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 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 Shortening of the Symptom-Free Period in Rhesus Macaques Is Associated with Decreasing Nonsynonymous Variation in theenv Variable Regions of Simian Immunodeficiency Virus SIVsm during Passage

1998 ◽  
Vol 72 (9) ◽  
pp. 7494-7500 ◽  
Author(s):  
P. J. Spencer Valli ◽  
Vladimir V. Lukashov ◽  
Jonathan L. Heeney ◽  
Jaap Goudsmit
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Envelope Gene ◽  
Nucleotide Substitutions ◽  
Variable Regions ◽  
Immunodeficiency Virus ◽  
The Mean ◽  
The Difference ◽  
Nonsynonymous Variation

ABSTRACT During six blood passages of simian immunodeficiency virus SIVsm in rhesus macaques, the asymptomatic period shortened from 18 months to 1 month. To study SIVsm envelope gene (env) evolution during passage in rhesus macaques, the C1 to CD4 binding regions of multiple clones were sequenced at seroconversion and again at death. Theenv variation found during adaptation was almost completely confined to the variable regions. Intrasample sequence variation among clones at seroconversion was lower than the variation among clones at death. Intrasample variation among clones from a single time point as well as intersample variation decreased during the passage. In the variable regions, the mean number of intrasample nonsynonymous nucleotide substitutions decreased from the first passage (5.26 × 10−2 ± 0.6 × 10−2 per site) to the fifth passage (2.24 × 10−2 ± 0.4 × 10−2 per site), whereas in the constant regions, the mean number of intrasample nonsynonymous nucleotide substitutions differed less between the first and fifth passages (1.14 × 10−2 ± 0.27 × 10−2 and 0.80 × 10−2 ± 0.24 × 10−2 per site). Shortening of the asymptomatic period coincided with a rise in theKs/Ka ratio (ratio between the number of synonymous [Ks] and the number of nonsynonymous [Ka] substitutions) from 1.080 in passage one to 1.428 in passage five and mimicked the difference seen in the intrahost evolution between asymptomatic and fast-progressing individuals infected with human immunodeficiency virus type 1. The distribution of nonsynonymous substitutions was biphasic, with most of the adaptation ofenv variable regions occurring in the first three passages. This phase, in which the symptom-free period fell to 4 months, was followed by a plateau phase of apparently reduced adaptation. Analysis of codon usage revealed decreased codon redundancy in the variable regions. Overall, the results suggested a biphasic pattern of adaptation and evolution, with extremely rapid selection in the first three passages followed by an equilibrium or stabilization of the variation between env clones at different time points in passages four to six.

scholarly journals Occult Systemic Infection and Persistent Simian Immunodeficiency Virus (SIV)-Specific CD4+-T-Cell Proliferative Responses in Rhesus Macaques That Were Transiently Viremic after Intravaginal Inoculation of SIV

1998 ◽  
Vol 72 (12) ◽  
pp. 10029-10035 ◽  
Author(s):  
Michael B. McChesney ◽  
Jennifer R. Collins ◽  
Ding Lu ◽  
Xusheng Lu ◽  
Judith Torten ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Sexual Transmission ◽  
Systemic Infection ◽  
Lymphoid Tissues ◽  
Vaginal Mucosa ◽  
Tissue Samples ◽  
Immunodeficiency Virus ◽  
Culture Negative ◽  
Ctl Responses

ABSTRACT The intact cervicovaginal mucosa is a relative barrier to the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In the simian immunodeficiency virus (SIV) macaque model of HIV infection, seronegative transient viremia (STV; virus isolation positive followed by repeated negative cultures) occurs after intravaginal inoculation of a low dose of pathogenic SIVmac251 (C. J. Miller, M. Marthas, J. Torten, N. Alexander, J. Moore, G. Doncel, and A. Hendrickx, J. Virol. 68:6391–6400, 1994). Thirty-one adult female macaques that had been inoculated intravaginally with pathogenic SIVmac251 became transiently viremic. One monkey that had been culture negative for a year after SIV inoculation became persistently viremic and developed simian AIDS. No other STV monkey developed persistent viremia or disease. Results of very sensitive assays showed that 6 of 31 monkeys had weak SIV-specific antibody responses. SIV-specific antibodies were not detected in the cervicovaginal secretions of 10 STV monkeys examined. Twenty of 26 monkeys had lymphocyte proliferative responses to p55 gag and/or gp130 env antigens; 3 of 6 animals, including the monkey that became persistently viremic, had detectable cytotoxic T-lymphocyte (CTL) responses to SIV. At necropsy, lymphoid tissues and vaginal mucosa were virus culture negative, but in 10 of 10 animals, SIV provirus was detected by PCR using gag-specific primer pairs. Fifty percent of the PCR-positive tissue samples were also positive for SIV gag RNA by reverse transcriptase PCR. Thus, transient viremia following intravaginal inoculation of pathogenic SIV is associated with persistent, systemic infection, either latent or very low level productive. Atypical immune responses, characterized by lymphocyte proliferation and some CTL responses in the absence of conventionally detectable antibodies, develop in transiently viremic monkeys.

scholarly journals Genetic Variation at the Mitochondrial Large-Subunit rRNA Locus of Pneumocystis Isolates from Simian Immunodeficiency Virus-Infected Rhesus Macaques

2003 ◽  
Vol 10 (6) ◽  
pp. 1037-1042 ◽  
Author(s):  
Karen A. Norris ◽  
Hans Wildschutte ◽  
Jennifer Franko ◽  
Kathryn F. Board
Keyword(s):  
Rhesus Macaque ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Large Subunit ◽  
Pneumocystis Carinii ◽  
Rrna Genes ◽  
Rrna Gene ◽  
Immunodeficiency Virus ◽  
Lsu Rrna Gene ◽  
Lsu Rrna

ABSTRACT The nucleotide sequences of a segment of the Pneumocystis mitochondrial large-subunit (mt LSU) rRNA gene from rhesus macaques coinfected with simian immunodeficiency virus (SIV) and Pneumocystis carinii were examined. Of 12 isolates examined, 3 were found to be identical and the others showed substantial sequence variation, with up to 13% divergence among variants. We identified two general sequence types that differed at several sites, including a conserved 26-nucleotide insertion. Four monkeys had evidence of two Pneumocystis variants present simultaneously, indicative of a mixed infection. There was a high degree of variance between the rhesus macaque-derived Pneumocystis mt LSU rRNA gene sequence and the cognate sequences in Pneumocystis organisms derived from other hosts. Analysis of the mt LSU rRNA genes of Pneumocystis organisms derived from rhesus macaques and several other mammalian hosts supports the observation that rhesus macaque-derived Pneumocystis is most closely related to human-derived Pneumocystis. In addition, the data identify the mt LSU rRNA gene as an informative locus for transmission and epidemiological studies of the SIV-rhesus macaque model of Pneumocystis infection.

scholarly journals Simian Immunodeficiency Virus Utilizes Human and Sooty Mangabey but Not Rhesus Macaque STRL33 for Efficient Entry

2000 ◽  
Vol 74 (11) ◽  
pp. 5075-5082 ◽  
Author(s):  
Stefan Pöhlmann ◽  
Benhur Lee ◽  
Silke Meister ◽  
Mandy Krumbiegel ◽  
George Leslie ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Cellular Membrane ◽  
Single Amino Acid ◽  
Sooty Mangabey ◽  
Target Cells ◽  
Specific Sequence ◽  
Immunodeficiency Virus ◽  
Sooty Mangabeys

ABSTRACT It has been established that many simian immunodeficiency virus (SIV) isolates utilize the orphan receptors GPR15 and STRL33 about as efficiently as the chemokine receptor CCR5 for entry into target cells. Most studies were performed, however, with coreceptors of human origin. We found that SIV from captive rhesus macaques (SIVmac) can utilize both human and simian CCR5 and GPR15 with comparable efficiencies. Strikingly, however, only human STRL33 (huSTRL33), not rhesus macaque STRL33 (rhSTRL33), functioned efficiently as an entry cofactor for a variety of isolates of SIVmac and SIV from sooty mangabeys. A single amino acid substitution of S30R in huSTRL33 impaired coreceptor activity, and the reverse change in rhSTRL33 greatly increased coreceptor activity. In comparison, species-specific sequence variations in N-terminal tyrosines in STRL33 had only moderate effects on SIV entry. These results show that a serine residue located just outside of the cellular membrane in the N terminus of STRL33 is critical for SIV coreceptor function. Interestingly, STRL33 derived from sooty mangabeys, a natural host of SIV, also contained a serine at the corresponding position and was used efficiently as an entry cofactor. These results suggest that STRL33 is not a relevant coreceptor in the SIV/macaque model but may play a role in SIV replication and transmission in naturally infected sooty mangabeys.

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 In Vivo Replication Capacity Rather Than In Vitro Macrophage Tropism Predicts Efficiency of Vaginal Transmission of Simian Immunodeficiency Virus or Simian/Human Immunodeficiency Virus in Rhesus Macaques

1998 ◽  
Vol 72 (4) ◽  
pp. 3248-3258 ◽  
Author(s):  
Christopher J. Miller ◽  
Marta Marthas ◽  
Jennifer Greenier ◽  
Ding Lu ◽  
Peter J. Dailey ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Systemic Infection ◽  
Molecular Clone ◽  
Macrophage Tropism ◽  
Immunodeficiency Virus

ABSTRACT We used the rhesus macaque model of heterosexual human immunodeficiency virus (HIV) transmission to test the hypothesis that in vitro measures of macrophage tropism predict the ability of a primate lentivirus to initiate a systemic infection after intravaginal inoculation. A single atraumatic intravaginal inoculation with a T-cell-tropic molecular clone of simian immunodeficiency virus (SIV), SIVmac239, or a dualtropic recombinant molecular clone of SIV, SIVmac239/1A11/239, or uncloned dualtropic SIVmac251 or uncloned dualtropic simian/human immunodeficiency virus (SHIV) 89.6-PD produced systemic infection in all rhesus macaques tested. However, vaginal inoculation with a dualtropic molecular clone of SIV, SIVmac1A11, resulted in transient viremia in one of two rhesus macaques. It has previously been shown that 12 intravaginal inoculations with SIVmac1A11 resulted in infection of one of five rhesus macaques (M. L. Marthas, C. J. Miller, S. Sutjipto, J. Higgins, J. Torten, B. L. Lohman, R. E. Unger, H. Kiyono, J. R. McGhee, P. A. Marx, and N. C. Pedersen, J. Med. Primatol. 21:99–107, 1992). In addition, SHIV HXBc2, which replicates in monkey macrophages, does not infect rhesus macaques following multiple vaginal inoculations, while T-cell-tropic SHIV 89.6 does (Y. Lu, P. B. Brosio, M. Lafaile, J. Li, R. G. Collman, J. Sodroski, and C. J. Miller, J. Virol. 70:3045–3050, 1996). These results demonstrate that in vitro measures of macrophage tropism do not predict if a SIV or SHIV will produce systemic infection after intravaginal inoculation of rhesus macaques. However, we did find that the level to which these viruses replicate in vivo after intravenous inoculation predicts the outcome of intravaginal inoculation with each virus.

scholarly journals Structured-Tree Topology and Adaptive Evolution of the Simian Immunodeficiency Virus SIVsm Envelope during Serial Passage in Rhesus Macaques According to Likelihood Mapping and Quartet Puzzling

1998 ◽  
Vol 72 (5) ◽  
pp. 3673-3683 ◽  
Author(s):  
P. J. Spencer Valli ◽  
Jaap Goudsmit
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Adaptive Evolution ◽  
Sequence Data ◽  
Rhesus Macaques ◽  
Serial Passage ◽  
Sooty Mangabey ◽  
Envelope Gene ◽  
New Host ◽  
Immunodeficiency Virus ◽  
Likelihood Mapping

ABSTRACT Species-specific strains of simian immunodeficiency virus (SIV) are nonpathogenic in African primates. The SIV strain most closely related to human immunodeficiency virus type 2 (HIV-2) is SIVsm, the strain specific to the sooty mangabey (Cercocebus atys). Infection of Asian primates with SIV causes AIDS and allows the study of the adaptive evolution of a lentivirus to replicate efficiently in a new host, providing a useful animal model of HIV infection and AIDS in humans. Serial passage of SIVsm from sooty mangabeys in rhesus macaques drastically shortened the time of disease progression from 1.5 years to 1 month as the retrovirus adapted to these Asian hosts. In the present study we analyzed the quasispecies nature of the SIVsm envelope gene (env) during serial population passage in rhesus macaques. We asked ourselves if phylogenetic evidence could be provided for the structured topology of the SIVsm env tree and subsequently for the adaptive evolution of SIVsm env. Likelihood mapping showed that phylogenetic reconstruction of the passage was possible because a high percentage of the sequence data had a “tree-like” form. Subsequently, quartet puzzling was used and produced a phylogeny with a structure parallel to the known infection history. The adaptation of SIVsm to Asian rhesus macaques appears to be an ordered process in which the env evolves in a tree-like manner, particularly in its constant regions.

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