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

2012 ◽  
Vol 86 (18) ◽  
pp. 9583-9589 ◽  
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.

scholarly journals Immunogenicity of Recombinant Fiber-Chimeric Adenovirus Serotype 35 Vector-Based Vaccines in Mice and Rhesus Monkeys

2005 ◽  
Vol 79 (22) ◽  
pp. 14161-14168 ◽  
Author(s):  
Anjali Nanda ◽  
Diana M. Lynch ◽  
Jaap Goudsmit ◽  
Angelique A. C. Lemckert ◽  
Bonnie A. Ewald ◽  
...  
Keyword(s):  
Rhesus Monkeys ◽  
In Vivo Studies ◽  
Preclinical Studies ◽  
Adenovirus Serotype ◽  
Immunodeficiency Virus ◽  
Serotype 5 ◽  
Fiber Proteins ◽  
Hiv 1

ABSTRACT Preexisting immunity to adenovirus serotype 5 (Ad5) has been shown to suppress the immunogenicity of recombinant Ad5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 (HIV-1) in both preclinical studies and clinical trials. A potential solution to this problem is to utilize rAd vectors derived from rare Ad serotypes, such as Ad35. However, rAd35 vectors have appeared less immunogenic than rAd5 vectors in preclinical studies to date. In this study, we explore the hypothesis that the differences in immunogenicity between rAd5 and rAd35 vectors may be due in part to differences between the fiber proteins of these viruses. We constructed capsid chimeric rAd35 vectors containing the Ad5 fiber knob (rAd35k5) and compared the immunogenicities of rAd5, rAd35k5, and rAd35 vectors expressing simian immunodeficiency virus Gag and HIV-1 Env in mice and rhesus monkeys. In vitro studies demonstrated that rAd35k5 vectors utilized the Ad5 receptor CAR rather than the Ad35 receptor CD46. In vivo studies showed that rAd35k5 vectors were more immunogenic than rAd35 vectors in both mice and rhesus monkeys. These data suggest that the Ad5 fiber knob contributes substantially to the immunogenicity of rAd vectors. Moreover, these studies demonstrate that capsid chimeric rAd vectors can be constructed to combine beneficial immunologic and serologic properties of different Ad serotypes.

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

2009 ◽  
Vol 83 (16) ◽  
pp. 7894-7908 ◽  
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.

scholarly journals The Human Immunodeficiency Virus Type 1nef Gene Can to a Large Extent Replace Simian Immunodeficiency Virus nef In Vivo

1999 ◽  
Vol 73 (10) ◽  
pp. 8371-8383 ◽  
Author(s):  
Frank Kirchhoff ◽  
Jan Münch ◽  
Silke Carl ◽  
Nicole Stolte ◽  
Kerstin Mätz-Rensing ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Chimeric Viruses

ABSTRACT The nef gene of the pathogenic simian immunodeficiency virus (SIV) 239 clone was replaced with primary human immunodeficiency virus type 1 (HIV-1) nef alleles to investigate whether HIV-1 Nef can substitute for SIV Nef in vivo. Initially, two rhesus macaques were infected with the chimeric viruses (Nef-SHIVs). Most of the nef alleles obtained from both animals predicted intact open reading frames. Furthermore, forms containing upstream nucleotide substitutions that enhanced expression of the inserted gene became predominant. One animal maintained high viral loads and slowly progressed to immunodeficiency. nef long terminal repeat sequences amplified from this animal were used to generate a second generation of Nef-SHIVs. Two macaques, which were subsequently infected with a mixture of cloned chimeric viruses, showed high viral loads and progressed to fatal immunodeficiency. Five macaques received a single molecular clone, named SHIV-40K6. The SHIV-40K6 nef allele was active in CD4 and class I major histocompatibility complex downregulation and enhanced viral infectivity and replication. Notably, all of the macaques inoculated with SHIV-40K6 showed high levels of viral replication early in infection. During later stages, however, the course of infection was variable. Three animals maintained high viral loads and developed immunodeficiency. Of the remaining two macaques, which showed decreasing viral loads after the acute phase of infection, only one efficiently controlled viral replication and remained asymptomatic during 1.5 years of follow-up. The other animal showed an increasing viral load and developed signs of progressive infection during later stages. Our data demonstrate that HIV-1 nefcan, to a large extent, functionally replace SIVmac nef in vivo.

scholarly journals Induction of AIDS in Rhesus Monkeys by a Recombinant Simian Immunodeficiency Virus Expressing nef of Human Immunodeficiency Virus Type 1

1999 ◽  
Vol 73 (7) ◽  
pp. 5814-5825 ◽  
Author(s):  
Louis Alexander ◽  
Zhenjian Du ◽  
Anita Y. M. Howe ◽  
Susan Czajak ◽  
Ronald C. Desrosiers
Keyword(s):  
Human Immunodeficiency Virus ◽  
Simian Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Rhesus Monkeys ◽  
Consensus Sequence ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT A nef gene is present in all primate lentiviruses, including human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus of macaque monkeys (SIVmac). However, thenef genes of HIV-1 and SIVmac exhibit minimal sequence identity, and not all properties are shared by the two. Nef sequences of SIVmac239 were replaced by four independentnef alleles of HIV-1 in a context that was optimal for expression. The sources of the HIV-1 nef sequences included NL 4-3, a variant NL 4-3 gene derived from a recombinant-infected rhesus monkey, a patient nef allele, and a nefconsensus sequence. Of 16 rhesus monkeys infected with these SHIVnef chimeras, 9 maintained high viral loads for prolonged periods, as observed with the parental SIVmac239, and 6 have died with AIDS 52 to 110 weeks postinfection. Persistent high loads were observed at similar frequencies with the four different SIV recombinants that expressed these independent HIV-1 nefalleles. Infection with other recombinant SHIVnef constructions resulted in sequence changes in infected monkeys that either created an open nef reading frame or optimized the HIV-1nef translational context. The HIV-1 nef gene was uniformly retained in all SHIVnef-infected monkeys. These results demonstrate that HIV-1 nef can substitute for SIVmac nef in vivo to produce a pathogenic infection. However, the model suffers from an inability to consistently obtain persisting high viral loads in 100% of the infected animals, as is observed with the parental SIVmac239.

scholarly journals Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703–positive individuals and their transmission recipients

2009 ◽  
Vol 206 (4) ◽  
pp. 909-921 ◽  
Author(s):  
Hayley Crawford ◽  
Wendy Lumm ◽  
Alasdair Leslie ◽  
Malinda Schaefer ◽  
Debrah Boeras ◽  
...  
Keyword(s):  
Viral Load ◽  
Hiv Replication ◽  
Rapid Disease Progression ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Cellular Immune ◽  
Ctl Responses

HLA-B*57 is the class I allele most consistently associated with control of human immunodeficiency virus (HIV) replication, which may be linked to the specific HIV peptides that this allele presents to cytotoxic T lymphocytes (CTLs), and the resulting efficacy of these cellular immune responses. In two HIV C clade–infected populations in South Africa and Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703–restricted CTL responses select for escape mutations in three Gag p24 epitopes, in a predictable order. We show that the accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703–restricted CTL responses. In HLA-B*5703–mismatched recipients, the previously described early benefit of transmitted HLA-B*5703–associated escape mutations is abrogated by the increase in viral load coincident with reversion. Rapid disease progression is observed in HLA-matched recipients to whom mutated virus is transmitted. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in the absence of adequate, continued CTL responses. These data underline the need for a CTL vaccine against multiple conserved epitopes.

scholarly journals Primary Human Immunodeficiency Virus Type 2 (HIV-2) Isolates Infect CD4-Negative Cells via CCR5 and CXCR4: Comparison with HIV-1 and Simian Immunodeficiency Virus and Relevance to Cell Tropism In Vivo

1999 ◽  
Vol 73 (9) ◽  
pp. 7795-7804 ◽  
Author(s):  
Jacqueline D. Reeves ◽  
Sam Hibbitts ◽  
Graham Simmons ◽  
Áine McKnight ◽  
José M. Azevedo-Pereira ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Surface ◽  
Simian Immunodeficiency Virus ◽  
Productive Infection ◽  
Envelope Glycoproteins ◽  
Surface Receptors ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Cell surface receptors exploited by human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) for infection are major determinants of tropism. HIV-1 usually requires two receptors to infect cells. Gp120 on HIV-1 virions binds CD4 on the cell surface, triggering conformational rearrangements that create or expose a binding site for a seven-transmembrane (7TM) coreceptor. Although HIV-2 and SIV strains also use CD4, several laboratory-adapted HIV-2 strains infect cells without CD4, via an interaction with the coreceptor CXCR4. Moreover, the envelope glycoproteins of SIV of macaques (SIVMAC) can bind to and initiate infection of CD4− cells via CCR5. Here, we show that most primary HIV-2 isolates can infect either CCR5+ or CXCR4+ cells without CD4. The efficiency of CD4-independent infection by HIV-2 was comparable to that of SIV, but markedly higher than that of HIV-1. CD4-independent HIV-2 strains that could use both CCR5 and CXCR4 to infect CD4+cells were only able to use one of these receptors in the absence of CD4. Our observations therefore indicate (i) that HIV-2 and SIV envelope glycoproteins form a distinct conformation that enables contact with a 7TM receptor without CD4, and (ii) the use of CD4 enables a wider range of 7TM receptors to be exploited for infection and may assist adaptation or switching to new coreceptors in vivo. Primary CD4− fetal astrocyte cultures expressed CXCR4 and supported replication by the T-cell-line-adapted ROD/B strain. Productive infection by primary X4 strains was only triggered upon treatment of virus with soluble CD4. Thus, many primary HIV-2 strains infect CCR5+ or CXCR4+ cell lines without CD4 in vitro. CD4− cells that express these coreceptors in vivo, however, may still resist HIV-2 entry due to insufficient coreceptor concentration on the cell surface to trigger fusion or their expression in a conformation nonfunctional as a coreceptor. Our study, however, emphasizes that primary HIV-2 strains carry the potential to infect CD4− cells expressing CCR5 or CXCR4 in vivo.

scholarly journals Effect of 3-Hydroxyphthaloyl-β-Lactoglobulin on Vaginal Transmission of Simian Immunodeficiency Virus in Rhesus Monkeys

1999 ◽  
Vol 43 (4) ◽  
pp. 978-980 ◽  
Author(s):  
Michael S. Wyand ◽  
Kelledy H. Manson ◽  
Christopher J. Miller ◽  
A. Robert Neurath
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Virus Type ◽  
Rhesus Monkeys ◽  
Heterosexual Transmission ◽  
Degree Of Protection ◽  
Immunodeficiency Virus ◽  
Β Lactoglobulin ◽  
Hiv 1

ABSTRACTHeterosexual transmission of human immunodeficiency virus type 1 (HIV-1) is the major cause of the ongoing AIDS epidemic. Application of chemical barrier methods is expected to contribute to the worldwide control of this epidemic. Bovine β-lactoglobulin modified by 3-hydroxyphthalic anhydride (3-hydroxyphthaloyl-β-lactoglobulin [3HP-β-LG]) was shown to inhibit HIV-1, HIV-2, simian immunodeficiency virus (SIV), herpes simplex virus type 1 and 2, andChlamydia trachomatisinfection in vitro. Here, we show that 3HP-β-LG not formulated into any vehicle protected three of six rhesus monkeys against vaginal infection by SIV. Incorporation of the compound into an appropriate vehicle is expected to increase the degree of protection. 3HP-β-LG may be effective as a vaginal inhibitor of HIV-1 infection in humans.

scholarly journals Polyethylene Glycol 40-Modified Peptide with High Therapeutic Efficacy in Simian-Human Immunodeficiency Virus-Acutely Infected Rhesus Monkeys

2020 ◽  
Vol 94 (14) ◽  
Author(s):  
Mingli Li ◽  
Shuihong Cheng ◽  
Yibo Ding ◽  
Chen Wang ◽  
Yong Feng ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Half Life ◽  
Rhesus Monkeys ◽  
Glycosylation Site ◽  
Control Treatment ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Anti-human immunodeficiency virus type 1 (anti-HIV-1) fusion peptides have been studied for nearly 2 decades, but few candidates have found useful clinical applications. One factor underlying the failure of such agents to reach the clinic is their poor pharmacokinetic properties, and many efforts have been made to overcome this problem. In this study, we modified C34, a peptide inhibitor of HIV-1 fusion, at its conserved glycosylation site using polyethylene glycols (PEGs) of different molecular weights. PEG40-NC, a conjugate of C34 and branched PEG 40 kDa (PEG40), which has been previously shown to improve the pharmacokinetic profiles of proteins, showed a significantly extended half-life (t1/2; 10.39 h in rats), which compensated for decreased in vitro activity (50% effective concentration [EC50] of 18.51 nM). PEG40-NC also showed a mechanism of action similar to that of C34. PEG40-NC monotherapy in acutely simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys significantly suppressed viral load compared with a control treatment. Efficacy was linked to the extended half-life and lymphatic exposure conferred by attached PEG40. These results highlight the potential of further clinical investigations of PEG40-NC in combination with antiretroviral therapy or other anti-HIV agents. IMPORTANCE Poor pharmacokinetics have severely hindered the clinical use of anti-HIV peptides. Different small molecules, such as lipid, cholesterol, and small PEG, were designed to modify peptides to improve their pharmacokinetics. In this study, we incorporated large branched PEG to anti-HIV peptide and obtained a conjugate with extended half-life and improved in vivo efficacy. The strategy we developed in this study can also be applicable for the development of other peptide candidates.

scholarly journals Engineered CD4- and CXCR4-Using Simian Immunodeficiency Virus from African Green Monkeys Is Neutralization Sensitive and Replicates in Nonstimulated Lymphocytes

2002 ◽  
Vol 76 (21) ◽  
pp. 10627-10636 ◽  
Author(s):  
Renate R. König ◽  
Egbert Flory ◽  
Stefanie Steidl ◽  
Jeanette Neumann ◽  
Cheick Coulibaly ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Interleukin 2 ◽  
Cell Entry ◽  
V3 Loop ◽  
Coreceptor Usage ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Green Monkeys

ABSTRACT During human immunodeficiency virus type 1 (HIV-1) infection, disease progression correlates with the occurrence of variants using the coreceptor CXCR4 for cell entry. In contrast, apathogenic simian immunodeficiency virus (SIV) from African green monkeys (SIVagm), specifically the molecular virus clone SIVagm3mc, uses CCR5, Bob, and Bonzo as coreceptors throughout the course of infection. The influence of an altered coreceptor usage on SIVagm3mc replication was studied in vitro and in vivo. The putative coreceptor binding domain, the V3 region of the surface envelope (SU) glycoprotein, was replaced by the V3 loop of a CD4- and CXCR4-tropic HIV-1 strain. The resulting virus, termed SIVagm3-X4mc, exclusively used CD4 and CXCR4 for cell entry. Consequently, its in vitro replication was inhibited by SDF-1, the natural ligand of CXCR4. Surprisingly, SIVagm3-X4mc was able to replicate in vitro not only in interleukin-2- and phytohemagglutinin-stimulated but also in nonstimulated peripheral blood mononuclear cells (PBMCs) from nonhuman primates. After experimental infection of two pig-tailed macaques with either SIVagm3-X4mc or SIVagm3mc, the coreceptor usage was maintained during in vivo replication. Cell-associated and plasma viral loads, as well as viral DNA copy numbers, were found to be comparable between SIVagm3mc and SIVagm 3-X4mc infections, and no pathological changes were observed up to 14 months postinfection. Interestingly, the V3 loop exchange rendered SIVagm3-X4mc susceptible to neutralizing antibodies present in the sera of SIVagm3-X4mc- and SIVagm3mc-infected pig-tailed macaques. Our study describes for the first time a successful exchange of a V3 loop in nonpathogenic SIVagm resulting in CD4 and CXCR4 usage and modulation of virus replication in nonstimulated PBMCs as well as sensitivity toward neutralization.

scholarly journals In Vitro Characterization of a Simian Immunodeficiency Virus-Human Immunodeficiency Virus (HIV) Chimera Expressing HIV Type 1 Reverse Transcriptase To Study Antiviral Resistance in Pigtail Macaques

2004 ◽  
Vol 78 (24) ◽  
pp. 13553-13561 ◽  
Author(s):  
Zandrea Ambrose ◽  
Valerie Boltz ◽  
Sarah Palmer ◽  
John M. Coffin ◽  
Stephen H. Hughes ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Simian Immunodeficiency Virus ◽  
Antiviral Resistance ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Pigtail Macaques

ABSTRACT Antiviral resistance is a significant obstacle in the treatment of human immunodeficiency virus type 1 (HIV-1)-infected individuals. Because nonnucleoside reverse transcriptase inhibitors (NNRTIs) specifically target HIV-1 reverse transcriptase (RT) and do not effectively inhibit simian immunodeficiency virus (SIV) RT, the development of animal models to study the evolution of antiviral resistance has been problematic. To facilitate in vivo studies of NNRTI resistance, we examined whether a SIV that causes immunopathogenesis in pigtail macaques could be made sensitive to NNRTIs. Two simian-human immunodeficiency viruses (SHIVs) were derived from the genetic background of SIVmne: SIV-RT-YY contains RT substitutions intended to confer NNRTI susceptibility (V181Y and L188Y), and RT-SHIVmne contains the entire HIV-1 RT coding region. Both mutant viruses grew to high titers in vitro but had reduced fitness relative to wild-type SIVmne. Although the HIV-1 RT was properly processed into p66 and p51 subunits in RT-SHIVmne particles, the RT-SHIVmne virions had lower levels of RT per viral genomic RNA than HIV-1. Correspondingly, there was decreased RT activity in RT-SHIVmne and SIV-RT-YY particles. HIV-1 and RT-SHIVmne were similarly susceptible to the NNRTIs efavirenz, nevirapine, and UC781. However, SIV-RT-YY was less sensitive to NNRTIs than HIV-1 or RT-SHIVmne. Classical NNRTI resis tance mutations were selected in RT-SHIVmne after in vitro drug treatment and were monitored in a sensitive allele-specific real-time RT-PCR assay. Collectively, these results indicate that RT-SHIVmne may be a useful model in macaques for the preclinical evaluation of NNRTIs and for studies of the development of drug resistance in vivo.

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