Specific passage of simian immunodeficiency virus fromend-stage disease results in accelerated progression to AIDS in rhesus macaques

To determine whether passage of late-stage variants of simian immunodeficiency virus (SIV) would lead to a more virulent infection and rapid disease progression, a study was designed to examine the effects of selective transmission of SIV from late-stage cases of AIDS in Macaca mulatta. In a uniform group of 10 age-matched animals from the same genetic breeding stock infected with SIVB670, it took 7 months before one of the ten animals developed AIDS. Passage of virus taken from this animal immediately prior to death resulted in death of the recipient due to AIDS within 4 months. Again, subsequent passage of virus taken late in disease resulted in an accelerated disease course, with AIDS developing within 2·5 and 1·8 months in two recipients. The fourth passage of virus taken late in disease from the most rapid progressor (1·8 months) resulted in AIDS developing in this recipient within 1 month of infection. During each consecutive passage in vivo, the loss of memory T cells became more acute. Evidence that the virus became more virulent with selective passage of late-stage variants was provided by the markedly increased levels of both plasma antigen and viral RNA. Subsequent in vivo passage from end-stage AIDS selected for a strain of SIV capable of causing the acute development of AIDS as rapidly as 1 month post-infection. The pathology of acute AIDS in these cases closely resembled that seen after a chronic disease course.

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Chronic Binge Alcohol-Induced Dysregulation of Mitochondrial-Related Genes in Skeletal Muscle of Simian Immunodeficiency Virus-Infected Rhesus Macaques at End-Stage Disease

Alcohol and Alcoholism ◽

10.1093/alcalc/agw107 ◽

2017 ◽

Cited By ~ 2

Author(s):

Anthony A. Duplanty ◽

Liz Simon ◽

Patricia E. Molina

Keyword(s):

Skeletal Muscle ◽

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Stage Disease ◽

Immunodeficiency Virus ◽

End Stage

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Characteristics of a Pathogenic Molecular Clone of an End-Stage Serum-Derived Variant of Simian Immunodeficiency Virus (SIVF359)

Journal of Virology ◽

10.1128/jvi.75.19.9328-9338.2001 ◽

2001 ◽

Vol 75 (19) ◽

pp. 9328-9338 ◽

Cited By ~ 3

Author(s):

Lennart Holterman ◽

Rob Dubbes ◽

James Mullins ◽

Gerald Learn ◽

Henk Niphuis ◽

...

Keyword(s):

Simian Immunodeficiency Virus ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Peripheral Blood Lymphocytes ◽

Peripheral Blood Mononuclear ◽

Molecular Clone ◽

Immunodeficiency Virus ◽

End Stage

ABSTRACT End-stage simian immunodeficiency virus (SIV) isolates are suggested to be the most fit of the evolved virulent variants that precipitate the progression to AIDS. To determine if there were common characteristics of end-stage variants which emerge from accelerated cases of AIDS, a molecular clone was derived directly from serum following in vivo selection of a highly virulent SIV isolate obtained by serial end-stage passage in rhesus monkeys (Macaca mulatta). This dominant variant caused a marked cytopathic effect and replicated to very high levels in activated but not resting peripheral blood lymphocytes. Furthermore, although this clone infected but did not replicate to detectable levels in rhesus monocyte-derived macrophages, these cells were able to transmit infection to autologous T cells upon contact. Interestingly, although at low doses this end-stage variant did not use any of the known coreceptors except CCR5, it was able to infect and replicate in human peripheral blood mononuclear cells homozygous for the Δ32 deletion of CCR5, suggesting the use of a novel coreceptor. It represents the first pathogenic molecular clone of SIV derived from viral RNA in serum and provides evidence that not only the genetic but also the biological characteristics acquired by highly fit late-stage disease variants may be distinct in different hosts.

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Downregulation of Robust Acute Type I Interferon Responses Distinguishes Nonpathogenic Simian Immunodeficiency Virus (SIV) Infection of Natural Hosts from Pathogenic SIV Infection of Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.02612-09 ◽

2010 ◽

Vol 84 (15) ◽

pp. 7886-7891 ◽

Cited By ~ 133

Author(s):

Levelle D. Harris ◽

Brian Tabb ◽

Donald L. Sodora ◽

Mirko Paiardini ◽

Nichole R. Klatt ◽

...

Keyword(s):

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Acute Infection ◽

Type I ◽

Acute Type ◽

Type I Ifn ◽

Immunodeficiency Virus ◽

Natural Hosts ◽

Siv Infection

ABSTRACT The mechanisms underlying the AIDS resistance of natural hosts for simian immunodeficiency virus (SIV) remain unknown. Recently, it was proposed that natural SIV hosts avoid disease because their plasmacytoid dendritic cells (pDCs) are intrinsically unable to produce alpha interferon (IFN-α) in response to SIV RNA stimulation. However, here we show that (i) acute SIV infections of natural hosts are associated with a rapid and robust type I IFN response in vivo, (ii) pDCs are the principal in vivo producers of IFN-α/β at peak acute infection in lymphatic tissues, and (iii) natural SIV hosts downregulate these responses in early chronic infection. In contrast, persistently high type I IFN responses are observed during pathogenic SIV infection of rhesus macaques.

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Effects of in Vivo Cd8+ T Cell Depletion on Virus Replication in Rhesus Macaques Immunized with a Live, Attenuated Simian Immunodeficiency Virus Vaccine

Journal of Experimental Medicine ◽

10.1084/jem.191.11.1921 ◽

1999 ◽

Vol 191 (11) ◽

pp. 1921-1932 ◽

Cited By ~ 112

Author(s):

Karin J. Metzner ◽

Xia Jin ◽

Fred V. Lee ◽

Agegnehu Gettie ◽

Daniel E. Bauer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Simian Immunodeficiency Virus ◽

Cd8 T Cells ◽

Rhesus Macaques ◽

Cd8 T Cell ◽

T Cell Depletion ◽

Challenge Virus ◽

Immunodeficiency Virus

The role of CD8+ T lymphocytes in controlling replication of live, attenuated simian immunodeficiency virus (SIV) was investigated as part of a vaccine study to examine the correlates of protection in the SIV/rhesus macaque model. Rhesus macaques immunized for >2 yr with nef-deleted SIV (SIVmac239Δnef) and protected from challenge with pathogenic SIVmac251 were treated with anti-CD8 antibody (OKT8F) to deplete CD8+ T cells in vivo. The effects of CD8 depletion on viral load were measured using a novel quantitative assay based on real-time polymerase chain reaction using molecular beacons. This assay allows simultaneous detection of both the vaccine strain and the challenge virus in the same sample, enabling direct quantification of changes in each viral population. Our results show that CD8+ T cells were depleted within 1 h after administration of OKT8F, and were reduced by as much as 99% in the peripheral blood. CD8+ T cell depletion was associated with a 1–2 log increase in SIVmac239Δnef plasma viremia. Control of SIVmac239Δnef replication was temporally associated with the recovery of CD8+ T cells between days 8 and 10. The challenge virus, SIVmac251, was not detectable in either the plasma or lymph nodes after depletion of CD8+ T cells. Overall, our results indicate that CD8+ T cells play an important role in controlling replication of live, attenuated SIV in vivo.

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Intrinsic Susceptibility of Rhesus Macaque Peripheral CD4+ T Cells to Simian Immunodeficiency Virus In Vitro Is Predictive of In Vivo Viral Replication

Journal of Virology ◽

10.1128/jvi.74.20.9388-9395.2000 ◽

2000 ◽

Vol 74 (20) ◽

pp. 9388-9395 ◽

Cited By ~ 42

Author(s):

Simoy Goldstein ◽

Charles R. Brown ◽

Houman Dehghani ◽

Jeffrey D. Lifson ◽

Vanessa M. Hirsch

Keyword(s):

T Cell ◽

Simian Immunodeficiency Virus ◽

Rank Order ◽

Rhesus Macaques ◽

Target Cells ◽

Plasma Viremia ◽

Immunodeficiency Virus ◽

Siv Infection

ABSTRACT Previous studies with simian immunodeficiency virus (SIV) infection of rhesus macaques suggested that the intrinsic susceptibility of peripheral blood mononuclear cells (PBMC) to infection with SIV in vitro was predictive of relative viremia after SIV challenge. The present study was conducted to evaluate this parameter in a well-characterized cohort of six rhesus macaques selected for marked differences in susceptibility to SIV infection in vitro. Rank order relative susceptibility of PBMC to SIVsmE543-3-infection in vitro was maintained over a 1-year period of evaluation. Differential susceptibility of different donors was maintained in CD8+T-cell-depleted PBMC, macrophages, and CD4+ T-cell lines derived by transformation of PBMC with herpesvirus saimiri, suggesting that this phenomenon is an intrinsic property of CD4+target cells. Following intravenous infection of these macaques with SIVsmE543-3, we observed a wide range in plasma viremia which followed the same rank order as the relative susceptibility established by in vitro studies. A significant correlation was observed between plasma viremia at 2 and 8 weeks postinoculation and in vitro susceptibility (P < 0.05). The observation that the two most susceptible macaques were seropositive for simian T-lymphotropic virus type 1 may suggests a role for this viral infection in enhancing susceptibility to SIV infection in vitro and in vivo. In summary, intrinsic susceptibility of CD4+ target cells appears to be an important factor influencing early virus replication patterns in vivo that should be considered in the design and interpretation of vaccine studies using the SIV/macaque model.

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Identification of Mhc-Mamu-DQB1 allele combinations associated with rapid disease progression in rhesus macaques infected with simian immunodeficiency virus

AIDS ◽

10.1097/00002030-199709000-00024 ◽

1997 ◽

Vol 11 (9) ◽

pp. 1196-1198 ◽

Cited By ~ 17

Author(s):

U. Sauermann ◽

M. Krawczak ◽

G. Hunsmann ◽

C. Stahl-Hennig

Keyword(s):

Disease Progression ◽

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Rapid Disease Progression ◽

Immunodeficiency Virus ◽

Dqb1 Allele

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Comprehensive Analysis of Nef Functions Selected in Simian Immunodeficiency Virus-Infected Macaques

Journal of Virology ◽

10.1128/jvi.78.19.10588-10597.2004 ◽

2004 ◽

Vol 78 (19) ◽

pp. 10588-10597 ◽

Cited By ~ 24

Author(s):

Michael Schindler ◽

Jan Münch ◽

Matthias Brenner ◽

Christiane Stahl-Hennig ◽

Jacek Skowronski ◽

...

Keyword(s):

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Surface Expression ◽

Viral Fitness ◽

Cell Surface Expression ◽

Mhc I ◽

Mhc Ii ◽

Immunodeficiency Virus

ABSTRACT A variety of simian immunodeficiency virus (SIVmac) nef mutants have been investigated to clarify which in vitro Nef functions contribute to efficient viral replication and pathogenicity in rhesus macaques. Most of these nef alleles, however, were only functionally characterized for their ability to down-modulate CD4 and class I major histocompatibility complex (MHC-I) cell surface expression and to enhance SIV replication and infectivity. To obtain information on the in vivo relevance of more recently established Nef functions, we examined the ability of a large panel of constructed SIVmac Nef mutants and of variants that emerged in infected macaques to down-regulate CD3, CD28, and MHC-II and to up-regulate the MHC-II-associated invariant chain (Ii). We found that all these four Nef functions were restored in SIV-infected macaques. In most cases, however, the initial mutations and the changes selected in vivo affected several in vitro Nef functions. For example, truncated Nef proteins that emerged in animals infected with SIVmac239 containing a 152-bp deletion in nef efficiently modulated both CD3 and Ii surface expression. Overall, our results suggest that the effect of Nef on each of the six cellular receptors investigated contributes to viral fitness in the infected host but also indicate that modulation of CD3, MHC-I, MHC-II, or Ii surface expression alone is insufficient for SIV virulence.

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Genetic Analysis of Simian Immunodeficiency Virus Expressed in Milk and Selectively Transmitted through Breastfeeding

Journal of Virology ◽

10.1128/jvi.80.8.3721-3731.2006 ◽

2006 ◽

Vol 80 (8) ◽

pp. 3721-3731 ◽

Cited By ~ 14

Author(s):

Jenna Rychert ◽

Nedra Lacour ◽

Angela Martin Amedee

Keyword(s):

Simian Immunodeficiency Virus ◽

Negative Charge ◽

Rhesus Macaques ◽

Chronic Phase ◽

Disease Course ◽

Viral Loads ◽

Immunodeficiency Virus ◽

Single Genotype ◽

Efficient Expression ◽

Maternal Disease

ABSTRACT To develop effective intervention strategies that prevent breast milk transmission of human immunodeficiency virus (HIV), we must understand the specific viral properties and mechanisms responsible for infant infection. We have used lactating rhesus macaques infected with a pathogenic simian immunodeficiency virus (SIV) stock to analyze the viral genotypes expressed in plasma and milk throughout the disease course and to identify those variants ultimately transmitted to infants through breastfeeding. In these studies we observed mother-to-infant transmission of SIV/DeltaB670 by eight females during the chronic phase of disease, and we analyzed by heteroduplex tracking assays and sequence analysis the distribution and fluctuations in viral genotypes expressed. Each female expressed multiple V1 envelope genotypes in milk near the time of transmission, while a single genotype was found in each of the infants. Variants transmitted to infants were not expressed throughout the maternal disease course but were only detected near the time of transmission. The emergence of the transmitted genotype in the dam typically occurred in plasma before milk and was coincident with increased milk viral loads. Transmitted genotypes tended to be longer and more glycosylated and had a less negative charge over the V1 region compared to viral genotypes expressed in milk but not transmitted. These observations demonstrate that specific viral genotypes are selectively transmitted to infants through breastfeeding and support the hypothesis that transmission occurs as genotypes adapt for efficient expression in milk.

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