Enhanced In Vitro Transcytosis of Simian Immunodeficiency Virus Mediated by Vaccine-Induced Antibody Predicts Transmitted/Founder Strain Number After Rectal Challenge

ABSTRACT Rhesus macaques immunized with simian immunodeficiency virus SIVmac239Δnef but not protected from SIVmac251 challenge were studied to determine the genetic and biological characteristics of the breakthrough viruses. Assessment of SIV genetic diversity (env V1-V2) revealed a reduction in the number of viral species in the immunized, unprotected macaques, compared to the number in nonimmunized controls. However, no evidence for selection of a specific V1-V2 genotype was observed, and biologically cloned isolates from the animals with breakthrough virus were similar with respect to replication kinetics and coreceptor use in vitro.

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Gag-Specific Cellular Immunity DeterminesIn VitroViral Inhibition andIn VivoVirologic Control following Simian Immunodeficiency Virus Challenges of Vaccinated Rhesus Monkeys

Journal of Virology ◽

10.1128/jvi.00996-12 ◽

2012 ◽

Vol 86 (18) ◽

pp. 9583-9589 ◽

Cited By ~ 30

Author(s):

Kathryn E. Stephenson ◽

Hualin Li ◽

Bruce D. Walker ◽

Nelson L. Michael ◽

Dan H. Barouch

Keyword(s):

Simian Immunodeficiency Virus ◽

Rhesus Monkeys ◽

Viral Inhibition ◽

Viral Loads ◽

Immunodeficiency Virus ◽

Virologic Control ◽

Cellular Immune ◽

Hiv 1

A comprehensive vaccine for human immunodeficiency virus type 1 (HIV-1) would block HIV-1 acquisition as well as durably control viral replication in breakthrough infections. Recent studies have demonstrated that Env is required for a vaccine to protect against acquisition of simian immunodeficiency virus (SIV) in vaccinated rhesus monkeys, but the antigen requirements for virologic control remain unclear. Here, we investigate whether CD8+T lymphocytes from vaccinated rhesus monkeys mediate viral inhibitionin vitroand whether these responses predict virologic control following SIV challenge. We observed that CD8+lymphocytes from 23 vaccinated rhesus monkeys inhibited replication of SIVin vitro. Moreover, the magnitude of inhibition prior to challenge was inversely correlated with set point SIV plasma viral loads after challenge. In addition, CD8 cell-mediated viral inhibition in vaccinated rhesus monkeys correlated significantly with Gag-specific, but not Pol- or Env-specific, CD4+and CD8+T lymphocyte responses. These findings demonstrate thatin vitroviral inhibition following vaccination largely reflects Gag-specific cellular immune responses and correlates within vivovirologic control following infection. These data suggest the importance of including Gag in an HIV-1 vaccine in which virologic control is desired.

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Neutralization and enhancement of in vitro and in vivo HIV and simian immunodeficiency virus infections

AIDS ◽

10.1097/00002030-199001001-00025 ◽

1990 ◽

Vol 4 (Supp 1) ◽

pp. S163 ◽

Cited By ~ 7

Author(s):

W. Edward Robinson ◽

William M. Mitchell

Keyword(s):

Simian Immunodeficiency Virus ◽

Virus Infections ◽

Immunodeficiency Virus

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Regulation of Indoleamine 2,3-Dioxygenase Expression in Simian Immunodeficiency Virus-Infected Monkey Brains

Journal of Virology ◽

10.1128/jvi.76.23.12233-12241.2002 ◽

2002 ◽

Vol 76 (23) ◽

pp. 12233-12241 ◽

Cited By ~ 39

Author(s):

E. M. E. Burudi ◽

M. Cecilia G. Marcondes ◽

Debbie D. Watry ◽

Michelle Zandonatti ◽

Michael A. Taffe ◽

...

Keyword(s):

Simian Immunodeficiency Virus ◽

Aids Dementia Complex ◽

Motor Disorder ◽

Infected Monkey ◽

Macaque Model ◽

Indoleamine 2,3 Dioxygenase ◽

Immunodeficiency Virus ◽

Tryptophan Catabolism ◽

Ifn Γ

ABSTRACT The human immunodeficiency virus type 1-associated cognitive-motor disorder, including the AIDS dementia complex, is characterized by brain functional abnormalities that are associated with injury initiated by viral infection of the brain. Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in tryptophan catabolism in extrahepatic tissues, can lead to neurotoxicity through the generation of quinolinic acid and immunosuppression and can alter brain chemistry via depletion of tryptophan. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model of AIDS, we demonstrate that cells of the macrophage lineage are the main source for expression of IDO in the SIV-infected monkey brain. Animals with SIV encephalitis have the highest levels of IDO mRNA, and the level of IDO correlates with gamma interferon (IFN-γ) and viral load levels. In vitro studies on mouse microglia reveal that IFN-γ is the primary inducer of IDO expression. These findings demonstrate the link between IDO expression, IFN-γ levels, and brain pathology signs observed in neuro-AIDS.

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Expanded Tissue Targets for Foamy Virus Replication with Simian Immunodeficiency Virus-Induced Immunosuppression

Journal of Virology ◽

10.1128/jvi.80.2.663-670.2006 ◽

2006 ◽

Vol 80 (2) ◽

pp. 663-670 ◽

Cited By ~ 57

Author(s):

S. M. Murray ◽

L. J. Picker ◽

M. K. Axthelm ◽

M. L. Linial

Keyword(s):

Small Intestine ◽

T Cell ◽

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Foamy Virus ◽

Viral Rna ◽

Cell Depletion ◽

T Cell Depletion ◽

Immunodeficiency Virus

ABSTRACT Foamy viruses (FV) are the oldest known genus of retroviruses and have persisted in nonhuman primates for over 60 million years. FV are efficiently transmitted, leading to a lifelong nonpathogenic infection. Transmission is thought to occur through saliva, but the detailed mechanism is unknown. Interestingly, this persistent infection contrasts with the rapid cytopathicity caused by FV in vitro, suggesting a host defense against FV. To better understand the tissue specificity of FV replication and host immunologic defense against FV cytopathicity, we quantified FV in tissues of healthy rhesus macaques (RM) and those severely immunosuppressed by simian immunodeficiency virus (SIV). Contrary to earlier findings, we find that all immunocompetent animals consistently have high levels of viral RNA in oral tissues but not in other tissues examined, including the small intestine. Strikingly, abundant viral transcripts were detected in the small intestine of all of the SIV-infected RM, which has been shown to be a major site of SIV (and human immunodeficiency virus)-induced CD4+ T-cell depletion. In contrast, there was a trend to lower viral RNA levels in oropharyngeal tissues of SIV-infected animals. The expansion of FV replication to the small intestine but not to other CD4+ T-cell-depleted tissues suggests that factors other than T-cell depletion, such as dysregulation of the jejunal microenvironment after SIV infection, likely account for the expanded tissue tropism of FV replication.

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Simian Immunodeficiency Virus SIVrcm, a Unique CCR2-Tropic Virus, Selectively Depletes Memory CD4+ T Cells in Pigtailed Macaques through Expanded Coreceptor Usage In Vivo

Journal of Virology ◽

10.1128/jvi.00444-09 ◽

2009 ◽

Vol 83 (16) ◽

pp. 7894-7908 ◽

Cited By ~ 20

Author(s):

Rajeev Gautam ◽

Thaidra Gaufin ◽

Isolde Butler ◽

Aarti Gautam ◽

Mary Barnes ◽

...

Keyword(s):

T Cells ◽

Simian Immunodeficiency Virus ◽

Effector Memory ◽

Coreceptor Usage ◽

New Host ◽

Viral Loads ◽

Immunodeficiency Virus ◽

Memory Cd4 T Cells

ABSTRACT Simian immunodeficiency virus SIVrcm, which naturally infects red-capped mangabeys (RCMs), is the only SIV that uses CCR2 as its main coreceptor due to the high frequency of a CCR5 deletion in RCMs. We investigated the dynamics of SIVrcm infection to identify specific pathogenic mechanisms associated with this major difference in SIV biology. Four pigtailed macaques (PTMs) were infected with SIVrcm, and infection was monitored for over 2 years. The dynamics of in vivo SIVrcm replication in PTMs was similar to that of other pathogenic and nonpathogenic lymphotropic SIVs. Plasma viral loads (VLs) peaked at 107 to 109 SIVrcm RNA copies/ml by day 10 postinoculation (p.i.). A viral set point was established by day 42 p.i. at 103 to 105 SIVrcm RNA copies/ml and lasted up to day 180 p.i., when plasma VLs decreased below the threshold of detection, with blips of viral replication during the follow-up. Intestinal SIVrcm replication paralleled that of plasma VLs. Up to 80% of the CD4+ T cells were depleted by day 28 p.i. in the gut. The most significant depletion (>90%) involved memory CD4+ T cells. Partial CD4+ T-cell restoration was observed in the intestine at later time points. Effector memory CD4+ T cells were the least restored. SIVrcm strains isolated from acutely infected PTMs used CCR2 coreceptor, as reported, but expansion of coreceptor usage to CCR4 was also observed. Selective depletion of effector memory CD4+ T cells is in contrast with predicted in vitro tropism of SIVrcm for macrophages and is probably due to expansion of coreceptor usage. Taken together, these findings emphasize the importance of understanding the selective forces driving viral adaptation to a new host.

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Compensatory Substitutions Restore Normal Core Assembly in Simian Immunodeficiency Virus Isolates with Gag Epitope Cytotoxic T-Lymphocyte Escape Mutations

Journal of Virology ◽

10.1128/jvi.00068-06 ◽

2006 ◽

Vol 80 (16) ◽

pp. 8168-8177 ◽

Cited By ~ 27

Author(s):

Wendy W. Yeh ◽

Evan M. Cale ◽

Pimkwan Jaru-Ampornpan ◽

Carol I. Lord ◽

Fred W. Peyerl ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Amino Acid ◽

Simian Immunodeficiency Virus ◽

Structural Integrity ◽

Viral Escape ◽

Amino Acid Substitutions ◽

Structural Constraints ◽

Immunodeficiency Virus ◽

Dominant Epitope

ABSTRACT The evolution of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) as they replicate in infected individuals reflects a balance between the pressure on the virus to mutate away from recognition by dominant epitope-specific cytotoxic T lymphocytes (CTL) and the structural constraints on the virus' ability to mutate. To gain a further understanding of the strategies employed by these viruses to maintain replication competency in the face of the intense selection pressure exerted by CTL, we have examined the replication fitness and morphological ramifications of a dominant epitope mutation and associated flanking amino acid substitutions on the capsid protein (CA) of SIV/simian-human immunodeficiency virus (SHIV). We show that a residue 2 mutation in the immunodominant p11C, C-M epitope (T47I) of SIV/SHIV not only decreased CA protein expression and viral replication, but it also blocked CA assembly in vitro and virion core condensation in vivo. However, these defects were restored by the introduction of upstream I26V and/or downstream I71V substitutions in CA. These findings demonstrate how flanking compensatory amino acid substitutions can facilitate viral escape from a dominant epitope-specific CTL response through the effects of these associated mutations on the structural integrity of SIV/SHIV.

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Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1509731112 ◽

2015 ◽

Vol 112 (34) ◽

pp. 10780-10785 ◽

Cited By ~ 21

Author(s):

Samantha L. Burton ◽

Katie M. Kilgore ◽

S. Abigail Smith ◽

Sharmila Reddy ◽

Eric Hunter ◽

...

Keyword(s):

Simian Immunodeficiency Virus ◽

Neutralizing Antibodies ◽

Rhesus Macaques ◽

Neutralizing Antibody ◽

Active Immunization ◽

Antibody Responses ◽

Challenge Virus ◽

Gm Csf ◽

Immunodeficiency Virus

Although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nAbs) against the challenge virus will prevent infection. This paradigm is based on a series of studies in which passive transfer of HIV-specific nAbs protected rhesus macaques (RMs) from subsequent mucosal challenge with a chimeric human/simian immunodeficiency virus. However, it is unknown whether nAb titers define protection in the setting of active immunization. Here we determined serum nAb titers against breakthrough transmitted/founder (T/F) SIVsmE660-derived envelope glycoprotein (Env) variants from 14 RMs immunized with SIVmac239-based DNA-prime/modified vaccinia virus Ankara-boost vaccine regimens that included GM-CSF or CD40L adjuvants and conferred significant but incomplete protection against repeated low-dose intrarectal challenge. A single Env variant established infection in all RMs except one, with no identifiable genetic signature associated with vaccination breakthrough compared with T/F Envs from four unvaccinated monkeys. Breakthrough T/F Env pseudoviruses were potently neutralized in vitro by heterologous pooled serum from chronically SIVsmE660-infected monkeys at IC50 titers exceeding 1:1,000,000. Remarkably, the T/F Env pseudoviruses from 13 of 14 monkeys were also susceptible to neutralization by autologous prechallenge serum at in vitro IC50 titers ranging from 1:742–1:10,832. These titers were similar to those observed in vaccinated RMs that remained uninfected. These data suggest that the relationship between serum nAb titers and protection from mucosal SIV challenge in the setting of active immunization is more complex than previously recognized, warranting further studies into the balance between immune activation, target cell availability, and protective antibody responses.

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