucosal Transmission ◽  
Cellular Targets ◽  
Macaque Model ◽  
Immunodeficiency Virus ◽  
Internal Iliac ◽  
Infected Cells ◽  
Hiv 1

We used the simian immunodeficiency virus (SIV)/rhesus macaque model to study events that underlie sexual transmission of human immunodeficiency virus type 1 (HIV-1). Four female rhesus macaques were inoculated intravaginally with SIVmac251, and then killed 2, 5, 7, and 9 d later. A technique that detected polymerase chain reaction-amplified SIV in situ showed that the first cellular targets for SIV were in the lamina propria of the cervicovaginal mucosa, immediately subjacent to the epithelium. Phenotypic and localization studies demonstrated that many of the infected cells were likely to be dendritic cells. Within 2 d of inoculation, infected cells were identified in the paracortex and subcapsular sinus of the draining internal iliac lymph nodes. Subsequently, systemic dissemination of SIV was rapid, since culturable virus was detectable in the blood by day 5. From these results, we present a model for mucosal transmission of SIV and HIV-1.

scholarly journals Efficacy of Multivalent Adenovirus-Based Vaccine against Simian Immunodeficiency Virus Challenge

2009 ◽  
Vol 84 (6) ◽  
pp. 2996-3003 ◽  
Author(s):  
Danilo R. Casimiro ◽  
Kara Cox ◽  
Aimin Tang ◽  
Kara J. Sykes ◽  
Meizhen Feng ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
High Dose ◽  
Virus Challenge ◽  
Study Results ◽  
Immunodeficiency Virus ◽  
Virological Outcomes ◽  
Serotype 5 ◽  
Hiv 1 ◽  
Simian Immunodeficiency Virus Challenge

ABSTRACT The prophylactic efficacies of several multivalent replication-incompetent adenovirus serotype 5 (Ad5) vaccines were examined in rhesus macaques using an intrarectal high-dose simian immunodeficiency virus SIVmac239 challenge model. Cohorts of Mamu-A*01+/B*17− Indian rhesus macaques were immunized with one of several combinations of Ad5 vectors expressing Gag, Pol, Nef, and Env gp140; for comparison, a Mamu-A*01+ cohort was immunized using the Ad5 vector alone. There was no sign of immunological interference between antigens in the immunized animals. In general, expansion of the antigen breadth resulted in more favorable virological outcomes. In particular, the order of efficacy trended as follows: Gag/Pol/Nef/Env ≈ Gag/Pol > Gag ≈ Gag/Pol/Nef > Nef. However, the precision in ranking the vaccines based on the study results may be limited by the cohort size, and as such, may warrant additional testing. The implications of these results in light of the recent discouraging results of the phase IIb study of the trivalent Ad5 HIV-1 vaccine are discussed.

scholarly journals Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

2015 ◽  
Vol 89 (16) ◽  
pp. 8130-8151 ◽  
Author(s):  
Katie M. Kilgore ◽  
Megan K. Murphy ◽  
Samantha L. Burton ◽  
Katherine S. Wetzel ◽  
S. Abigail Smith ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Nonhuman Primate ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Cd40 Ligand ◽  
Antibody Activity ◽  
Immunodeficiency Virus ◽  
Antibody Profile ◽  
Hiv 1

ABSTRACTAntibodies that can neutralize diverse viral strains are likely to be an important component of a protective human immunodeficiency virus type 1 (HIV-1) vaccine. To this end, preclinical simian immunodeficiency virus (SIV)-based nonhuman primate immunization regimens have been designed to evaluate and enhance antibody-mediated protection. However, these trials often rely on a limited selection of SIV strains with extreme neutralization phenotypes to assess vaccine-elicited antibody activity. To mirror the viral panels used to assess HIV-1 antibody breadth, we created and characterized a novel panel of 14 genetically and phenotypically diverse SIVsm envelope (Env) glycoproteins. To assess the utility of this panel, we characterized the neutralizing activity elicited by four SIVmac239 envelope-expressing DNA/modified vaccinia virus Ankara vector- and protein-based vaccination regimens that included the immunomodulatory adjuvants granulocyte-macrophage colony-stimulating factor, Toll-like receptor (TLR) ligands, and CD40 ligand. The SIVsm Env panel exhibited a spectrum of neutralization sensitivity to SIV-infected plasma pools and monoclonal antibodies, allowing categorization into three tiers. Pooled sera from 91 rhesus macaques immunized in the four trials consistently neutralized only the highly sensitive tier 1a SIVsm Envs, regardless of the immunization regimen. The inability of vaccine-mediated antibodies to neutralize the moderately resistant tier 1b and tier 2 SIVsm Envs defined here suggests that those antibodies were directed toward epitopes that are not accessible on most SIVsm Envs. To achieve a broader and more effective neutralization profile in preclinical vaccine studies that is relevant to known features of HIV-1 neutralization, more emphasis should be placed on optimizing the Env immunogen, as the neutralization profile achieved by the addition of adjuvants does not appear to supersede the neutralizing antibody profile determined by the immunogen.IMPORTANCEMany in the HIV/AIDS vaccine field believe that the ability to elicit broadly neutralizing antibodies capable of blocking genetically diverse HIV-1 variants is a critical component of a protective vaccine. Various SIV-based nonhuman primate vaccine studies have investigated ways to improve antibody-mediated protection against a heterologous SIV challenge, including administering adjuvants that might stimulate a greater neutralization breadth. Using a novel SIV neutralization panel and samples from four rhesus macaque vaccine trials designed for cross comparison, we show that different regimens expressing the same SIV envelope immunogen consistently elicit antibodies that neutralize only the very sensitive tier 1a SIV variants. The results argue that the neutralizing antibody profile elicited by a vaccine is primarily determined by the envelope immunogen and is not substantially broadened by including adjuvants, resulting in the conclusion that the envelope immunogen itself should be the primary consideration in efforts to elicit antibodies with greater neutralization breadth.

scholarly journals Route of Simian Immunodeficiency Virus Inoculation Determines the Complexity but Not the Identity of Viral Variant Populations That Infect Rhesus Macaques

2001 ◽  
Vol 75 (8) ◽  
pp. 3753-3765 ◽  
Author(s):  
Jennifer L. Greenier ◽  
Christopher J. Miller ◽  
Ding Lu ◽  
Peter J. Dailey ◽  
Fabien X. Lü ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Simian Immunodeficiency Virus ◽  
Hiv Transmission ◽  
Rhesus Macaques ◽  
Systemic Infection ◽  
Envelope Gene ◽  
Homogeneous Population ◽  
Viral Variant ◽  
Effective Strategies ◽  
Immunodeficiency Virus

ABSTRACT A better understanding of the host and viral factors associated with human immunodeficiency virus (HIV) transmission is essential to developing effective strategies to curb the global HIV epidemic. Here we used the rhesus macaque-simian immunodeficiency virus (SIV) animal model of HIV infection to study the range of viral genotypes that are transmitted by different routes of inoculation and by different types of viral inocula. Analysis of transmitted variants was undertaken in outbred rhesus macaques inoculated intravenously (IV) or intravaginally (IVAG) with a genetically heterogeneous SIVmac251 stock derived from a well-characterized rhesus macaque viral isolate. In addition, we performed serial IV and IVAG passage experiments using plasma from SIV-infected macaques as the inoculum. We analyzed the V1-V2 region of the SIV envelope gene from virion-associated RNA in plasma from infected animals by the heteroduplex mobility assay (HMA) and by DNA sequence analysis. We found that a more diverse population of SIV genetic variants was present in the earliest virus-positive plasma samples from all five IV SIVmac251-inoculated monkeys and from two of five IVAG SIVmac251-inoculated monkeys. In contrast, we found a relatively homogeneous population of SIV envelope variants in three of five monkeys inoculated IVAG with SIVmac251 stock and in two monkeys infected after IVAG inoculation with plasma from an SIV-infected animal. In some IVAG-inoculated animals, the transmitted SIV variant was the most common variant in the inoculum. However, a specific viral variant in the SIVmac251 stock was not consistently transmitted by IVAG inoculation. Thus, it is likely that host factors or stochastic processes determine the specific viral variants that infect an animal after IVAG SIV exposure. In addition, our results clearly demonstrate that the route of inoculation is associated with the extent and breadth of the genetic complexity of the viral variant population in the earliest stages of systemic infection.

scholarly journals Differential Restriction of Human Immunodeficiency Virus Type 2 and Simian Immunodeficiency Virus SIVmac by TRIM5α Alleles

2005 ◽  
Vol 79 (18) ◽  
pp. 11580-11587 ◽  
Author(s):  
Laura M. J. Ylinen ◽  
Zuzana Keckesova ◽  
Sam J. Wilson ◽  
Srinika Ranasinghe ◽  
Greg J. Towers
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Squirrel Monkey ◽  
New World ◽  
Rhesus Macaques ◽  
Innate Immune ◽  
Sooty Mangabey ◽  
Immunodeficiency Virus ◽  
Primate Lentiviruses ◽  
Hiv 1

ABSTRACT Primate lentiviruses have narrow host ranges, due in part to their sensitivities to mammalian intracellular antiviral factors such as APOBEC3G and TRIM5α. Despite the protection provided by this innate immune system, retroviruses are able to transfer between species where they can cause disease. This is true for sooty mangabey simian immunodeficiency virus, which has transferred to humans as HIV-2 and to rhesus macaques as SIVmac, where it causes AIDS. Here we examine the sensitivities of the closely related HIV-2 and SIVmac to restriction by TRIM5α. We show that rhesus TRIM5α can restrict HIV-2 but not the closely related SIVmac. SIVmac has not completely escaped TRIM5α, as shown by its sensitivity to distantly related TRIM5α from the New World squirrel monkey. Squirrel monkey TRIM5α blocks SIVmac infection after DNA synthesis and is not saturable with restriction-sensitive virus-like particles. We map the determinant for TRIM5α sensitivity to the structure in the capsid protein that recruits CypA into HIV-1 virions. We also make an SIV, mutated at this site, which bypasses restriction in all cells tested.

scholarly journals Efavirenz Therapy in Rhesus Macaques Infected with a Chimera of Simian Immunodeficiency Virus Containing Reverse Transcriptase from Human Immunodeficiency Virus Type 1

2004 ◽  
Vol 48 (9) ◽  
pp. 3483-3490 ◽  
Author(s):  
Michael J. Hofman ◽  
Joanne Higgins ◽  
Timothy B. Matthews ◽  
Niels C. Pedersen ◽  
Chalet Tan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Simian Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Rhesus Macaques ◽  
Immunodeficiency Virus ◽  
Resistant Mutants ◽  
Hiv 1

ABSTRACT The specificity of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for the RT of human immunodeficiency virus type 1 (HIV-1) has prevented the use of simian immunodeficiency virus (SIV) in the study of NNRTIs and NNRTI-based highly active antiretroviral therapy. However, a SIV-HIV-1 chimera (RT-SHIV), in which the RT from SIVmac239 was replaced with the RT-encoding region from HIV-1, is susceptible to NNRTIs and is infectious to rhesus macaques. We have evaluated the antiviral activity of efavirenz against RT-SHIV and the emergence of efavirenz-resistant mutants in vitro and in vivo. RT-SHIV was susceptible to efavirenz with a mean effective concentration of 5.9 ± 4.5 nM, and RT-SHIV variants selected with efavirenz in cell culture displayed 600-fold-reduced susceptibility. The efavirenz-resistant mutants of RT-SHIV had mutations in RT similar to those of HIV-1 variants that were selected under similar conditions. Efavirenz monotherapy of RT-SHIV-infected macaques produced a 1.82-log-unit decrease in plasma viral-RNA levels after 1 week. The virus load rebounded within 3 weeks in one treated animal and more slowly in a second animal. Virus isolated from these two animals contained the K103N and Y188C or Y188L mutations. The RT-SHIV-rhesus macaque model may prove useful for studies of antiretroviral drug combinations that include efavirenz.

scholarly journals Simian Immunodeficiency Virus SIVmac239, but Not SIVmac316, Binds and Utilizes Human CD4 More Efficiently than Rhesus CD4

2017 ◽  
Vol 91 (18) ◽  
Author(s):  
Christoph H. Fellinger ◽  
Matthew R. Gardner ◽  
Charles C. Bailey ◽  
Michael Farzan
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Human Case ◽  
Human Infection ◽  
Sooty Mangabey ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT Rhesus macaques are used to model human immunodeficiency virus type 1 (HIV-1) infections, but they are not natural hosts of HIV-1 or any simian immunodeficiency virus (SIV). Rather, they became infected with SIV through cross-species transfer from sooty mangabeys in captivity. It has been shown that HIV-1 utilizes rhesus CD4 less efficiently than human CD4. However, the relative ability of SIV envelope glycoproteins to bind or utilize these CD4 orthologs has not been reported. Here we show that several SIV isolates, including SIVmac239, are more efficiently neutralized by human CD4-Ig (huCD4-Ig) than by the same molecule bearing rhesus CD4 domains 1 and 2 (rhCD4-Ig). An I39N mutation in CD4 domain 1, present in human and sooty mangabey CD4 orthologs, largely restored rhCD4-Ig neutralization of SIVmac239 and other SIV isolates. We further observed that SIVmac316, a derivative of SIVmac239, bound to and was neutralized by huCD4-Ig and rhCD4-Ig with nearly identical efficiencies. Introduction of two SIVmac316 CD4-binding site residues (G382R and H442Y) into the SIVmac239 envelope glycoprotein (Env) markedly increased its neutralization sensitivity to rhesus CD4-Ig without altering neutralization by human CD4-Ig, SIV neutralizing antibodies, or sera from SIV-infected macaques. These changes also allowed SIVmac239 Env to bind rhCD4-Ig more efficiently than huCD4-Ig. The variant with G382R and H442Y (G382R/H442Y variant) also infected cells expressing rhesus CD4 with markedly greater efficiency than did unaltered SIVmac239 Env. We propose that infections of rhesus macaques with SIVmac239 G382R/H442Y might better model some aspects of human infections. IMPORTANCE Rhesus macaque infection with simian immunodeficiency virus (SIV) has served as an important model of human HIV-1 infection. However, differences between this model and the human case have complicated the development of vaccines and therapies. Here we report the surprising observation that SIVmac239, a commonly used model virus, more efficiently utilizes human CD4 than the CD4 of rhesus macaques, whereas the closely related virus SIVmac316 uses both CD4 orthologs equally well. We used this insight to generate a form of SIVmac239 envelope glycoprotein (Env) that utilized rhesus CD4 more efficiently, while retaining its resistance to antibodies and sera from infected macaques. This Env can be used to make the rhesus model more similar in some ways to human infection, for example by facilitating infection of cells with low levels of CD4. This property may be especially important to efforts to eradicate latently infected cells.

scholarly journals Low-Dose Mucosal Simian Immunodeficiency Virus Infection Restricts Early Replication Kinetics and Transmitted Virus Variants in Rhesus Monkeys

2010 ◽  
Vol 84 (19) ◽  
pp. 10406-10412 ◽  
Author(s):  
Jinyan Liu ◽  
Brandon F. Keele ◽  
Hui Li ◽  
Sheila Keating ◽  
Philip J. Norris ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Monkeys ◽  
Low Dose ◽  
High Dose ◽  
Transmitted Virus ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Eclipse Phase ◽  
Early Replication ◽  
Hiv 1

ABSTRACT Defining the earliest virologic events following human immunodeficiency virus type 1 (HIV-1) transmission may be critical for the design of vaccine strategies aimed at blocking acquisition of HIV-1 infection. In particular, the length of the eclipse phase and the number of transmitted virus variants may define the window in which a prophylactic vaccine must act. Here we show that the dose of the virus inoculum affects these key virologic parameters following intrarectal simian immunodeficiency virus (SIV) infection of rhesus monkeys. Low-dose SIV infection resulted in a lengthened eclipse phase, fewer transmitted virus variants, and decreased innate immune activation compared with these parameters in high-dose SIV infection. These data suggest a mechanism by which it may be considerably easier for a vaccine to protect against low-risk HIV-1 transmission than against high-risk HIV-1 transmission. These findings have implications for the design and interpretation of HIV-1 vaccine efficacy studies.

scholarly journals Preexisting Infection with Human T-Cell Lymphotropic Virus Type 2 neither Exacerbates nor Attenuates Simian Immunodeficiency Virus SIVmac251 Infection in Macaques

2010 ◽  
Vol 84 (6) ◽  
pp. 3043-3058 ◽  
Author(s):  
Shari N. Gordon ◽  
Anna R. Weissman ◽  
Valentina Cecchinato ◽  
Claudio Fenizia ◽  
Zhong-Min Ma ◽  
...  
Keyword(s):  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Virus Type ◽  
Rhesus Macaques ◽  
T Cell Response ◽  
Lymphoid Tissues ◽  
Human T Cell ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Coinfection with human T-cell lymphotropic virus type 2 (HTLV-2) and human immunodeficiency virus type 1 (HIV-1) has been reported to have either a slowed disease course or to have no effect on progression to AIDS. In this study, we generated a coinfection animal model and investigated whether HTLV-2 could persistently infect macaques, induce a T-cell response, and impact simian immunodeficiency virus SIVmac251-induced disease. We found that inoculation of irradiated HTLV-2-infected T cells into Indian rhesus macaques elicited humoral and T-cell responses to HTLV-2 antigens at both systemic and mucosal sites. Low levels of HTLV-2 provirus DNA were detected in the blood, lymphoid tissues, and gastrointestinal tracts of infected animals. Exposure of HTLV-2-infected or naïve macaques to SIVmac251 demonstrated comparable levels of SIVmac251 viral replication, similar rates of mucosal and peripheral CD4+ T-cell loss, and increased T-cell proliferation. Additionally, neither the magnitude nor the functional capacity of the SIV-specific T-cell-mediated immune response was different in HTLV-2/SIVmac251 coinfected animals versus SIVmac251 singly infected controls. Thus, HTLV-2 targets mucosal sites, persists, and importantly does not exacerbate SIVmac251 infection. These data provide the impetus for the development of an attenuated HTLV-2-based vectored vaccine for HIV-1; this approach could elicit persistent mucosal immunity that may prevent HIV-1/SIVmac251 infection.

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